Hyperpolarizing Vasodilators Activate ATP-sensitive K ⁺ Channels in Arterial Smooth Muscle

Abstract

Vasodilators are used clinically for the treatment of hypertension and heart failure. The effects of some vasodilators seem to be mediated by membrane hyperpolarization. The molecular basis of this hyperpolarization has been investigated by examining the properties of single K+ channels in arterial smooth muscle cells. The presence of adenosine triphosphate (ATP)-sensitive K+ channels in these cells was demonstrated at the single channel level. These channels were opened by the hyperpolarizing vasodilator cromakalim and inhibited by the ATP-sensitive K+ channel blocker glibenclamide. Furthermore, in arterial rings the vasorelaxing actions of the drugs diazoxide, cromakalim, and pinacidil and the hyperpolarizing actions of vasoactive intestinal polypeptide and acetylcholine were blocked by inhibitors of the ATP-sensitive K+ channels, suggesting that all these agents may act through a common pathway in smooth muscle by opening ATP-sensitive K+ channels.

The Role of Myocardial KATP‐Channel Blockade in the Protective Effects of Glibenclamide against Ischaemia in the Rat Heart

“…The increases in coronary blood flow during the preischaemic period (normoxia) observed after treatment with the K ATP channel openers pinacidil and diazoxide are in close agreement with previous studies (Standen et al 1989;Richer et al 1990;D'Alonzo et al 1994;Maczewski & Beresewicz 1997). These increases can be explained by relaxation of the vascular smooth muscle cells due to hyperpolarization of the membrane.…”

Effects of lemakalim on changes in Ca2+concentration and mechanical activity induced by noradrenaline in the rabbit mesenteric artery

“…A sulphonylurea, glibenclamide, inhibits the membrane hyperpolarization induced by (± )-cromakalim in smooth muscle cells of the rabbit mesenteric artery (Standen et al, 1989). The effects of cromakalim are stereospecific, the (-)-enantiomer (lemakalim) having a more potent vasodilator action than its racemic form (Buckingham et al, 1986;Hof et al, 1988).…”

Blockade of vascular ATP-sensitive potassium channels reduces the vasodilator response to ischaemia in humans

“…These so-called ATPsensitive potassium (K ATP ) channels were suggested to play a cardioprotective role during ischaemia. Later, K ATP channels were also found in skeletal muscle [2], smooth muscle [3] and pancreatic beta cells [4] from animals. In pancreatic beta cells the K ATP channels mediate insulin secretion [5] and are a target for sulphonylurea derivatives in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) [6].…”