INOTROPIC AND CORONARY VASODILATORY ACTIONS OF THE K-ADENOSINE TRIPHOSPHATE CHANNEL MODULATOR NICORANDIL IN HUMAN TISSUE

The present study aimed to characterize the inotropic and vasodilatory properties of the K-ATP channel opener nicorandil (NIC) in isolated h uman cardiac tissue. For comparison, the Ca++ channel blockers diltiaz em (DIL) and nifedipine (NIF) have been studied. Concentration-depende nt effects of NIC, DIL and NIF on the force of contraction (FOG) and t he vascular tone have been studied on left ventricular papillary muscl e strips (dilated cardiomyopathy, New York Heart Association Class IV, n = 20; nonfailing, donor hearts, n = 4), on right auricular trabecul ae (nonfailing, n = 5) and on precontracted (prostaglandin F-2 alpha:0 .3, 0.5 or 1 mu mol/l) isolated human coronary artery rings (cardiac t ransplantation, n = 15). NIC, DIL and NIF concentration-dependently re duced the FOC of the papillary muscle preparations. However, the IC25 for the negative inotropic effect was significantly higher for NIC com pared to DIL and NIF. The maximal negative inotropic effects of NIC, D IL and NIF (100 mu mol/l) were -48.2 +/- 4.1, -92.9 +/- 0.9 and -93.4 +/- 1.4% of the basal FOC. The negative inotropic actions of NIC were similar in the human failing and the nonfailing ventricular and in the right atrial myocardium. Whereas pretreatment with methylene blue, an inhibitor of guanylyl cyclase, had no effect on the negative inotropi c action of NIC, it was almost abolished by glibenclamide, a selective antagonist of the ATP-dependent K channels. NIC, DIL and NIF relaxed the coronary artery rings with 97.1 +/- 0.5, 90.7 +/- 0.9 and 96.4 +/- 0.7% of maximal relaxation (papaverine, 100 mu mol/l). The rank order of vasodilatory potency was NIF > NIC > DIL. In conclusion, NIC is as effective as DIL and NIF in relaxing human coronary artery rings. How ever, NIC showed significantly lower negative inotropic effects when c ompared with the Ca++ channel antagonists. The negative inotropic acti on of NIC is probably due to an interaction with the ATP-dependent K c hannels. In addition, activation of guanylyl cyclase does not seem to exert any negative inotropic action in the human myocardium.