AJP - Endo Journal of Neurophysiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 274: E867-E876, 1998;
0193-1849/98 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cassis, L. A.
Right arrow Articles by Lodder, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cassis, L. A.
Right arrow Articles by Lodder, R. A.
Vol. 274, Issue 5, E867-E876, May 1998

Mechanisms contributing to angiotensin II regulation of body weight

Lisa A. Cassis, Dana E. Marshall, Michael J. Fettinger, Brady Rosenbluth, and Robert A. Lodder

Divisions of Pharmacology and Experimental Therapeutics and Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

Previous studies in our laboratory have implicated adipose tissue as a potential site for local angiotensin II (ANG II) synthesis. However, functions of ANG II in adipose tissue and the impact of ANG II on body weight regulation are not well defined. To study the effect of ANG II on body weight, a chronic ANG II infusion model was used. In study 1, a low dose of ANG II (175 ng · kg-1 · min-1) was infused into rats for 14 days. Plasma ANG II levels were not elevated after 14 days of infusion. ANG II-infused rats did not gain weight over the 14-day protocol and exhibited a lower body weight than controls on day 8. Food intake was not altered, but water intake was increased in ANG II-infused rats. Blood pressure gradually increased to significantly elevated levels by day 14. Thermal infrared imaging demonstrated an increase in abdominal surface temperature. Measurement of organ mass demonstrated site-specific reductions in white adipose tissue mass after ANG II infusion. In study 2, the dose-response relationship for ANG II infusion (200, 350, and 500 ng · kg-1 · min-1) was determined. Body weight (decrease), blood pressure (increase), white adipose mass (decrease), plasma ANG II levels (increase), and plasma leptin levels (decrease) were altered in a dose-related manner after ANG II infusion. In study 3, the effect of ANG II infusion (350 ng · kg-1 · min-1) was examined in rats treated with the vasodilator hydralazine. Hydralazine treatment normalized blood pressure in ANG II-infused rats. The effect of ANG II to decrease body weight was augmented in hydralazine-treated rats. These results demonstrate that low levels of ANG II infusion regulate body weight through mechanisms related to increased peripheral metabolism and independent of elevations in blood pressure.

weight gain; renin-angiotensin system; metabolism; infrared imagery

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

ANGIOTENSIN II (ANG II), the primary peptide of the renin-angiotensin system, is important in the regulation of blood pressure and fluid and electrolyte balance (25). Alterations in the synthesis of and responsiveness to ANG II have been implicated in the disease states of hypertension (14) and congestive heart failure (2). On the basis of a variety of evidence, including demonstration of components necessary for synthesis of ANG II, localization of ANG II receptors, measurements of immunoreactive ANG II, and functional responsiveness to ANG II, local tissue renin-angiotensin systems have been proposed (13, 28). Many of the postulated tissue renin-angiotensin systems have been implicated in the local control of cardiovascular functions. For example, evidence supports the existence of tissue renin-angiotensin systems in blood vessels (28), heart (12), kidney (13), adrenal (24), and brain (9). Production of ANG II locally in these tissues contributes to the regulation of vascular resistance and structure, cardiac contractile state and hypertrophy, cell growth, sodium and water retention, and activity of the sympathetic nervous system.

Previous studies in our laboratory demonstrated a high level of angiotensinogen mRNA expression (8), renin-like activity (32), localization of high-affinity ANG II receptors (6), and ANG II regulation of sympathetic neurotransmission (7) in rat adipose tissue. These results suggest adipose tissue as a potential site for a local tissue renin-angiotensin system. However, in contrast to the well-defined role of ANG II in tissue sites of cardiovascular relevance, the functional role of ANG II in adipose tissue metabolism and associated alterations in body weight are not well defined.

Recent studies demonstrate that infusion of high pressor doses (500 ng · kg-1 · min-1) of ANG II to rats resulted in a marked reduction (26%) in body weight (3). The effect of high-dose ANG II infusion on body weight was suggested to be independent of elevations in blood pressure (3). In these studies, measurements of plasma ANG II levels in rats chronically infused with ANG II were not performed; thus comparisons of plasma ANG II levels in rats from this chronic high-dose ANG II infusion model with levels observed previously in patients with cardiovascular abnormalities such as congestive heart failure could not be made. Interestingly, it was noted that in heart failure patients exhibiting five- to eightfold elevations in plasma ANG II levels (26, 35), anorexia, wasting, and cachexia are frequent problems, culminating in the dysregulation of body weight (29). Alternatively, in the obese population, expanded fluid volumes result in suppressed activity of the systemic renin-angiotensin system (17, 19). We hypothesize that conditions characterized by chronic alterations in the systemic or tissue renin-angiotensin systems are associated with dysregulation of body weight due to the metabolic effects of ANG II. The present study utilized a previously established model for examination of ANG II mechanisms in hypertension, the chronic ANG II infusion model, to determine mechanisms for ANG II regulation of body weight.

    METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References

General experimental design. Three different studies were performed. In study 1, the effect of chronic low-dose (175 ng · kg-1 · min-1) ANG II infusion on body weight, food and water intake, and blood pressure was examined. ANG II or saline (n = 5/group) was infused into rats for 14 days. In study 2, the dose-response relationship for ANG II infusion on body weight, blood pressure, and food and water intake was examined. Four groups of rats (n = 3/group) were examined for 7 days and infused with saline or ANG II at doses of 200, 350, and 500 ng · kg-1 · min-1. In study 3, the effect of ANG II on body weight was examined in rats that were treated with the vasodilator hydralazine. Four groups (n = 4/group) of rats were examined for 7 days, saline infused with or without hydralazine, and ANG II infused with or without hydralazine. In all three studies, body weight and food and water intake were measured daily, and measurements of blood pressure were taken every 3-5 days.

Angiotensin II infusion model. Male Sprague-Dawley rats (Harlan Laboratories, Indianapolis, IN) were used in all studies. Rats ranged in body weight from 350 to 450 g. All rats were housed two per cage in an approved animal facility for 1 wk before use under normal light-dark cycles and were given free access to food and water. During each experimental protocol, rats were housed individually for measurement of body weight and food and water intake on a daily basis at 10:00 AM. Baseline measurements of food intake, water intake, and blood pressure were performed on all rats in an individual study for a minimum of 3 days preceding each experimental protocol.

For ANG II infusion, rats were anesthetized with diethyl ether and shaved in the interscapular region; then osmotic minipumps (model 2002 for 14-day infusion, model 2001 for 7-day infusion; Alza, Palo Alto, CA) were implanted subcutaneously. Minipumps contained either ANG II (Sigma Chemical, St. Louis, MO; 175-500 ng · kg-1 · min-1 infusion rate) or sterile saline and were primed according to the manufacturer's instructions preceding implantation to assure immediate subcutaneous delivery of ANG II. The skin overlaying the minipump was closed with surgical staples, and rats were allowed to recover on warmed heating pads.

Indirect systolic pressure by tail cuff plethysmography. In study 1, systolic pressure was measured in conscious restrained rats by use of a Narco system. In studies 2 and 3, systolic pressure was measured on ether-anesthetized rats using an inflatable tail cuff, a pressure and pulse transducer, and a recording polygraph. Alterations in blood pressure from anesthesia were controlled for across ANG II- and saline-infused rats. The systolic pressure from three separate measurements was averaged from each rat. Baseline systolic pressure was recorded for 3 days preceding implantation of osmotic minipumps. After implantation of ANG II-containing minipumps, blood pressure was measured every 3-5 days.

Hydralazine treatment. Hydralazine (15 mg/kg) was administered in the drinking water of individual rats in study 3. Hydralazine dosing was based on an average water consumption of 40-60 ml of water intake per day. The dose of hydralazine in the drinking water was adjusted daily on the basis of the preceding 24-h water intake and daily body weight measurements in individual rats.

Thermal infrared imaging. Thermal infrared (IR) imaging was used in study 1 as an index of peripheral energy expenditure. Thermal IR imaging was performed using a liquid nitrogen-cooled InSb focal plane array camera (temperature precision = 0.03°C; 3,000-5,000 nm; Cincinnati Electronics, Mason, OH) with sound annotation capability. No external light source was used in comparing heat radiation in the different rats, so the intensity of features in each rat image corresponded to the level of blackbody emission from the skin and fur. Temperature calibration was accomplished using a blackbody source closely coupled to a mercury thermometer. The IR images were collected as 1-s segments of real-time video and saved on computer disk. The IR video camera had a frame collection rate of 51.44 frames/s, making sample target immobilization unnecessary. Thermal IR heat radiation was determined in joules per second (W) using standard software based on Stefan's Law.

Measurement of plasma ANG II. Trunk blood was collected in heparanized vacuum test tubes containing the following buffer: 0.15 mM pepstatin A, 20 mM phenanthroline, 125 mM EDTA, 0.2% neomycin, 2% ethanol, 2% DMSO, and 0.1 M kallikrein, pH 7.4. The inhibitors in this buffer were added to eliminate breakdown of angiotensin peptides as well as further production of peptides during sample handling (4). Plasma was obtained by centrifugation (3,000 g) of blood at 4°C for 30 min. Plasma samples were partially purified using Sep-Pak C18 column chromatography (Waters, Milford, MA), with the columns preequilibrated with 4 ml of methanol, 4 ml of water, and 10 ml of buffer. Angiotensin peptides were eluted from the columns with 2 ml of methanol-water-trifluoracetic acid (70:29:1). The eluate was evaporated overnight using a speed-vac (Savant). Plasma ANG II was measured in preextracted samples, which were reconstituted in 100 µl of ANG II RIA buffer (0.1 M K2HPO4, 3.0 mM EDTA, 0.15 mM 8-hydroxyquinoline, and 0.25% BSA, pH 7.2), sonicated for 5 min, and stored at -20°C. Angiotensin content in each sample was measured by ANG II RIA using a polyclonal ANG II antibody (kindly supplied by Dr. A. Freedlender, University of Virginia) exhibiting minimal cross-reactivity to ANG I (2%) and angiotensin 5-8 (4%) but 100% cross-reactivity to ANG III, angiotensin 3-8, and angiotensin 4-8. The sensitivity of the RIA was 2 pg/ml.

Measurement of plasma leptin. Blood was obtained as described above, and an aliquot (500 µl) of plasma was removed for measurement of plasma leptin levels by use of a commercial RIA kit (Linco Research, St. Louis, MO) with a rat leptin antibody. The sensitivity of the kit for rat leptin was 0.5 ng/ml and required 100 µl of rat plasma for assay.

Statistical analysis. For all studies, data are means ± SE. In study 1, data (blood pressure, body weight, food and water intake) were analyzed using a two-way ANOVA, with ANG II as a between-group factor and time of infusion as a within-group repeated measure. In study 2, data were analyzed using a two-way ANOVA, with ANG II dose as a between-group factor and time as a within-group repeated measure. In study 3, data were analyzed using a three-way ANOVA, with ANG II dose and hydralazine treatment as between-group factors and time as a within-group repeated measure. Post hoc analysis was performed using Duncan's multiple range test.

    RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Study 1. The purpose of this study was to determine the effect of chronic low-dose ANG II infusion on the regulation of body weight. In study 1, ANG II was administered at an infusion dose of 175 ng · kg-1 · min-1 to rats for a period of 14 days. Plasma ANG II levels after 14 days of infusion were not significantly different between ANG II- and saline-infused rats (saline: 37.3 ± 1.5; ANG II: 34.3 ± 8.2 pg/ml). Measurements of systolic blood pressure demonstrated a significant between-group effect of ANG II [F(1,7) = 57.7, P < 0.001] and a significant interaction between ANG II and time of infusion [F(5,35) = 2.7, P < 0.05]. Systolic blood pressure was significantly increased in ANG II-infused rats over baseline (day 0) levels by day 1 of ANG II infusion (Fig. 1). Moreover, systolic pressure in ANG II-infused rats was increased compared with saline controls at day 1. Initial increases in blood pressure (days 1 and 3) in ANG II-infused rats were followed by a return to levels not significantly different from saline-infused controls or from baseline measurements (day 0, ANG II-infused rats) on days 4 and 7. Despite three baseline measurements before initiation of the experimental protocol, systolic pressures measured in conscious, restrained, saline-infused rats decreased over the time course of the study, suggesting that habituation to the restraining apparatus occurred over the time course of study. For this reason, systolic pressures were measured on ether-anesthetized rats in studies 2 and 3. After 14 days of ANG II infusion, systolic blood pressure was significantly increased in ANG II-infused rats compared with saline controls and compared with baseline measurements (day 0; Fig. 1).


View larger version (15K):
[in this window]
[in a new window]
  		Fig. 1.   Effect of angiotensin (ANG) II infusion (175 ng · kg-1 · min-1) on systolic blood pressure. In study 1, rats were infused with saline or ANG II subcutaneously by osmotic minipump for 14 days, and systolic blood pressure was measured. Baseline measurements of systolic pressure were performed for 3 days before pump implantation. Systolic pressure increased in ANG II-infused rats over controls at 1 and 3 days of infusion, followed by a decline to levels not significantly different from controls on days 4 and 7. At 14 days, systolic pressure was significantly increased in ANG II-infused rats over saline-infused controls and from baseline measurements in the ANG II group before pump implantation (day 0). Values are means ± SE of 5/group. * Significantly different (P < 0.05) from sham (saline-infused) controls; f significantly different (P < 0.05) from day 0 within each group.

Daily body weight measurements revealed a significant interaction between ANG II and time of infusion [F(15,105) = 3.1, P < 0.05]. The body weight of ANG II-infused rats was significantly different from saline-infused controls from day 8 of infusion through the remainder of the experimental protocol (Fig. 2A). Saline-infused rats gained 27 g in body weight over the 14-day experimental protocol; in contrast, ANG II-infused rats did not gain weight over the 14-day protocol. Thus the primary effect of low-dose ANG II infusion was to eliminate weight gain. The time course for the effect of ANG II on body weight (Fig. 2A) and mean arterial pressure (Fig. 1) illustrates that these two variables did not change in parallel.


View larger version (25K):
[in this window]
[in a new window]
  		Fig. 2.   Effect of ANG II infusion (175 ng · kg-1 · min-1) on body weight (A), food intake (B), and water intake (C). In study 1, rats were infused with saline or ANG II for 14 days, and body weight, food intake, and water intake were measured daily at 10:00 AM. Saline-infused rats gained weight over the 14-day protocol; in contrast, ANG II-infused rats did not gain weight (A). Body weight was significantly different in ANG II-infused rats compared with saline controls from day 8 onward. After an initial transient drop in food intake at day 1 after pump implantation, food intake was not altered in ANG II-infused rats (B). Water intake was increased in ANG II-infused rats compared with controls from day 3 onward (C). Values are means ± SE of 5/group. * Significantly different (P < 0.05) from saline control.

The effect of ANG II infusion on body weight was not the result of reductions in food intake (Fig. 2B). After an initial transient drop in food intake at 1-2 days after minipump implantation, ANG II infusion did not result in significant alterations in food intake. In contrast, infusion of ANG II significantly increased water intake (Fig. 2C). Increases in water intake were significant by 3 days of ANG II infusion and were maintained throughout the ANG II infusion protocol. Moreover, increases in water intake occurred before ANG II-induced reductions in body weight.

Thermal IR imaging demonstrated an increase in regional surface temperature in the tail and abdomen/thorax area of ANG II-infused rats compared with saline controls (Fig. 3A). An IR image of an ANG II-infused rat is illustrated in Fig. 3B. The surface temperature in the abdomen of the ANG II-infused rat was of higher intensity than that of the saline-infused control rat (Fig. 3A).


View larger version (78K):
[in this window]
[in a new window]
  		Fig. 3.   Thermal infrared (IR) imaging demonstrates an increase in tail and abdomen surface temperature. In study 1, rats were infused with saline or ANG II (175 ng · kg-1 · min-1) for 14 days. Thermal IR imaging was performed on day 14 using an InSb focal plane array camera. Temperature calibration was accomplished using a blackbody source closely coupled to a mercury thermometer. Surface temperature was increased in the tail and abdomen from ANG II-infused rats compared with saline controls (A). * Significantly different (P < 0.05) from saline control. B: image of an ANG II-infused rat. Note visible detection of temperature in abdomen and tail.

A variety of organs were removed from ANG II-infused and saline-infused rats at the end of the experimental protocol, and organ weight-to-body weight ratios were constructed to determine sites contributing to ANG II-induced decreases in body weight (Fig. 4). Of the tissues examined, ANG II-infused rats exhibited significant decreases in the relative mass of retroperitoneal white fat (RPF) (adipose tissue) and the diaphragm (skeletal muscle). The other organs examined maintained their relative mass after ANG II infusion.


View larger version (16K):
[in this window]
[in a new window]
  		Fig. 4.   Effect of ANG II infusion (175 ng · kg-1 · min-1) on organ mass. In study 1, rats were infused with saline (open bars) or ANG II (hatched bars) for 14 days. Organs were removed at 14 days and normalized as a percentage of body weight. ISBAT, interscapular brown adipose tissue; EF, epididymal fat; RPF, retroperitoneal fat; LV, left ventricle; Diaph, diaphragm. Mass of RPF and diaphragm was decreased in ANG II-infused rats compared with saline controls. Values are means ± SE of 5/group. * Significantly different (P < 0.05) from saline control.

Study 2. To determine whether the effect of ANG II on body weight was dose dependent, rats were administered either saline or 200, 350, or 500 ng · kg-1 · min-1 ANG II via osmotic minipump for 7 days. Measurement of plasma ANG II levels demonstrated a significant effect of ANG II [F(3,11) = 5.9, P < 0.05; Table 1]. Measurement of blood pressure demonstrated a significant effect of ANG II dose [F(3,8) = 7.2, P < 0.05], a significant effect of time of infusion [F(3,24) = 32, P < 0.05], and a significant interaction between ANG II dose and time of infusion [F(9,24) = 2.5, P < 0.05]. Mean arterial pressure was significantly increased in rats receiving 350 ng · kg-1 · min-1 of ANG II infusion over controls at day 3, with blood pressure increased over controls at all three doses of ANG II by day 7 of ANG II infusion (Fig. 5). Moreover, at day 7 of ANG II infusion, blood pressure increases in rats receiving 500 ng · kg-1 · min-1 ANG II were significantly greater than those observed in rats receiving the ANG II dose of 200 ng · kg-1 · min-1.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Plasma ANG II levels in rats from study 2 


View larger version (19K):
[in this window]
[in a new window]
  		Fig. 5.   Dose-related effects of ANG II infusion on systolic blood pressure. In study 2, rats were infused with saline or 200, 350, or 500 ng · kg-1 · min-1 ANG II for 7 days. Systolic blood pressure was measured before minipump implantation (day 0) and at 3, 5, and 7 days postimplantation. Systolic pressure increased in a dose- and time-dependent manner with ANG II infusion. Values are means ± SE of 3/dose. * Significantly different (P < 0.05) from control; f significantly different (P < 0.05) from 200 ng · kg-1 · min-1 ANG II-infused rats.

