S51

DIABETES, VOLUME 45, SUPPLEMENT 1, JANUARY 1996, PAGES S51-S58

Role of Kinins in the Pathophysiology of Myocardial Ischemia

In Vitro and In Vivo Studies

Wolfgang Linz, Gabriele Wiemer, and Bernward A. Scholkens

In ischemia, the heart generates and releases kinins as mediators that seem to have cardioprotective actions. Kinin-generating pathways are present in the heart. Kininogen, kininogenases, kinins, and B₂ kinin receptors can be measured in cardiac tissue. Kinins are released under conditions of ischemia. In anesthetized rats and dogs with coronary artery ligation and in human patients with myocardial infarction, kinin plasma levels are increased. In isolated rat hearts, the outflow of kinins is enhanced during ischemia but markedly attenuated after deendothelialization, pointing to the coronary vascular endothelium as the main possible source. Kinins administered locally exert beneficial cardiac effects. In isolated rat hearts with ischemia-reperfusion injuries, perfusion with bradykinin (BK) reduces the duration and incidence of ventricular fibrillation, improves cardiodynamics, reduces release of cytosolic enzymes, and preserves energyrich phosphates and glycogen stores. In anesthetized animals, intracoronary BK iff followed by comparable beneficial changes and limits infarct size. Inhibition of breakdown of BK and related peptides induces beneficial cardiac effects. Treatment with ACE inhibitors such as ramipril increases cardiac kinin levels and reduces postischemic reperfusion injuries in isolated rat hearts and infarct size in anesthetized animals. The importance of an intact endothelium that continuously generates kinins is supported by observations that basal and ramipril-induced release of kinins and PGI₂ is markedly reduced after deendothelialization of isolated hearts. Blockade of B₂ kinin receptors increases ischemia-induced effects. Endothelial formation of NO and PGI₂ by ACE inhibition iff prevented by the specific B₂ kinin receptor antagonist icatibant. In isolated hearts, ischemia-reperfusion injuries deteriorate with icatibant, which also abolishes the cardioprotective effects of ACE inhibitors and of exogenous BK. Infarct size reduction by ACE inhibitors and by BK in anesthetized animals is reversed by icatibant. Kinins contribute to the cardioprotective effects associated with ischemic preconditioning because preconditioning or BK-induced antiarrhythmic and infarct size-limiting effects are attenuated by icatibant. In conclusion, kinins may act as mediators of endogenous cardioprotective mechanisms. Kinins are generated and released during ischemia, with subsequent formation of PGI2 and NO probably derived mainly from the coronary vascular endothelium. Their cardioprotective profile resembles that of ACE inhibitors. Diabetes 45 (Suppl. 1):S51-S58, 1996

Last updated: 5/30/96
For ADA Related Issues contact CustomerService@diabetes.org
For Technical Issues contact webmaster@diabetes.org