Attenuation of Spontaneous Hypertension in Rats by a Vasopressin Antagonist

Although abnormalities in the vasopressin system have been reported in spontaneously hypertensive rats (SHR), neither short-term nor long-term administration of the vasopressin antagonist d(CH2)5-Tyr(Me)arginine vasopressin (AVP), which selectively blocks the action of vasopressin on vascular (V1) receptors, altered the course of hypertension in SHR. In the current study, long-term administration of a different vasopressin antagonist, d(CH2)5-D-Tyr(Me)VAVP, to SHR and Wistar-Kyoto rats (WKY) from 4 to 12 weeks of age significantly attenuated the development of systolic hypertension in SHR (p < 0.05) without altering Mood pressure in normotensive WKY. The antagonist was delivered subcutaneously by osmopump at 0.1 μ Systolic blood pressure was monitored twice weekly by tail plethysmography beginning at 5 weeks of age. In a second group of SHR, the drug infusion was continued until 18 weeks of age. In this group, the attenuation of systolic hypertension by the drug was extended and became more prominent (p < 0.007). Resting mean arterial pressure measured by Indwelling catheters in the conscious state at 18 weeks of age was significantly reduced in the antagonist-treated SHR (144 ± 4 vs 157 ± 4 mm Hg;p < 0.05). Heart rate also was significantly reduced by the drug (351 ± 6 vs 392 ± 7 beats/min; p < 0.001). Following measurement of mean arterial pressure in the rats at 18 weeks of age, the osmopumps were removed and systolic blood pressure, mean arterial pressure, and heart rate were observed until 22 weeks of age. All of these parameters returned to the levels observed in untreated SHR within 2 weeks after drug withdrawal. Although this antagonist has both V, and V2 (antidiuretlc) antagonist properties, the infusion protocol used in this study resulted in antagonism of the pressor action of vasopressin but incomplete antagonism of the antldluretk action of vasopressin. Thus, the mechanism responsible for the antihypertensive action of this antagonist is not clear, but the results suggest that long-term blockade of the actions of endogenous vasopressin does alter the course of hypertension in SHR.