Roles of vasopressin and endothelin in deoxycorticosterone acetate-salt hypertensive rats
The contributions and interactions of the vasopressin (AVP) and endothelin (ET) systems were investigated in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. All the experiments utilized chronically instrumented rats implanted with telemetry devices for recording blood pressure (BP) and Transonic flowprobes for recording cardiac output (CO). In the first study, bosentan, a non-selective ET-antagonist, and BMS-182874, a selective ETA-antagonist, were injected into DOCA-salt hypertensive and SHAM-rats intravenously. Unlike SHAM-rats, bosentan and BMS-182874 lowered BP and TPR dramatically in DOCA-salt hypertensive rats. These results suggest that the contribution of ET to the maintenance of high BP in this hypertensive animal is exerted at the level of the resistance vessels. In the second study, [d(CH2)51, O-Me-Tyr2,Arg8]-vasopressin, a V1-antagonist, was administered in the absence and presence of bosentan. Administration of the V1-antagonist alone failed to lower BP and TPR in this hypertensive model. However, the V1-antagonist lowered BP and TPR when the ET system was blocked. In other experiments, bosentan alone reduced BP and TPR in DOCA-rats, but the responses to bosentan were exaggerated when V1 -receptors were blocked. These results indicate that AVP contributes to the maintenance of hypertension via its vasoconstrictor effects. It also reveals the redundant nature of the AVP and ET systems in regulating hemodynamics in DOCA-salt hypertensive rats. In the third study, a range of doses of AVP was infused intravenously before or after bosentan treatment. Increases in BP and TPR elicited by AVP were blunted by bosentan both in DOCA-salt hypertensive and SHAM-rats. The effect of bosentan was greater in the hypertensive rats. Unlike AVP, responses to Ang II were not modified by bosentan. These findings provide direct evidence that ET contributes to the hemodynamic responses of AVP. This contribution to the pressor activity of AVP is exerted at the level of the resistance function of the circulation. In conclusion, the results of this thesis demonstrate the involvement of both the ET and AVP systems and their redundant relationship in the control of systemic hemodynamics in the DOCA-salt model of hypertension. The results also demonstrate a contribution of ET to the pressor activity of AVP in this model.
Doctor of Philosophy (Ph.D.)