Cytochrome P-450 metabolite of arachidonic acid mediates bradykinin-induced negative inotropic effect

R. Rastaldo, N. Paolocci, A. Chiribiri, C. Penna, D. Gattullo, P. Pagliaro

Research output: Contribution to journalArticlepeer-review

Abstract

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 μM) or proadifen (5 μM) abolished the cardiodepression by BK, which was not affected by nitric oxide and cyclooxygenase inhibitors (35 μM NG-nitro-L-arginine methyl ester and 10 μM 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 μl), 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.

Original languageEnglish (US)
Pages (from-to)H2823-H2832
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume280
Issue number6 49-6
DOIs
StatePublished - 2001

Keywords

  • Coronary perfusion pressure
  • Endothelium
  • Epoxyeicosatrienoic acids
  • Left ventricular pressure
  • Myocardial contractility

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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