Studies were carried out using instrumented unanesthetized rats to determine the long-term effects of arginine vasopressin (AVP) and a specific vasopressin V₁ receptor agonist (V₁AG; [Phe², Ile³, Orn⁸]- vasopressin) on the renal medullary blood flow and arterial blood pressure. It was hypothesized that the hypertension observed with chronic medullary infusion of a V₁ receptor agonist may be associated with a sustained reduction of blood flow, whereas infusion of AVP may fail to produce a sustained reduction of blood flow and thereby be unable to produce hypertension. Uninephrectomized Sprague-Dawley rats were prepared with implanted renal cortical and medullary optical fibers for daily measurements of cortical and medullary blood flow using laser-Doppler flowmetry techniques. An implanted renal medullary interstitial infusion catheter delivered either AVP or a specific V₁AG at a dose of 2 ng · kg¹ · min¹ over a period of 5 days. The V₁AG produced no change of cortical blood flow but a chronic 35% reduction of medullary blood flow (P < 0.05) and mild hypertension (11 ± 4 mmHg, P < 0.05). AVP produced only an initial, nonsignificant 1- to 2-day reduction of medullary blood flow (13%) and failed to raise arterial pressure significantly. We conclude that a sustained V₁AG response is necessary to achieve a chronic reduction of medullary blood flow and hypertension. The present data are consistent with the idea that chronic stimulation of V₂ receptors by AVP offsets the vasoconstrictor and hypertension actions of AVP-induced stimulation of medullary V₁ receptors.