THE CARDIOPROTECTIVE, VASORELAXANT AND ELECTROPHYSIOLOGICAL PROFILE OF THE LARGE-CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNEL OPENER NS-004

A series of compounds have been reported which open the large conductance calcium activated potassium channel (maxi-K). By utilizing the most potent compound, NS-004 [1-(5-chloro-2-hydroxyphenyl)-5-trifluromethyl-1,3-dihydro-2-benzimidazol-2-one], we studied the role of maxi-K channels in ischemic myocardium. Isolated rat hearts were pretreated with vehicle or NS-004 (6-36 muM). NS-004 caused a concentration-dependent reduction in left ventricular developed pressure and an increase in coronary flow. In global ischemia (25 min), a concentration-dependent increase in time to contracture was found in NS-004 (6-20 muM)-treated hearts (EC25 = 8.6 muM). Neither iberiotoxin (50 nM), a maxi-K blocker, nor glyburide (1 muM), an adenosine triphosphate-sensitive potassium channel blocker, reversed the preischemic or ischemic effects of 20 muM NS-004. NS-004 relaxed phenylephrine- and KCl- contracted rat aortic smooth muscle (IC50 = 9.2 muM). This relaxation was unaffected by 50 and 200 nM iberiotoxin. Whole cell potassium currents in ventricular myocytes demonstrated no significant increases in outward potassium current after treatment with NS-004 (1-20 muM). A small, but significant, increase in outward potassium current was observed with 50 muM NS-004. When peak inward L-type calcium currents were measured in ventricular myocytes, a concentration-dependent inhibition was observed in the presence of NS-004 (1-50 muM). Iberiotoxin (50 nM) did not alter the inhibition of inward calcium current observed in the presence of NS-004. These results indicate that the cardioprotective effects of NS-004 are probably due to blockade of inward calcium current rather than opening of maxi-K channels.