Karnail S. Atwal* and Gary J. Grover Pages 585 - 595 ( 11 )
ATP-sensitive potassium channel (KATP) openers are potent antihypertensive agents due to their peripheral vasodilating properties. Although KATP openers have been shown to be direct cardioprotective agents, they carry a certain degree of liability for their use as cardioprotective agents. Their potent coronary and peripheral vasodilating properties can cause complications such as coronary artery steal and hypotension resulting in underperfusion of the tissue already at risk. Also, cardioprotection is not related to action potential shortening and the development of agents devoid of this activity would be desirable. Recent studies indicate that the beneficial effects of myocardial preconditioning might be mediated via opening of the KATP· Therefore, the opening of KATP might constitute an endogenous protective mechanism used by the heart under ischemic stress. Development of therapeutics to mimic this powerful protective mechanism is an attractive approach for the discovery of myocardial protecting agents. In this review, we describe the progress made towards understanding the cardioprotective properties of ATP openers including the discovery of agents that might offer a higher margin of safety for the treatment of myocardial ischemia with this class of agents. We found distinct structure-activity relationships for the cardioprotective and vasorelaxant potencies of KATP openers. Based on the structure-activity relationship studies, we were able to find cardioprotective KATP openers (BMS- 180448) which, despite being equipotent to the first generation agents (e.g., cromakalim) as cardioprotectants, had lower vasorelaxant potencies. The cardioprotecti ve effects of these selective KATP openers in animal models of myocardial ischemia-reperfusion are also discussed in this review.