Karnail S. Atwal Pages 227 - 238 ( 12 )
The ATP-sensitive potassium channel (KATP) openers (e.g., Cromakalim) were originally developed for the treatment of hypertension, primarily due to their potent peripheral vasodilating properties. However, the clinical studies have failed to demonstrate any advantage of these compounds over the more established antihypertensive agents. Experimen tal studies have shown that the KATP openers may be effective for the treat ment of a variety of diseases (asthma, urinary incontinence, ischemia etc.) besides hypertension. However, their clinical utility is limited due to lack of tissue selectivity. We have shown that KATP openers have direct cardioprotective properties which do ,!lOt require contribution from vasodilation. However, the first generation agents offer a narrow window of safety for the treatment of myocardial ischemia due to their potent peripheral vasodilating properties which can compromise the tissue already at risk. Our efforts to find cardioprotective KATP openers with a lower degree of vasorelaxant potency relative to the first generation agents have resulted in the identification of a new class of agents (5). Their structure-activity relationships for antiischemic activity and efficacy in vivo are summarized in this review. The structure-activity studies show that an electron withdrawing group at C6 of the benzopyran ring, a gem-dimethyl at C2, a trans-hydroxyl at C3, an sp3 carbon at C3/C4 and an aryl ring attached to the nitrogen of the cyanoguanidine moiety are required for antiischemic activity. The mechanism of action of these compounds appear to involve opening of the KATP as structurally distinct Kdistinct KATP blockers abolish the cardioprotective effects of these compounds. Unlike the first generation compounds (e.g., cromakalim), the more selective KATP openers can be administered iv to observe antiischemic efficacy. The mechanism of antiischemic activity of KATP openers does not appear to involve the sarcolemmal KATP as their antiischemic activity is independent of action potential shortening. Progress at understanding the molecular mechanism of action of KATP openers and opportunities for future research are also discussed in this article.