Modulation of endothelin-1 effects on rat hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP.
Endothelin-1 (ET-1) has been demonstrated to produce numerous cardiac effects and increased production of the peptide has been shown in cardiac disease states. Although the cardiac effects of ET-1 have been examined extensively on its own, few studies have reported potential cross-talk between ET-1 with other endothelium-derived factors. We examined whether nitric oxide (NO) can modulate the effects of ET-1 on isolated rat hearts or ventricular myocytes. At 0.05 nM, ET-1 produced no effects on either systolic or diastolic function although a two-fold increase in left ventricular end-diastolic pressure (LVEDP) was observed in hearts pretreated with 10 microM of the NO synthase inhibitor L-NAME. Higher concentrations of ET-1 (0.5 and 5 nM) produced a direct elevation in LVEDP which was enhanced by L-NAME and totally blocked by the NO donor S-nitrosoacetylpenicillamine (SNAP, 10 microM) although responses to 5 nM ET-1 were highly variable with no significant differences between treatment groups. SNAP totally prevented ventricular fibrillation produced by either 0.05 or 0.5 nM ET-1 whereas the pro-fibrillatory actions of 5 nM ET-1 were unaffected. In cardiac myocytes, SNAP significantly attenuated the elevation in intracellular Ca2+ produced by ET-1 (5 nM). The positive inotropic actions of ET-1 on either hearts or myocytes were unaffected by any treatment. The protective effect of SNAP against ET-1 in both isolated hearts (reduction in LVEDP and incidence of fibrillation) as well as ventricular myocytes (attenuation of the elevation in intracellular Ca2+) was mimicked by 8-bromo-cyclic GMP (50 microM). Our study suggests that NO protects against the cardiotoxic effects of ET-1, possibly via inhibition of intracellular Ca2+ elevations, a property shared by cGMP, the likely mediator of the biological effects of NO.
Ebihara
Y
Y
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Haist
J V
JV
Karmazyn
M
M
D000818:Animals; D001481:Basal Metabolism; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D006706:Homeostasis; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014693:Ventricular Fibrillation / Q000188:drug therapy
D002316:Cardiotonic Agents; D016232:Endothelins; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D006152:Cyclic GMP; D002118:Calcium