title: Factors affecting the regional haemodynamic responses to glyceryl trinitrate and molsidomine in conscious rats.
abstract: 1. A series of experiments was performed in conscious, unrestrained, male, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics. 2. Infusion of glyceryl trinitrate (GTN, 0.1 mg kg-1 min-1, i.v.) for 10 min elicited tachycardia, but no sustained change in mean arterial blood pressure. Renal haemodynamics were unaffected, but there were reductions in hindquarters flow and vascular conductance together with substantial increases in flow and conductance in the mesenteric vascular bed. 3. In the presence of captopril (2 mg kg-1 bolus, and 1 mg kg-1 h-1 infusion, i.v.) GTN elicited significant hypotension and increases in renal blood flow and vascular conductance, indicating that activation of the renin-angiotension system opposed the dilator effects of GTN in this vascular bed. However, the mesenteric and hindquarters haemodynamic effects of GTN were not affected by captopril. In contrast, in the presence of enalaprilat (2 mg kg-1 bolus, and 1 mg kg-1 h-1 infusion, i.v.) there was significant enhancement of the mesenteric, as well as renal, haemodynamic effects of GTN. Hence, these results provide no evidence for the sulphydryl groups in captopril exerting a specific effect to enhance the haemodynamic actions of GTN in our experimental protocols. 4. Administration of molsidomine alone (1 mg kg-1, i.v. bolus) elicited tachycardia and hypotension; there were no changes in mesenteric or hindquarters haemodynamics, but renal flow and vascular conductance fell. Thus, the hypotensive effect of molsidomine was probably due to a reduction in cardiac output, consequent upon venodilatation. 5. In the presence of captopril or enalaprilat, molsidomine evoked renal and mesenteric vasodilatations in association with hypotension, indicating that activation of the renin-angiotensin system contributed to the lack of vasodilator responses to administration of molsidomine alone. However, since the effects of enalaprilat were more marked than those of captopril (in spite of the dose of both drugs being supramaximal for inhibition of angiotensin-converting enzyme), other factors must have been involved. 6. In a separate experiment, pretreatment with the nitric oxide synthesis inhibitor, N0-nitro-L-arginine methyl ester (1 mg kg- 1 h-1, i.v.), enhanced the mesenteric vasodilator effect of molsidomine. Collectively, these results are consistent with in vitro data showing that endogenous nitric oxide can inhibit the vasodilator effects of nitric oxide derived from molsidomine, and that the sulphydryl groups of captopril can protect endogenous nitric oxide from inactivation by oxygen-derived free radicals, thereby enhancing the inhibitory effect of endogenous nitric oxide on the vasodilator responses to exogenous nitric oxide derived from molsidomine (or GTN).
authors.affiliation: Department of Physiology and Pharmacology, University of Nottingham Medical School, Queen's Medical Centre.
authors.forename: K
authors.initials: K
authors.lastname: Phillips
authors.forename: S M
authors.initials: SM
authors.lastname: Gardiner
authors.forename: P A
authors.initials: PA
authors.lastname: Kemp
authors.forename: T
authors.initials: T
authors.lastname: Bennett
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004656:Enalapril / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply; D008297:Male; D008981:Molsidomine / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester; D005996:Nitroglycerin / Q000494:pharmacology*; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013152:Splanchnic Circulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004656:Enalapril; D001120:Arginine; D002216:Captopril; D008981:Molsidomine; D005996:Nitroglycerin; D019331:NG-Nitroarginine Methyl Ester