REGIONAL HEMODYNAMIC-EFFECTS OF ANTAGONISTS OF ANGIOTENSIN-II, ENDOTHELIN AND ADRENOCEPTORS IN CONSCIOUS, VASOPRESSIN-DEFICIENT, GENETICALLY HYPERTENSIVE RATS

1 Male, vasopressin-deficient, normotensive (DI/N) and hypertensive (D I/H) rats were chronically instrumented (all surgery under sodium meth ohexitone anaesthesia) to allow assessment of resting haemodynamic sta tus and responses to antagonism of AT(1)-receptors (Experiment 1), ETA (A)- and ET(B)-receptors (Experiment 2) or adrenoceptors (Experiment 3 ). 2 Before any treatment, mean arterial blood pressure (MAP) was high er, and hindquarters vascular conductance was consistently lower in al l groups of DI/H rats than in DI/N rats. 3 In Experiment 1, losartan ( 10 mg kg(-1) i.v.), an AT(1)-receptor antagonist, was given 5 h after s.c. injection of saline, (DI/N, n=8; DI/H, n=8) or hyperoncotic polye thylene glycol, (DI/N, n=9; DI/H, n=9) to induce isosmotic hypovolaemi a. In the volume-replete state, losartan caused similar small falls in MAP in the two groups (maximum Delta MAP; DI/N, -9+/-2; DI/H, -15+/-5 mmHg), but the mesenteric and hindquarters vasodilatations were great er in DI/N rats. In the volume-depleted state the effects of losartan were augmented (Delta MAP; DI/N, -32+/-3; DI/H. -31+/-3 mmHg), but its vasodilator effects were still greater in DI/N than in DI/H rats. 4 I n Experiment 2, infusion of the ET(A)-ET(B)-receptor antagonist, SE 20 9670 (600 mu g kg(-1) h(-1); DI/N, n=8; DI/H, n=9), had haemodynamic e ffects that were not different from those during saline infusion in DI /N (n=7) and DI/H rats (n=8). 5 In Experiment 3, sequential administra tion of the beta(2)-adrenoceptor antagonist, ICI 118551 (0.2 mg kg(-1) bolus, 0.1 mg kg(-1) h(-1) infusion), the alpha(2)-adrenoceptor antag onist, idazoxan (0.75 mg kg(-1) bolus, 1 mg kg(-1) h(-1) infusion), an d losartan (10 mg kg(-1) bolus) had only slight haemodynamic effects i n DI/N (n=8) and DI/H (n=9) rats. Subsequent administration of the alp ha(1)-adrenoceptor antagonist, prazosin (0.5 mg kg(-1) bolus, 0.8 mg k g(-1) h(-1) infusion) caused marked hypotension, although MAP was stil l higher in DI/H (95+/-4 mmHg) than in DI/N (75+/-4 mmHg) rats. Howeve r, in this circumstance there were no significant differences between renal, or mesenteric, or hindquarters vascular conductances in the two groups. 6 The results indicate that the hypertension and hindquarters vasoconstriction in DI/H rats is not dependent on AII or endothelin. Moreover, the relative elevation in MAP in DI/H persists in the presen ce of antagonism of beta(2), alpha(2)- and alpha(1)-adrenoceptors, in spite of no significant difference in regional vascular conductances.