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Regional haemodynamic effects of antagonists of angiotensin II, endothelin and adrenoceptors in conscious, vasopressin‐deficient, genetically hypertensive rats
Author(s) -
Gardiner S.M.,
March J.E.,
Kemp P.A.,
Bennett T.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15406.x
Subject(s) - losartan , vasopressin , endocrinology , medicine , hemodynamics , mean arterial pressure , angiotensin ii , endothelin receptor , saline , vasodilation , blood pressure , receptor , heart rate
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 AT 1 ‐receptors (Experiment 1), ET A ‐ and ET B ‐ 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 AT 1 ‐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 ET A ‐ET B ‐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 β 2 ‐adrenoceptor antagonist, ICI 118551 (0.2 mg kg −1 bolus, 0.1 mg kg −1 h −1 infusion), the α 2 ‐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 α 1 ‐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 β 2 , α 2 ‐ and α 1 ‐adrenoceptors, in spite of no significant difference in regional vascular conductances.