Examination of body weight in ANG II-infused rats demonstrated a significant interaction between ANG II dose and time of infusion [F(8,64) = 25, P < 0.01]. At the lowest dose of ANG II infused (200 ng · kg-1 · min-1), body weight was significantly decreased from saline-infused controls at day 7 of ANG II infusion (Fig. 6A). However, at ANG II infusion doses of 350 and 500 ng · kg-1 · min-1, body weight was significantly decreased from saline-infused controls by day 5 of ANG II infusion and remained lower throughout the remainder of the experimental protocol. The time course for the effect of ANG II infusion on body weight (Fig. 6A) and blood pressure (Fig. 5) illustrates that these two variables did not change in parallel.


View larger version (22K):
[in this window]
[in a new window]
  		Fig. 6.   Dose-related effects of ANG II infusion on body weight (A), food intake (B), and water intake (C). In study 2, rats were infused with saline or 200, 350, or 500 ng · kg-1 · min-1 of ANG II for 7 days. ANG II infusion resulted in a time-dependent decrease in body weight (A) compared with saline controls (sham). All doses of ANG II infusion resulted in an initial transient drop in food intake (B), followed by a return to food intake levels that were not significantly different from control. There were no significant effects of ANG II infusion on water intake (C). Values are means ± SE of 3/dose. * Significantly different (P < 0.05) from control.

There was no significant effect of ANG II dose on food intake; however, there was a significant effect of the time of ANG II infusion on food intake [F(2,56) = 12.3, P < 0.01]. Reductions in food intake were evident at all three doses of ANG II infused 1 day after minipump implantation and returned to control levels by 7 days of ANG II infusion (Fig. 6B). The time course for the return of food intake to normal levels was dependent on the ANG II infusion dose. Water intake was not significantly altered by ANG II infusion (Fig. 6C). Examination of the relative mass (%body weight) of organs removed from ANG II- and saline-infused rats demonstrated a site-specific decrease in the mass of RPF (Fig. 7) that was dependent on ANG II dose. Interestingly, measurement of plasma leptin levels at day 7 demonstrated a significant between-group effect of ANG II [F(3,11) = 4, P < 0.05] and a decrease in plasma leptin levels at the ANG II dose of 500 ng · kg-1 · min-1 (Fig. 8).


View larger version (35K):
[in this window]
[in a new window]
  		Fig. 7.   Dose-related effects of ANG II infusion on organ mass. In study 2, rats were infused with saline or 200, 350, or 500 ng · kg-1 · min-1 of ANG II for 7 days. Organs were removed on day 7, and organ weight was normalized as a percentage of body weight. See Fig. 4 for abbreviations. ANG II infusion resulted in a dose-related decrease in mass of retroperitoneal white fat. Values are means ± SE of 3/dose. * Significantly different (P < 0.05) from saline control.


View larger version (13K):
[in this window]
[in a new window]
  		Fig. 8.   ANG II infusion results in a decrease in plasma leptin levels. In study 2, rats were infused with saline or 200, 350, or 500 ng · kg-1 · min-1 of ANG II for 7 days. Plasma was collected on day 7, and leptin levels were measured with a commercial rat leptin RIA. Statistical analysis demonstrated a significant effect of ANG II dose on plasma leptin levels. At a dose of 500 ng · kg-1 · min-1, ANG II infusion resulted in a decrease in plasma leptin levels. Values are means ± SE of 3/dose. * Significantly different (P < 0.05) from saline control.

Study 3. The purpose of this study was to determine whether the effects of ANG II on body weight were independent of ANG II-induced increases in blood pressure. In study 3, ANG II was infused at a dose of 350 ng · kg-1 · min-1 for a period of 7 days. This dose of ANG II was chosen on the basis of results from study 2 demonstrating maximal effects of ANG II on body weight at an infusion dose of 350 ng · kg-1 · min-1. The vasodilator hydralazine was administered (10 mg/kg) in the drinking water of ANG II-infused and saline-infused rats for 3 days before minipump implantation and for the period corresponding to ANG II infusion.

Measurement of systolic pressure demonstrated a significant effect of ANG II infusion [F(1,12) = 14.7, P < 0.01] and hydralazine treatment [F(1,12) = 6.1, P < 0.05] and a significant interaction between ANG II infusion and hydralazine treatment [F(1,12) = 5.4, P < 0.05]. Blood pressure was significantly increased in ANG II-infused rats compared with saline-infused controls by day 2 and throughout the remainder of the experimental protocol (Fig. 9). In contrast, blood pressure did not increase in ANG II-infused rats treated with hydralazine.


View larger version (20K):
[in this window]
[in a new window]
  		Fig. 9.   Hydralazine treatment normalizes blood pressure in ANG II-infused rats. In study 3, rats were infused with ANG II (350 ng · kg-1 · min-1) or saline for 7 days. Separate groups of ANG II-infused rats and saline controls were treated with the vasodilator hydralazine (10 mg/kg) in drinking water for 3 days before minipump implantation and for remainder of protocol. Measurement of systolic pressure demonstrated an increase in pressure in ANG II-infused rats that was prevented by treatment with hydralazine. Values are means ± SE of 4/group. * Significantly different (P < 0.05) from saline control.

Examination of body weight demonstrated a significant effect of time of infusion [F(7,84) = 5.3, P < 0.01] and a significant interaction between ANG II and time of infusion [F(7,84) = 26.4, P < 0.01]. Both groups of saline-infused rats (with or without hydralazine) increased their body weight over the 7-day experimental protocol (Fig. 10A). In contrast, ANG II-infused rats did not change in body weight over the 7-day protocol. Body weight of ANG II-infused rats was significantly decreased from saline-infused controls beginning at day 5 of ANG II infusion. Interestingly, ANG II-infused rats receiving hydralazine exhibited reductions in body weight over the 7-day experimental protocol. Beginning at day 3 of ANG II infusion, body weights of hydralazine-treated rats infused with ANG II were significantly less than controls. Moreover, beginning at day 4, the body weights of ANG II-infused rats receiving hydralazine were significantly less than ANG II-infused rats. Thus, despite elimination of ANG II-induced increases in blood pressure with hydralazine treatment, the effect of ANG II on body weight was maintained in hydralazine-treated rats.


View larger version (22K):
[in this window]
[in a new window]
  		Fig. 10.   Effects of treating ANG II-infused rats with hydralazine on body weight (A), food intake (B), and water intake (C). In study 3, rats were infused with saline (with or without hydralazine) or ANG II (350 ng · kg-1 · min-1; with or without hydralazine) for 7 days, and body weight was measured 4 days before pump implantation and throughout remainder of protocol. Body weight decreased in ANG II-infused rats in a time-dependent manner. Body weight decreases were augmented in ANG II-infused rats treated with hydralazine. Food intake (B) decreased in ANG II-infused rats compared with saline controls. Decreases in food intake were not prevented in hydralazine-treated rats. Water intake (C) increased in ANG II-infused rats treated with hydralazine. Values are means ± SE of 4/group. * Significantly different (P < 0.05) from saline control; f significantly different (P < 0.05) from ANG II-infused rats (without hydralazine).

In study 3, there was a significant effect of ANG II on food intake [F(1,12) = 29.8, P < 0.01] and a significant effect of time of ANG II infusion [F(1,12) = 10.2, P < 0.01]. Beginning at day 1 of ANG II infusion, food intake was significantly decreased in ANG II-infused rats with or without hydralazine compared with saline controls (with or without hydralazine) (Fig. 10B). In contrast, at a dose of 350 ng · kg-1 · min-1 of ANG II infusion, water intake did not significantly increase (Fig. 10C). In ANG II-infused rats treated with hydralazine, water intake increased by day 1 of infusion and throughout the remainder of the experimental protocol.

Infusion of ANG II at 350 ng · kg-1 · min-1 resulted in an increase in the relative mass of the left ventricle and a decrease in the relative mass of RPF (Fig. 11). Alterations in the mass of each of these organs were not reversed with normalization of blood pressure in hydralazine-treated rats. Plasma leptin levels were significantly decreased in ANG II-infused rats compared with saline controls (Fig. 12). However, in ANG II-infused rats treated with hydralazine, plasma leptin levels were diminished but not significantly different from controls (with or without hydralazine) or ANG II-infused rats. Thus treatment with hydralazine resulted in a partial reversal of ANG II-induced decreases in plasma leptin levels.


View larger version (26K):
[in this window]
[in a new window]
  		Fig. 11.   Effect of hydralazine (Hyd) treatment on ANG II-induced alterations in organ mass. In study 3, rats were infused with saline (with or without Hyd) or ANG II (350 ng · kg-1 · min-1; with or without Hyd) for 7 days. ANG II infusion resulted in a decrease in organ mass of RPF, which was augmented in hydralazine-treated rats. ANG II infusion resulted in an increase in LV mass that was not prevented by treatment with hydralazine. Values are means ± SE of 4/group. * Significantly different (P < 0.05) from saline controls.


View larger version (14K):
[in this window]
[in a new window]
  		Fig. 12.   Effect of hydralazine treatment on ANG II-induced decreases in plasma leptin levels. In study 3, rats were infused with saline (with or without Hyd) or ANG II (350 ng · kg-1 · min-1; with or without Hyd) for 7 days. ANG II infusion resulted in a decrease in plasma leptin levels. In Hyd-treated rats, plasma leptin levels were not different from ANG II-infused rats or saline controls (with or without Hyd). Values are means ± SE of 4/group. * Significantly different (P < 0.05) from saline controls.

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

This study clearly demonstrates that ANG II infusion dose dependently alters the rate of weight gain and decreases body weight through pressor-independent mechanisms. Mechanisms defined in the present study that contribute to the effect of ANG II on body weight include an increase in surface body temperature (energy expenditure), transient alterations in food intake, and alterations in plasma leptin levels. In hydralazine-treated rats with normalized blood pressure, infusion of ANG II resulted in marked reductions in body weight, demonstrating that the effect of ANG II on body weight was independent of blood pressure. With the use of infusion doses of ANG II that gradually increased blood pressure and did not elevate plasma ANG II levels, ANG II infusion was associated with a total elimination of weight gain.

Infusion of ANG II to rats has been studied extensively as a model for human renovascular and high-renin hypertension (1, 23, 34). Models of ANG II infusion have been classified as "pressor" and "subpressor," referring to the direct vasoconstrictor effects of ANG II to elicit immediate increases in blood pressure vs. slower mediated effects of ANG II at doses that do not directly influence blood pressure (34). Results from the present dose-response studies for ANG II infusion demonstrate that, at doses of ANG II infusion classified previously in the literature as pressor (>200 ng · kg-1 · min-1) and subpressor (<200 ng · kg-1 · min-1) (34), ANG II infusion resulted in a total elimination of weight gain and a decrease in body weight compared with saline-infused controls.

Results from study 1 demonstrate that, after infusion of ANG II at a dose of 175 ng · kg-1 · min-1 for 14 days, plasma ANG II levels were not elevated. Plasma ANG II levels measured in control rats in the present study are in agreement with literature values for rat plasma ANG II, ranging from 8 to 30 pg/ml (31). Previous studies suggest that at infusion doses of 200 ng · kg-1 · min-1, plasma ANG II levels increased threefold; however, elevations in plasma ANG II levels were not statistically significant because of a large variability (61% coefficient of variation) in measurements (15). In the present study, measurements of ANG II levels in rat plasma were not associated with marked variability (controls: 4-10%; ANG II infused: 10-20% coefficient of variation). The threshold dose of ANG II infusion resulting in an increase in plasma ANG II levels in the present study was 350 ng · kg-1 · min-1. At doses of ANG II infusion <200 ng · kg-1 · min-1, alterations in systemic ANG II levels were not evident and are suggested to represent the high end of physiological ANG II levels.

