Norepinephrine release and ventricular fibrillation in myocardial ischemia/reperfusion: roles of angiotensin and bradykinin.
Exogenous bradykinin (BK), acting at B2-receptors, enhances norepinephrine (NE) release and exacerbates arrhythmias (VF) in myocardial ischemia/reperfusion. Inhibition of BK formation (with serine proteinase inhibitors) alleviates NE release and VF, whereas prevention of BK degradation (with kininase inhibitors) potentiates them. Yet serine proteinase and kininase inhibitors also prevent the formation of angiotensin (AII), a potent NE-release enhancer. Thus we assessed the respective contribution of AII and BK to NE release and VF by using selective B2- and AT1-receptor antagonists. Isolated guinea pig hearts were subjected to 10- and 20-min global ischemia and 45-min reperfusion. NE overflow (pmol/g) was approximately 8 (exocytotic) and approximately 750 (carrier mediated). VF, associated with carrier-mediated NE release, lasted approximately 2 min. The B2-receptor antagonist Hoe 140 (30 nM) affected neither NE overflow nor VF. In contrast, the AT1-receptor antagonist EXP3174 (100 nM) markedly reduced exocytotic and carrier-mediated NE release and shortened VF. When EXP3174 was combined with Hoe 140, NE overflow and VF were decreased even further. Thus in myocardial ischemia, local AII production contributes to NE release and VF via AT1-receptors. Although BK production increases in myocardial ischemia, the effects of BK on adrenergic nerve terminals are uncovered only when BK half-life is prolonged and/or when AII effects are suppressed.
Maruyama
R
R
Department of Pharmacology, Cornell University Weill Medical College, New York, New York 10021, USA.
Hatta
E
E
Levi
R
R
D057911:Angiotensin Receptor Antagonists; D000809:Angiotensins / Q000502:physiology*; D000818:Animals; D001920:Bradykinin / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D005089:Exocytosis / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D015427:Reperfusion Injury / Q000378:metabolism*; D014693:Ventricular Fibrillation / Q000378:metabolism*
D057911:Angiotensin Receptor Antagonists; D000809:Angiotensins; D065168:Bradykinin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D001920:Bradykinin; D009638:Norepinephrine