CARDIOPROTECTIVE EFFECTS OF A NOVEL CALCIUM-ANTAGONIST RELATED TO THESTRUCTURE OF CROMAKALIM

A novel pyranoquinoline analog (BMS-188107) of the ATP-sensitive potas sium channel (K(ATP)) opener cromakalim was previously shown to be dev oid of K(ATP) opening activity in nonischemic myocardium and vascular smooth muscle, but appeared to be a relatively potent calcium antagoni st. This clear differentiation between channels within a structural se ries is a novel finding. With the idea that K(ATP) Openers are often m ore active in ischemic relative to nonischemic myocardium, we determin ed the cardioprotective effects of this agent in isolated rat hearts a nd whether these anti-ischemic effects are abolished by K(ATP) blockad e. Isolated rat hearts were subjected to 25 min of global ischemia and 30 min of reperfusion and the severity of ischemic/reperfusion injury was determined. BMS-1 88107 was given before ischemia at 0.5 to 10 mu M. Pretreatment (before ischemia) with BMS-188107 caused significant c ardiodepressant activity and increased coronary flow only at a concent ration of 10 muM, although modest negative inotropic effects were obse rved at the 0.5 and 1 muM concentrations. Significant improvements in postischemic contractile function and reductions in lactate dehydrogen ase release were observed with 1 to 10 muM BMS-188107, indicating sign ificant reductions in ischemic/reperfusion injury. Neither the pre- no r the postischemic effects of 1 to 10 muM BMS-188107 were significantl y altered by the K(ATP) blockers socium 5-hydroxydecanoate (100 muM) o r glyburide (1 muM). Previous studies did not determine the effect of BMS-188107 on sodium channels and thus, the effect of this agent on ma ximum upstroke velocity of the action potential was determined. BMS-18 8107 had no significant effects on maximum upstroke velocity or other electrophysiological characteristics of action potentials recorded wit h intracellular microelectrodes in guinea pig papillary muscles, indic ating a lack of effects on sodium channels. To our knowledge, BMS-1881 07 represents the first analog of a K(ATP) opener found to block calci um channels with no apparent activity on K(ATP). The anti-ischemic and electrophysiological profile of activity of this compound is consiste nt with that of a calcium antagonist.