Measurement of plasma ANG II levels in ANG II-infused rats in the present study demonstrated a three- and sixfold increase at the two highest doses of ANG II infusion (350 and 500 ng · kg-1 · min-1, respectively). Previous investigators have demonstrated a sevenfold increase in plasma ANG II levels in patients with human heart failure (26). Increases in plasma ANG II levels in the rat model used in the present study (0, 3-, and 6-fold) are below the reported multiples of increase (7-fold) in systemic renin-angiotensin system activation in human heart failure (26, 35). Thus alterations in body weight were evident in ANG II-infused rats at doses resulting in minimal elevations in plasma ANG II levels. The significance of the observed effects of low-dose ANG II infusion on body weight may also relate to human obesity, in which plasma volume expansion is typical with suppressed activity of the renin-angiotensin system (17, 19).

Previous investigators have demonstrated that subcutaneous ANG II infusion at a dose of 200 ng · kg-1 · min-1 resulted in an increase in blood pressure within 1 day postinfusion (15). At a subcutaneous ANG II infusion dose of 76 ng · kg-1 · min-1, systolic blood pressure increased by day 2 of ANG II infusion (21). In agreement with previous studies, results from this study demonstrate that infusion of ANG II at a dose of 175 ng · kg-1 · min-1 resulted in an initial transient increase in systolic pressure at days 1 and 3 of infusion. In contrast to previous reports and results from the present study, at doses of 280 (11) and 200 ng · kg-1 · min-1 (18), administered intraperitoneally, systolic blood pressure did not increase after 7 days of ANG II infusion, suggesting that these ANG II doses were subpressor. Results from the present study demonstrate dose-dependent effects of ANG II infusion on systolic blood pressure that were influenced by the time of infusion. However, all doses of ANG II infusion used in the present study resulted in an early increase in systolic pressure. Thus distinctions between pressor and subpressor doses of ANG II infusion in the present study were not readily apparent.

At low-dose ANG II infusion in study 1, water intake increased. In agreement with these results, previous studies demonstrate dipsogenic effects of systemically administered ANG II (37). Interestingly, in the present study, high ANG II infusion doses (>175 ng · kg-1 · min-1) that significantly elevated plasma ANG II levels did not result in an increase in water intake. In contrast to results from the present study, previous investigators have suggested that the threshold for the dipsogenic effect of acutely administered ANG II is sime 200 pg of ANG II per milliliter of plasma (22). Interestingly, previous investigators have shown that, after repeated intracerebroventricular administration of ANG II, tachyphylaxis to the dipsogenic effect of ANG II developed (30). On the basis of results from previous studies, a lack of dipsogenic response to chronic high-dose ANG II infusion in the present study may have resulted from tachyphylaxis or desensitization of the ANG II receptor involved in the dipsogenic effects of ANG II (30, 38).

Previous investigators demonstrated that at a dose of ANG II infusion approximately threefold greater than that used in study 1 (175 ng · kg-1 · min-1), body weight was decreased from baseline starting values after 14 days of infusion (3). Results from study 1 extend previous findings by demonstrating that low doses of ANG II infusion classified at the threshold level for direct pressor effects markedly affected the rate of weight gain and body weight. In agreement with previous studies (3), results from this study demonstrate that higher pressor doses of ANG II result in a loss of body weight from baseline starting values. Throughout the present studies, the time course for increases in blood pressure in ANG II-infused rats did not parallel that for the effects of ANG II on body weight. Typically, increases in blood pressure were manifested 3-5 days before alterations in body weight. The time delay between blood pressure increases and elimination of weight gain after ANG II infusion suggests that these two variables are independent. Alternatively, the effect of ANG II to regulate body weight may be indirectly related to elevations in blood pressure with a time-lag delay.

Further studies using the vasodilator hydralazine demonstrated that the effect of ANG II on body weight was independent of blood pressure. These results are in agreement with previous studies demonstrating that decreases in body weight in high-dose ANG II-infused rats (500 ng · kg-1 · min-1) were independent of elevations in blood pressure (3). Interestingly, the effect of ANG II to decrease body weight was augmented in hydralazine-treated rats. Potential mechanisms for augmentation of ANG II regulation of body weight include reflex increases in sympathetic neurotransmission in hydralazine-treated rats in response to decreased peripheral vascular resistance. Hydralazine-mediated increases in sympathetic neurotransmission would potentially increase peripheral metabolism and elevate systemic ANG II production (increased kidney-derived renin release).

The present study utilized the noninvasive method of thermal IR imaging for the regional determination of surface temperature as an index of energy expenditure. Previous investigators have demonstrated the ability of IR thermography to detect changes in mean body surface temperature in postsurgical patients receiving total parenteral nutrition or in healthy subjects in the fasting state or after meal ingestion (33). Results from the present study demonstrate that after chronic low-dose ANG II infusion, tail surface temperature increases, suggesting that heat dissipation mechanisms were activated. In agreement with these results, previous investigators have demonstrated that acute high-dose ANG II injection resulted in an increase in tail skin temperature (36). In addition to alterations in tail temperature, results from this study demonstrate an increase in abdominal/thorax surface temperature after chronic ANG II infusion.

A variety of evidence demonstrates that ANG II facilitates the sympathetic nervous system (40). Moreover, the sympathetic nervous system is important in the control of peripheral lipid metabolism. Previous investigators chronically measured plasma norepinephrine (NE) levels in rats infused with ANG II (150 ng · kg-1 · min-1) and demonstrated that plasma NE levels increased by days 4-6 of infusion (16). Plasma catecholamine measurements were not performed in the present study. Thus it is unclear whether the effect of ANG II to decrease body weight and increase surface temperature was mediated indirectly through activation of the sympathetic nervous system. Future studies will determine the role of the sympathetic nervous system in the metabolic effects of ANG II.

Results from this study do not support a role for alterations in food intake as the primary mechanism for the effect of ANG II on body weight. Previous investigators demonstrated that pair feeding control rats to food intake levels of ANG II-infused rats (500 ng · kg-1 · min-1) resulted in similar levels of body weight reduction (3), suggesting that decreased food intake contributes to ANG II regulation of body weight. In the present study, high-dose ANG II infusion (>350 ng · kg-1 · min-1) resulted in a time-dependent reduction of food intake. Initial reductions in food intake in the present study and in previous studies (3) may represent effects of ANG II related to initial pressor-mediated increases in blood pressure and general animal malaise. However, at low doses of ANG II infusion, as in study 1, the effect of ANG II on weight gain and body weight occurred in the absence of significant reductions in food intake.

Assessment of relative organ mass in the present study demonstrated a preferential effect of ANG II infusion to reduce white adipose tissue mass. Retroperitoneal white adipose tissue was significantly reduced in all of the studies performed. In contrast, other organs examined maintained their relative mass after ANG II infusion, with the exception of the diaphragm (decreased) and left ventricle (increased). The relatively specific effects of ANG II to decrease the mass of retroperitoneal white adipose tissue suggest that effects of ANG II on weight gain and body weight may arise from augmented lipid metabolism. However, in the present study, the epididymal white fat pad did not exhibit reductions in mass after ANG II infusion. These results suggest site-specific alterations in adipose lipid metabolism and mass from ANG II infusion.

The cloning of the ob/ob gene and the identification of leptin have greatly expanded the field of obesity research (39). Biological effects of adipose-derived leptin include a decrease in food intake and an increase in energy expenditure (5, 27). Increases in energy expenditure after leptin administration are associated with elevations in NE turnover and enhanced brown adipose thermogenesis (10). In a feedback endocrine regulatory loop, the sympathetic nervous system has been demonstrated to negatively modulate leptin gene expression in white adipose tissue (20). In the present study, measurement of plasma leptin levels after chronic ANG II infusion demonstrated that high-dose ANG II resulted in a decrease in plasma leptin. A limitation of the present study is that chronic measurements of plasma leptin were not obtained during ANG II infusion; thus it is unclear whether suppressed leptin levels may represent a compensatory response to chronic ANG II infusion, potentially mediated through sympathetic nervous system negative feedback. Alternatively, decreases in plasma leptin levels after chronic ANG II infusion may arise from semifasted states of rats (decreased food intake) or reductions in the mass of white adipose tissue. Future studies will determine the role of leptin in ANG II regulation of body weight. Regardless, these studies are the first to demonstrate that ANG II influences plasma leptin secretion.

In summary, results from this study demonstrate that ANG II regulates body weight through pressor-independent mechanisms in a dose-dependent manner. Furthermore, mechanisms contributing to ANG II regulation of body weight include alterations in plasma leptin, mobilization of fat mass, and increased energy expenditure. These findings are relevant to disease states associated with heightened (congestive heart failure) or diminished (obesity) activity of the renin-angiotensin system. Moreover, results from this study support a functional role for ANG II production in adipose tissue and strengthen the physiological significance of an adipose renin-angiotensin system.

    ACKNOWLEDGEMENTS

The authors acknowledge Dr. Allen Hacker for the use of the Narco blood pressure equipment.

    FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute Grant HL-52934.

Address for reprint requests: L. A. Cassis, Rm. 417, College of Pharmacy, Rose St., Univ. of Kentucky, Lexington, KY 40536-0082.

Received 20 October 1997; accepted in final form 5 February 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

1.   Abraham, G., and G. Simon. Autopotentiation of pressor responses by subpressor angiotensin II in rats. Am. J. Hypertens. 7: 269-275, 1994[Medline].

2.   Baker, K. M., G. W. Booz, and D. E. Dostal. Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu. Rev. Physiol. 68: 905-921, 1992.

3.   Brink, M., J. Sellen, and P. Delafontaine. Angiotensin II causes weight loss and decreases circulating insulin-like growth factor 1 in rats through a pressor-independent mechanism. J. Clin. Invest. 97: 2509-2516, 1996[Medline].

4.   Campbell, D. J., A. M. Duncan, and A. Kladis. Measurements of angiotensin peptides. Hypertension 26: 843-845, 1995.

5.   Campfield, L. A., F. J. Smith, Y. Guisez, R. Devos, and P. Burn. Recombinant mouse ob protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269: 546-549, 1995[Abstract/Free Full Text].

6.   Cassis, L., M. Fettinger, A. Roe, U. Shenoy, and G. Howard. Characterization and regulation of angiotensin II receptor in rat adipose tissue. In: Recent Advances in Cellular and Molecular Aspects of Angiotensin Receptors, edited by M. Raizada. New York: Plenum, 1996, p. 39-47.

7.   Cassis, L. A., and L. P. Dwoskin. Presynaptic modulation of neurotransmitter release by endogenous angiotensin II in brown adipose tissue. J. Neural. Transm. Suppl. 34: 129-137, 1991[Medline].

8.   Cassis, L. A., J. A. Saye, and M. J. Peach. Location and regulation of rat angiotensinogen messenger RNA. Hypertension 11: 591-596, 1988[Abstract/Free Full Text].

9.   Chai, S. Y. Localization of components of the renin-angiotensin system and site of action of inhibitors. Azeneimittelforschung 43: 214-221, 1993[Medline].

10.   Collins, S., C. M. Kuhn, A. E. Petro, A. G. Swick, B. A. Chrunyk, and R. S. Surwit. Role of leptin in fat regulation. Nature 380: 677, 1996[Medline].

11.   Diz, D. I., P. G. Baer, and A. Nasjletti. Angiotensin II-induced hypertension in the rat: effects on the plasma concentrations, renal excretion, and tissue release of prostaglandins. J. Clin. Invest. 72: 466-477, 1983.

12.   Dostal, D. E., K. N. Rothblum, M. I. Chernin, G. R. Cooper, and K. M. Baker. Intracardiac detection of angiotensinogen and renin: a localized renin-angiotensin system in neonatal rat heart. Am. J. Physiol. 263 (Cell Physiol. 32): C838-C850, 1992[Abstract/Free Full Text].

13.   Dzau, V. J. A comparative study of the distributions of renin and angiotensin messenger ribonucleic acids in rat and mouse. Endocrinology 120: 2334-2338, 1987[Abstract/Free Full Text].

14.  Dzau, V. J. Cell biology and genetics of angiotensin in cardiovascular disease. J. Hypertens. 12, Suppl. 4: S3-S10, 1994.

15.   Griffin, S., W. Brown, F. MacPherson, J. McGrath, V. Wilson, N. Korsgaard, M. Mulvany, and A. Lever. Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism. Hypertension 17: 626-635, 1991[Abstract/Free Full Text].

16.   Henegar, J. R., G. L. Brower, A. Kabour, and J. J. Janicki. Catecholamine response to chronic ANG II infusion and its role in myocyte and coronary vascular damage. Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H1564-H1569, 1995[Abstract/Free Full Text].

17.   Hiramatsu, K., T. Yamada, K. Ichidawa, T. Izumiyama, and H. Nagata. Changes in endocrine activities relative to obesity in patients with essential hypertension. J. Am. Geriatr. Soc. 29: 25-30, 1981[Medline].

18.   Lachance, D., and R. Garcia. Atrial natriuretic factor release by angiotensin II in the conscious rat. Hypertension 11: 502-508, 1988[Abstract/Free Full Text].

19.   Levy, J., P. Lutz, M. Fischbach, J. Lutz, and C. Demangeat. Renin-angiotensin-aldosterone system in obese children. Arch. Fr. Pediatr. 39: 807-810, 1982[Medline].

20.   Li, H., M. Matheny, and P. J. Scarpace. beta 3-Adrenergic-mediated suppression of leptin gene expression in rats. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E1031-E1036, 1997[Abstract/Free Full Text].

21.   Luft, F., C. Wilcox, R. Unger, R. Kuhn, G. Demmert, P. Rohmeiss, D. Ganten, and R. Sterzel. Angiotensin-induced hypertension in the rat. Sympathetic nerve activity and prostaglandins. Hypertension 14: 396-403, 1989[Abstract/Free Full Text].

22.   Mann, J. F. E., A. K. Johnson, and D. Ganten. Plasma angiotensin II: dipsogenic levels and angiotensin-generating capacity of renin. Am. J. Physiol. 238 (Regulatory Integrative Comp. Physiol. 7): R372-R377, 1980[Abstract/Free Full Text].

23.   Melargno, M., and G. Fink. Inhibition of the slow pressor effect of angiotensin II contributes to the antihypertensive effect of angiotensin converting enzyme inhibitors in renovascular hypertension. J. Pharmacol. Exp. Ther. 278: 297-303, 1996[Abstract/Free Full Text].

24.   Mulrow, P. J. Adrenal renin: regulation and function. Front. Neuroendocrinol. 13: 47-60, 1992[Medline].

25.   Peach, M. J. Renin-angiotensin system: biochemistry and mechanisms of action. Physiol. Rev. 57: 313-370, 1977[Free Full Text].

26.   Pedersen, E. B., H. Danielsen, T. Jensen, M. Madsen, S. Sorensen, and O. Thomsen. Angiotensin II, aldosterone, and arginine vasopressin in plasma in congestive heart failure. Eur. J. Clin. Invest. 16: 56-60, 1986[Medline].

27.   Pelleymounter, M. A., M. J. Cullen, M. B. Baker, D. Winters, T. Boone, and F. Collins. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269: 540-543, 1995[Abstract/Free Full Text].

28.   Phillips, M. I. Levels of angiotensin and molecular biology of the tissue renin-angiotensin systems. Regul. Pept. 43: 1-20, 1993[Medline].

29.   Pittman, J., and P. Cohen. The pathogenesis of cardiac cachexia. N. Engl. J. Med. 271: 403-409, 1964.

30.   Quirk, W. S., J. W. Wright, and J. W. Harding. Tachyphylaxis of dipsogenic activity to intracerebroventricular administration of angiotensins. Brain Res. 452: 73-78, 1988[Medline].

31.   Seikaly, M. G., B. S. Arant, and F. D. Seney. Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J. Clin. Invest. 86: 1352-1357, 1990.

32.   Shenoy, U., and L. Cassis. Characterization of renin activity in brown adipose tissue. Am. J. Physiol. 272 (Cell Physiol. 41): C989-C999, 1997[Abstract/Free Full Text].

33.   Shuran, M., and R. Nelson. Quantitation of energy expenditure by infrared thermography. Am. J. Clin. Nutr. 53: 1361-1367, 1991[Abstract/Free Full Text].

34.   Simon, G., G. Abraham, and G. Cserep. Pressor and subpressor angiotensin II administration. Two experimental models of hypertension. Am. J. Hypertens. 8: 645-650, 1995[Medline].

35.   Staroukine, M., J. Devriendt, P. Decoodt, and A. Verniory. Relationships bewteen plasma epinephrine, norepinephrine, dopamine and angiotensin II concentrations, renin activity, hemodynamic state and prognosis in acute heart failure. Acta Cardiol. 39: 131-138, 1984[Medline].

36.   Wilson, K. M., and M. J. Fregly. Angiotensin II-induced hypothermia in rats. J. Appl. Physiol. 58: 534-543, 1985[Abstract/Free Full Text].

37.   Wong, P., S. Hart, A. Zaspal, A. Chiu, R. Ardecky, R. Smith, and P. Timmermans. Functional studies of nonpeptide angiotensin II receptor subtype-specific ligands: DuP 753 (AII-1) and PD123177 (AII-2). J. Pharmacol. Exp. Ther. 255: 584-592, 1990[Abstract/Free Full Text].

38.   Yang, C., J. Chan, and S. Chan. Unsustained dipsogenic response to chronic central infusion of angiotensin-III in spontaneously hypertensive rats. Endocrinology 132: 405-409, 1993[Abstract/Free Full Text].

39.   Zhang, Y., R. Proenca, J. Maffei, M. Barone, L. Leopold, and J. Friedman. Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425-432, 1994[Medline].

40.   Zimmerman, B., E. Syberte, and P. Wong. Interactions between sympathetic and renin-angiotensin system. Hypertension 2: 581-587, 1984.

AJP Endocrinol Metab 274(5):E867-E876
0193-1849/98 $5.00 Copyright © 1998 the American Physiological Society


This article has been cited by other articles:


Home page
 Physiol. GenomicsHome page
S. O. Kasper, C. S. Carter, C. M. Ferrario, D. Ganten, L. F. Ferder, W. E. Sonntag, P. E. Gallagher, and D. I. Diz
Growth, metabolism, and blood pressure disturbances during aging in transgenic rats with altered brain renin-angiotensin systems
Physiol Genomics, November 17, 2005; 23(3): 311 - 317.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. P. Porter and K. R. Potratz
Effect of intracerebroventricular angiotensin II on body weight and food intake in adult rats
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R422 - R428.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
L. Cassis, M. Helton, V. English, and G. Burke
Angiotensin II regulates oxygen consumption
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2002; 282(2): R445 - R453.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. C. Speth, W. T. Barry, M. S. Smith, and K. L. Grove
A comparison of brain angiotensin II receptors during lactation and diestrus of the estrous cycle in the rat
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 1999; 277(3): R904 - R909.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cassis, L. A.
Right arrow Articles by Lodder, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cassis, L. A.
Right arrow Articles by Lodder, R. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online