Abstract
Abstract: The ATP-sensitive potassium channel (KArP) 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 KArP 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 KArP 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 KArP 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 KArP as structurally distinct 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 KArP openers does not appear to involve the sarcolemmal KArP as their antiischemic activity is independent of action potential shortening. Progress at understanding the molecular mechanism of action of KArP openers and opportunities for future research are also discussed in this article.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
