Regional and cardiac haemodynamic responses to glyceryl trinitrate, acetylcholine, bradykinin and endothelin-1 in conscious rats: effects of NG-nitro-L-arginine methyl ester.
1. Conscious Long Evans rats, chronically instrumented for cardiovascular measurements, were challenged with i.v. bolus doses of glyceryl trinitrate (40 nmol kg-1), acetylcholine (1.2 nmol kg-1), bradykinin (3.2 nmol kg-1), or endothelin-1 (0.25 nmol kg-1). Under control conditions these doses produced similar falls in mean arterial blood pressure (glyceryl trinitrate, -20 +/- 3 mmHg; acetylcholine, -24 +/- 2 mmHg: bradykinin, -21 +/- 3 mmHg; endothelin-1, -25 +/- 3 mmHg), associated with renal, mesenteric and hindquarters vasodilatations (except for endothelin-1 which caused mesenteric vasoconstriction). 2. In the presence of NG-nitro-L-arginine methyl ester (L-NAME, 10 mgkg-1), a potent inhibitor of nitric oxide biosynthesis and endothelium-dependent vasorelaxation in vitro, the hypotensive responses to glyceryl trinitrate, acetylcholine, and endothelin-1 were increased, although that to bradykinin was not. However, comparing the differences between the response to glyceryl trinitrate and that to any other agonist in the absence and presence of L-NAME showed that there were relative attenuations of the hypotensive responses to bradykinin and endothelin-1, but not to acetylcholine, in the presence of L-NAME. 3. This comparative analysis showed that the renal and hindquarters vasodilator responses to bradykinin and endothelin-1 were attenuated in the presence of L-NAME, but the renal, mesenteric and hindquarters vasodilator responses to acetylcholine were not. However, when L-NAME was administered in the presence of pentolinium, captopril and the vasopressin V1-receptor antagonist, d(CH2)5[Tyr-(Et)]DAVP, (to abolish baroreflex and neurohumoral mechanisms), there was attenuation of the renal and mesenteric vasodilator effects of acetylcholine relative to those seen with glyceryl trinitrate. Under those conditions only the renal vasodilator effects of bradykinin and endothelin-1 were attenuated. 4. In separate experiments in conscious Long Evans rats, direct measurement of cardiac haemodynamics showed that the hypotensive responses to glyceryl trinitrate, acetylcholine, bradykinin and endothelin-l were entirely attributable to rises in total peripheral conductance since both in the absence and presence of L-NAME there were no reductions in cardiac index in response to these substances. 5. The results indicate that measurement of systemic arterial blood pressure alone in conscious rats does not permit reliable quantitation of the influence of L-NAME on regional vasodilator responses to glyceryl trinitrate, acetylcholine, bradykinin or endothelin-1. Furthermore, these substances exert effects in different vascular beds that may be differentially influenced by baroreflex mechanisms, neurohumoral mechanisms, or both. Moreover, except in the case of the renal vasodilator response to endothelin-1 (which was abolished in the presence of L-NAME), even when L-NAME caused attenuation of the vasodilator effects of acetylcholine or bradykinin (relative to glyceryl trinitrate), substantial responses remained. It is feasible that such responses in vivo are nitric oxide-independent.
Gardiner
S M
SM
Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham.
Compton
A M
AM
Kemp
P A
PA
Bennett
T
T
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D005996:Nitroglycerin / Q000494:pharmacology; D051381:Rats; D012079:Renal Circulation / Q000187:drug effects; D013152:Splanchnic Circulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D016232:Endothelins; D014665:Vasodilator Agents; D001120:Arginine; D005996:Nitroglycerin; D000109:Acetylcholine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester