Comparative Effects of the Potassium Channel Openers Cromakalim and Pinacidil and the Cromakalim Analog U-89232 on Isolated Vascular and Cardiac Tissue

Abstract

ATP-sensitive potassium (K⁺_Atp) channel openers such as cromakalim and pinacidil exhibit both potent vasodilatory and anti-ischemic properties. U-89232, a cyanoguanidine analog of cromakalim, has recently been found to exhibit myocardial protection during ischemia without altering in vivo hemodynamics. We examined the effects of U-89232, cromakalim and pinacidil in isolated vascular and cardiac tissue and tested whether glyburide, a Katp channel blocker, could antagonize their effects. All three compounds produced concentration-dependent relaxation in isolated vascular segmentswith cromakalim being approximately 100-fold more potent than either pinacidil or U-89232. Glyburide completely antagonized the effects of pinacidil but merely blunted the effects of cromakalim and U-89232. In an isolated rabbit cardiac tissue preparation, U-89232 had little effect on maximum tension in cardiac muscle, whereas cromakalim and pinacidil significantly decreased maximum developed tension in a concentration-dependent manner. Glyburide effectively antagonized the effects of cromakalim and pinacidil in cardiac tissue. These data suggest that U-89232, although chemically related to cromakalim, possesses activity which is not common to known potassium channel openers.

3,5‐Dibenzoyl‐4‐(3‐phenoxyphenyl)‐1,4‐dihydro‐2,6‐dimethylpyridine (DP7) as a new multidrug resistance reverting agent devoid of effects on vascular smooth muscle contractility

“…The antispasmodic activity of K + channel openers, such as cromakalim ( Norman et al , 1994 ), is reduced when extracellular K + concentration is raised; invariably, when the K + gradient across the membrane drops, the effect of K + channel openers disappears (Gurney, 1994; this paper). In contrast to what observed with cromakalim, however, DP7 did not show any antispasmodic activity even when the external K + concentration was kept at a value (30 m M ) which allows K + channel activation to be displayed, nor did it affect muscle contraction caused by intracellular stored Ca 2+ mobilization.…”

Cardioprotection with U 89232 Is Not Reversible with Glibenclamide: Evidence of a Novel Anti-lschemic Agent Derived from Cromakalim

“…In a separate series of studies [23] we have also found higher concentrations of U-89232 can relax precontracted (norepinephrine) vas cular segments from the rabbit mesenteric artery with potency nearly equal to that of pinacidil. In support of the novelty of U-89232, we also found that the concentration of glibenclamide [0.5 |iM] that completely blocks pinacidil-mediated vasodilation does not affect relaxation mediated by U-89232.…”

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

“…Consistent with these findings, myocardial (sarcolemmal) K-ATP channels are regarded to be closed under normal metabolic conditions (84) and thereby relatively insensitive to specific K-ATP blockers such as glyburide (23,25), whereas nonspecific K-channel blockade by tetraethylammonium, 3,4diaminopyridine, and barium increases in vitro myocardial contractility (123). Additionally, the selective vascular K-ATP channel openers pinacidil and cromakalim (85,107,110) reduce myocardial contractility at supra-vasorelaxant concentrations (23,103,123), and this negative inotropy is attenuated by glyburide (82,103). These data and reports thus strongly suggest that the generalized cardiodepression seen with higher doses and concentrations of PNU-37883A cannot be solely and directly attributed to its blockade of cardiac sarcolemmal K-ATP channels.…”