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


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.


CONCLUSIONS
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.
Pagliaro
P
P
Dipartimento di Scienze Cliniche e Biologiche dell'Università di Torino, Orbassano (TO), Italy.
Penna
C
C
Rastaldo
R
R
Mancardi
D
D
Crisafulli
A
A
Losano
G
G
Gattullo
D
D
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017830:Octoxynol / Q000494:pharmacology; D009924:Organ Culture Techniques; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D014230:Triazoles; D014665:Vasodilator Agents; C033020:1-aminobenzotriazole; D017830:Octoxynol; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester