Pharmacology of the K‐ATP Channel Blocking Morpholinoguanidine PNU‐37883A

The last two decades have seen enormous growth in our understanding of ion channel structure and function. In particular, adenosine-5 '-triphosphate-sensitiv e potassium (K-ATP) channels have been intensely investigated because of their wide distribution, key role in linking cellular metabolism to membrane potential, and therapeutic potential of K-ATP modulators (4,14,36,95). Many other reports have further described how K-ATP channels help to control insulin secretion (3,24,96), vascular smooth muscle tone (31,94,109), myocardial contractility and preconditioning (5,32,37,64), and renal tubular function (46, 93,104,118). Common to these many in depth investigations has been an armamentarium of specific channel modulators, such as the K-ATP openers pinacidil, minoxidil sulfate, and cromakalim, and the K-ATP channel blockers glyburide (glibenclamide) and sodium 5-hydroxydecanoate (Fig. 1). Newly added to this arsenal is the morpholinoguanidine PNU-37883A (originally designated U-37883A), which has been shown to functionally antagonize vascular K-ATP channel openers in vitro andin vivo (78) and to block K-ATP channels inXenopusoocyte follicles (41), rat renal tubules (116), vascular smooth muscle (47,122), and central neurons (67). As summarized in this review, PNU-37883A is a potent, euglycemic vascular K-ATP blocker that also exerts a K -sparing diuresis at higher doses. PNU-37883A thus represents a very important new experimental agent for examining K-ATP control of vascular smooth muscle tone, urinary electrolyte excretion, renin secretion, and neuronal function.