Functional and biochemical evidence for capsaicin-induced neural endothelin release in isolated working rat heart.
In isolated working rat heart, capsaicin elicited a concentration-dependent constriction of coronary arteries accompanied by decline of all cardiac parameters recorded (heart rate, coronary and aortic flow, left ventricular developed pressure, and first derivative of left ventricular developed pressure). The following evidence suggests that capsaicin-induced changes are mediated by endothelin of neural origin: (1) the capsaicin (10 nM)-evoked decrease in coronary flow resulting in deterioration of cardiac functions was mimicked by endothelin (0.1 nM); (2) the selective endothelin ET(A) receptor antagonist, cyclo (D-alpha-aspartyl-L-propyl-D-valyl-L-leucyl-D-tryptophyl) (1 microM), abolished the cardiac effects provoked by capsaicin (10 nM); (3) reduction of extracellular Ca2+ concentration from 2.4 to 1.2 or 0.6 mM inhibited the cardiac effects of capsaicin (10 nM) but not those induced by endothelin (0.1 nM); (4) perfusion of the heart with 0.1% (v/v) Triton X-100 damaged the endothelium and reversed the enhancement of coronary flow evoked by bethanechol (1 microM), decreased the basal flow, but was without effect on capsaicin-induced coronary constriction; (5) in response to capsaicin challenge (10-100 nM), the endothelin concentration measured in coronary effluent by means of radioimmunoassay increased up to sevenfold but remained unchanged in the presence of 0.6 mM Ca2+; (6) no reduction of coronary flow was induced by capsaicin (100 nM) applied to the heart of rats which were desensitised by capsaicin (150 mg/kg). It is concluded that, in the rat heart, capsaicin acting on VR1 capsaicin receptors elicits a release of endothelin from the sensory nerve terminals.
Szolcsanyi
J
J
Department of Pharmacology and Pharmacotherapy, University of Pecs, Hungary. szolcs@apacs.pote.hu
Oroszi
G
G
Nemeth
J
J
Szilvassy
Z
Z
Blasig
I E
IE
Tosaki
A
A
D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D018723:Bethanechol / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects*; D010277:Parasympathomimetics / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000959:Antihypertensive Agents; D016232:Endothelins; D010277:Parasympathomimetics; D010456:Peptides, Cyclic; D018723:Bethanechol; D002211:Capsaicin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)