CARDIOPROTECTIVE EFFECTS OF THE CYANOGUANIDINE POTASSIUM CHANNEL OPENER P-1075

P-1075 is a cyanoguanidine ATP-sensitive potassium channel opener (K(A TP)) that relaxes smooth muscle and shortens myocardial action potenti al duration (APD) at concentrations in the nanomolar range. Most K(ATP ) openers have antiischemic potencies in the micromolar range. We wish ed to determine if the relatively high cardiac potency of P-1075 could be translated into high antiischemic potency. Isolated rat hearts wer e pretreated with 10-300 nM P-1075 followed by 25-min global ischemia and 30-min reperfusion. Before ischemia, P-1075 had little effect on c ardiac function, although it did increase coronary flow. During ischem ia, P-1075 significantly increased time to contracture in a concentrat ion-dependent manner (EC25 = 57 nM). P-1075 also improved recovery of contractile function significantly and reduced lactate dehydrogenase ( LDH) release during reperfusion (at concentrations greater-than-or-equ al-to 60 nM). Treatment with 75 nM P-1075 both before and after ischem ia did not add to the protective effects observed after preischemic tr eatment. Treatment with P-1075 only during reperfusion was not cardiop rotective. The protective effects of P-1075 were completely abolished by the K(ATP) blocker glyburide (100 nM). In addition, P-1075 relaxed methoxamine-constricted aorta with a higher potency relative to antiis chemic potency. Thus, P-1075 has cardioprotective effects similar to t hat of other reference K(ATP) openers, except that P-1075 is approxima tely 100-fold more potent relative to most other tested K(ATP) openers . These results demonstrate that P-1075 is the first K(ATP) opener tha t protects ischemic myocardium at nanomolar concentrations.