title: Involvement of nitric oxide in the regional haemodynamic effects of perindoprilat and captopril in hypovolaemic Brattleboro rats.
abstract: 1. Male, homozygous Brattleboro (i.e. vasopressin-deficient) rats were chronically instrumented with pulsed Doppler flow probes and intravascular catheters, and were studied 5 h after a subcutaneous injection of an hyperoncotic solution of polyethylene glycol to render them hypovolaemic, and hence dependent on the renin-angiotensin system for maintenance of haemodynamic status. Pilot experiments showed that, in this model, primed infusion of perindoprilat (0.05 mg kg-1 bolus, 0.05 mg kg-1 h-1 infusion) or captopril (0.2 mg kg-1 bolus, 0.2 mg kg-1 h-1 infusion) just abolished the pressor effect of angiotensin I (120 pmol), and had similar initial hypotensive and renal hyperaemic vasodilator effects. 2. Perindoprilat had more sustained hypotensive, and mesenteric and hindquarters vasodilator effects than captopril in the presence of saline. In the presence of NG-nitro-L-arginine methyl ester (L-NAME 3 mg kg-1 h-1), the renal vasodilator effects of perindoprilat were unchanged, whereas the other haemodynamic effects of perindoprilat and captopril were reduced. Hence, in the presence of L-NAME, all haemodynamic effects of perindoprilat were greater than those of captopril. 3. The renal hyperaemic vasodilator effects of acetylcholine were abolished by L-NAME and by perindoprilat, and were markedly reduced by captopril. However, since perindoprilat and captopril caused such marked renal hyperaemic vasodilatation themselves, it is feasible this change in baseline status contributed to their effects. It is unlikely this could be a full explanation of the results, because the haemodynamic effects of lemakalim were unchanged under any experimental conditions. 4. Bradykinin alone, or in the presence of saline, caused mesenteric hyperaemic vasodilatation whereas, in the presence of perindoprilat or captopril, bradykinin caused marked renal and mesenteric vasoconstrictions. However, in the additional presence of L-NAME, the mesenteric vasoconstriction was reduced, yet the hypotensive effect of bradykinin was augmented. One possible explanation of these observations is that, in the presence of L-NAME and either perindoprilat or captopril, bradykinin caused marked coronary vasoconstriction, leading to a reduction in cardiac output. 5. Neither perindoprilat nor captopril impaired the pressor, or renal, mesenteric, or hindquarters vasoconstrictor effects of L-NAME. Indeed, in their presence, the effects of L-NAME were generally enhanced, consistent with perindoprilat and captopril causing activation of nitric oxide-dependent mechanisms that were subsequently inhibited by L-NAME.
authors: Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre.
authors: S M
authors: SM
authors: Gardiner
authors: T
authors: T
authors: Bennett
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D001810:Blood Volume; D001920:Bradykinin / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology*; D019806:Cromakalim; D006439:Hemodynamics / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D011910:Rats, Brattleboro; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001578:Benzopyrans; D007211:Indoles; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; C053500:perindoprilat; D009569:Nitric Oxide; D001120:Arginine; D002216:Captopril; D000109:Acetylcholine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester