The potassium channel activators cromakalim and pinacidil were recently shown to have anti-ischemic properties in isolated globally ischemic rat hearts. The effects of two reported blockers of ATP-sensitive potassium channels, glibenclamide (glyburide) and sodium 5-hydroxydecanoate, on the anti-ischemic efficacy of cromakalim were determined in this model. Buffer-perfused rat hearts were subjected to 25 minutes of ischemia followed by 30 minutes of reperfusion. Pretreatment of these hearts with 60 ,uM cromakalim significantly decreased indexes of contractile function but caused a significant improvement of postreperfusion function and a significant decrease in release of lactate dehydroxygenase and in end-diastolic pressure. Pretreatment with glibenclamide at concentrations that reversed the preischemic effects of cromakalim (0.05 and 1.0 ,M) also significantly reversed its postischemic protective effects. Sodium 5-hydroxydecanoate (100 and 300 ,uM) had no effect on the preischemic (negative inotropic) effects of cromakalim but completely reversed its cardioprotective effects. Sodium 5-hydroxydecanoate did not reverse the cardioprotective effects of the calcium entry blocker diltiazem. In phenylephrine-contracted rat aorta, glibenclamide (0.1-10 pM) inhibited cromakalim-induced relaxation, whereas sodium 5-hydroxydecanoate (10-1,000 JAM) had no effect. Similarly, the ability of cromakalim to shorten cardiac action potential duration in guinea pig papillary muscle and to increase outward whole-cell potassium currents in isolated myocytes was inhibited by glibenclamide, whereas sodium 5-hydroxydecanoate was without effect. Thus, both glibenclamide and sodium 5-hydroxydecanoate inhibited the effects of cromakalim after reperfusion; however, sodium 5 -hydroxydecanoate, unlike glibenclamide, had no effect in nonischemic preparations. These results suggest that sodium 5-hydroxydecanoate is an ischemia-selective inhibitor of ATP-sensitive potassium channels. (Circulation Research 1991;69:949-958 channel mechanism was implicated for the antiischemic effects of these compounds, since their protective actions were reversed by glibenclamide. Recently, sodium 5 -hydroxydecanoate (5 -HD, Figure 1), a proposed class III antiarrhythmic agent, which is structurally unrelated to glibenclamide, has been shown to inhibit cardiac ATP-sensitive potassium channels.10"11 A previous study12 indicated that 5-HD completely reversed the postischemic cardioprotective effects of cromakalim, yet 5-HD did not inhibit the preischemic coronary dilator effects of cromakalim. Glibenclamide completely inhibited both the preischemic coronary dilator effect and the postischemic cardioprotective effects of cromakalim. These preliminary observations led us to believe that 5-HD may possess some degree of ischemia selectivity. The use of coronary flow as an indicator of preischemic activity is imperfect, however, because the negative inotropic effects of cromakalim would complicate the interpretation of the coronary flow data. Therefore, to investigate...
The ATP-sensitive potassium channel (Katp) openers cromakalim (1), pinacidil (2), aprikalim (3), and diazoxide (4) are potent antihypertensive agents acting via peripheral H Diazoxide (4) vasodilation.1 The original excitement about the discovery
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