Thiorphan enhances bradykinin-induced vascular relaxation in hypoxic/hyperkalaemic porcine coronary artery

Relaxation induced by bradykinin is diminished by hypoxia in epicardial coronary arteries. The bradykinin-degrading enzyme, neutral endopeptidase (NEP, EC.3.4.24.11), is a potential target for coronary artery vasodilators. In this study, we examined the effect of thiorphan, an inhibitor of NEP, on the tone of porcine isolated coronary artery under hypoxic conditions. Endothelium-intact porcine isolated coronary artery rings were isometrically contracted with a prostaglandin F-2alpha, analogue (U46619, 0.75 muM) and potassium chloride (KCl, 30 mm), and relaxed with bradykinin (1-1000 nm) under normoxic (partial pressure of oxygen, Po-2 similar to 90-100 mmHg) and moderately hypoxic (pO(2) similar to 50-60 mmHg) conditions. Experiments were performed to study the effects of 30 min pre-treatment with the NEP-inhibitor, thiorphan (10 muM), both at physiological and at low Po(2)s. Hypoxia inhibited the bradykinin-induced relaxation in porcine epicardial coronary arteries. In normoxia, thiorphan significantly enhanced the decrease of coronary tone produced by bradykinin (1-10 nm) when U46619 was used as contractile agent. Under hypoxic conditions, in U46619 contracture, thiorphan did not influence, but in KCl contracture it enhanced the magnitude of relaxations induced by bradykinin. In the absence of bradykinin, thiorphan had no significant effect on the basal, KCl- and U46619-elevated tones and on the hypoxia-induced decrease of coronary artery tone. Inhibition of NEP-enzyme activity may effectively improve the relaxing capacity of epicardial coronary arteries under hypoxic/hyperkalemic conditions. This effect could be potentially utilized when the endothelial function and relaxation of the coronary arteries are impaired under clinical conditions.