Regional haemodynamic effects of antagonists of angiotensin II, endothelin and adrenoceptors in conscious, vasopressin‐deficient, genetically hypertensive rats

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Abstract
1 Male, vasopressin-deficient, normotensive (DI/N) and hypertensive (DI/H) rats were chronically instrumented (all surgery under sodium methohexitone anaesthesia) to allow assessment of resting haemodynamic status and responses to antagonism of AT1-receptors (Experiment 1), ETA- and ETB- receptors (Experiment 2) or adrenoceptors (Experiment 3). 2 Before any treatment, mean arterial blood pressure (MAP) was higher, and hindquarters vascular conductance was consistently lower in all groups of DI/H rats than in DI/N rats. 3 In Experiment 1, losartan (10 mg kg−1 i.v.), an AT1-receptor antagonist, was given 5 h after s.c. injection of saline, (DI/N, n = 8; DI/H, n = 8) or hyperoncotic polyethylene glycol, (DI/N, n = 9; DI/H, n = 9) to induce isosmotic hypovolaemia. In the volume-replete state, losartan caused similar small falls in MAP in the two groups (maximum Δ MAP; DI/N, −9±2; DI/H, −15±5 mmHg), but the mesenteric and hindquarters vasodilatations were greater in DI/N rats. In the volume-depleted state the effects of losartan were augmented (Δ 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 In Experiment 2, infusion of the ETA-ETB-receptor antagonist, SB 209670 (600 μg kg−1 h−1; DI/N, n = 8; DI/H, n = 9), had haemodynamic effects 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 administration of the β2-adrenoceptor antagonist, ICI 118551 (0.2 mg kg−1 bolus, 0.1 mg kg−1 h−1 infusion), the α2-adrenoceptor antagonist, idazoxan (0.75 mg kg−1 bolus, 1 mg kg−1 h−1 infusion), and losartan (10 mg kg−1 bolus) had only slight haemodynamic effects in DI/N (n = 8) and DI/H (n = 9) rats. Subsequent administration of the α1-adrenoceptor antagonist, prazosin (0.5 mg kg−1 bolus, 0.8 mg kg−1 h−1 infusion) caused marked hypotension, although MAP was still higher in DI/H (95±4 mmHg) than in DI/N (75±4 mmHg) rats. However, 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 All or endothelin. Moreover, the relative elevation in MAP in DI/H persists in the presence of antagonism of β2, α2- and α1-adrenoceptors, in spite of no significant difference in regional vascular conductances.