Endothelial cytochrome P450 contributes to the acetylcholine-induced cardiodepression in isolated rat hearts

• Published in: Acta physiologica Scandinavica 2004-09, Vol.182 (1), p.11-20
• Main Authors: Pagliaro, P., Penna, C., Rastaldo, R., Mancardi, D., Crisafulli, A., Losano, G., Gattullo, D.
• Format: Article
• Language: English
• Subjects: acetylcholine; Acetylcholine - pharmacology; Animals; Biological and medical sciences; Blood Pressure - drug effects; cardiodepression; Cyclooxygenase Inhibitors - pharmacology; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Heart - drug effects; Male; myocardium; Myocardium - enzymology; negative inotropic effect; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide Synthase - antagonists & inhibitors; Octoxynol - pharmacology; Organ Culture Techniques; Perfusion; Rats; Rats, Wistar; Triazoles - pharmacology; Vasodilator Agents - pharmacology; Ventricular Function, Left - drug effects; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0001-6772; 1365-201X
• DOI: 10.1111/j.1365-201X.2004.01339.x

Aims:  Acetylcholine (ACh) is known to reduce the contractility of the heart by acting on myocardial muscarinic M2 receptors. ACh induces also an endothelial‐dependent vasodilatation by causing the release of nitric oxide (NO), prostacyclin and endothelium‐derived hyperpolarizing factors from the vascular endothelium. It has been proposed that ACh elicits a hyperpolarization of the coronary endothelial cells which may be accompanied by the activation of cytochrome P450 (CYP) and the resulting release of epoxyeicosatrienoic acids (EETs). The study aims at investigating whether endothelial CYP is involved in the cardiodepression by ACh. Methods and results:  In isolated rat hearts, cardiodepression by ACh (i.e. 25–30% reduction of developed left ventricular pressure) was partially attenuated either by inhibition of CYP with 1‐aminobenzotriazole (ABT) or by endothelial dysfunction obtained with Triton X‐100. No attenuation of cardiodepression was seen after nitric oxide synthase and cyclooxygenase inhibition by l‐nitro‐arginine methyl ester and indomethacin, respectively. Conclusion:  The results suggest that the negative inotropic effect of ACh depends not only on a direct myocardial effect but also on the endothelial CYP activation.