Although arginine vasopressin (AVP), an antidiuretic hormone, has been widely acknowledged to play an important role in cardiovascular regulation via V1a receptors (V1aR), its precise significance remains unclear. In this study, we investigated the effects of long-standing high plasma AVP status on cardiovascular regulation in the AVP-overexpressing transgenic rat (Tg). Adult male homozygotes Tg were compared with age-matched normal Sprague-Dawley rats as controls. There were no significant differences in mean arterial blood pressure (MABP) or heart rate between Tg and control in the basal state. Subcutaneous injection of AVP significantly increased MABP in control, but did not cause any apparent increase in MABP in Tg. BP recovery from hemorrhage-induced hypotension was significantly delayed in Tg compared to control. Pretreatment with a selective V1aR antagonist, OPC-21268, which is thought to restore the down-regulation of V1aR, markedly improved both of these impaired responses. Northern blot analysis confirmed decreased expression of V1aR mRNA and that pretreatment with V1aR antagonist significantly restored the down-regulation of V1aR mRNA. These results suggest that Tg has decreased sensitivity to the hypertensive effect of AVP due to down-regulation of V1aR, which may function as an adaptive mechanism to maintain normal BP against chronic hypervasopressinemia. In addition, impaired restoration of BP after hemorrhage-induced hypotension in Tg supports a physiological role of AVP in cardiovascular regulation.