Cytochrome P-450 metabolite of arachidonic acid mediates bradykinin-induced negative inotropic effect.
This study focused on the mechanisms of the negative inotropic response to bradykinin (BK) in isolated rat hearts perfused at constant flow. BK (100 nM) significantly reduced developed left ventricular pressure (LVP) and the maximal derivative of systolic LVP by 20-22%. The cytochrome P-450 (CYP) inhibitors 1-aminobenzotriazole (1 mM and 100 microM) or proadifen (5 microM) abolished the cardiodepression by BK, which was not affected by nitric oxide and cyclooxygenase inhibitors (35 microM NG-nitro-L-arginine methyl ester and 10 microM indomethacin, respectively). The CYP metabolite 14,15-epoxyeicosatrienoic acid (14,15-EET; 50 ng/ml) produced effects similar to those of BK in terms of the reduction in contractility. After the coronary endothelium was made dysfunctional by Triton X-100 (0.5 microl), the BK-induced negative inotropic effect was completely abolished, whereas the 14,15-EET-induced cardiodepression was not affected. In hearts with normal endothelium, after recovery from 14,15-EET effects, BK reduced developed LVP to a 35% greater extent than BK in the control. In conclusion, CYP inhibition or endothelial dysfunction prevents BK from causing cardiodepression, suggesting that, in the rat heart, endothelial CYP products mediate the negative inotropic effect of BK. One of these mediators appears to be 14,15-EET.
Rastaldo
R
R
Dipartimento di Neuroscienze, Sezione di Fisiologia, dell'Università di Torino, 10043 Orbassano, TO, Italy.
Paolocci
N
N
Chiribiri
A
A
Penna
C
C
Gattullo
D
D
Pagliaro
P
P
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017830:Octoxynol / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013618:Tachyphylaxis / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014230:Triazoles; C033020:1-aminobenzotriazole; D016718:Arachidonic Acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D017830:Octoxynol; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D019001:Nitric Oxide Synthase; D015126:8,11,14-Eicosatrienoic Acid; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin