Molecular Basis, Pharmacology and Physiological Role of Cardiac K_ATP Channels

Abstract

ATP-dependent potassium (K_ATP) channels exist in high density in the sarcolemmal membrane of heart muscle cells. Under normoxic conditions these channels are closed, but they become active when the intracellular ATP level falls. This leads to a shortening of the action potential duration, rendering the heart susceptible for life-threatening arrhythmias. Molecular biology has revealed that K_ATP channels consist of heteromultimers of the inwardly rectifying channel Kir6.2 and the sulfonylurea receptor SUR. To date, three types of SURs were identified, representing the pancreatic (SUR1), the cardiac (SUR2A) and the smooth muscle (SUR2B) K_ATP channel. In order to develop a novel therapeutic principle against ischemia-induced life-threatening arrhythmias leading to sudden cardiac death, the cardioselective K_ATP channel blocker HMR 1883 was developed. This substance inhibits the sarcolemmal cardiac K_ATP channel activated by the channel opener rilmakalim halfmaximally at concentrations of 0.6–2.2 μmol/l, and substantially affects pancreatic K_ATP channels at 9–50 times higher concentrations. K_ATP channels of the coronary vascular system are only slightly blocked by HMR 1883 when activated by hypoxia. The substance was potently effective in preventing ventricular fibrillation in a conscious dog model, and thus can be considered to be a potential novel drug candidate against sudden cardiac death.

Nucleotide-gated KATPchannels integrated with creatine and adenylate kinases: Amplification, tuning and sensing of energetic signals in the compartmentalized cellular environment

“…It is conceivable that fast rate changes in bulk nucleotides could not be detected, amplified or transmitted, and thus would be filtered out by slower kinetic processes. Although K ATP channels can respond to oscillations in cellular metabolism [2], lack of detectable K ATP channel-dependent contribution to action potential duration in normal heart [49,50,54] indicates that the intracellular signal transmission system apparently does not communicate to the channel site brief changes in ATP levels during the cardiac contractile cycle [55]. Thus, at high diffusional limitations, the characteristic time of the response to a cytosolic signal should exceed the cardiac contractile cycle itself.…”

Effects of a Novel Cardioselective ATP-Sensitive Potassium Channel Antagonist, 1-[[5-[2-(5-Chloro-o-anisamido)ethyl]-β-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, Sodium Salt (HMR 1402), on Susceptibility to Ventricular Fibrillation Induced by Myocardial Ischemia: In Vitro and in Vivo Studies

“…Because the K ATP channels are only activated when intracellular ATP levels fall (Deutsch et al, 1991;Edwards and Weston, 1993), as during ischemia, drugs that block this channel would have minimal effects on the nonischemic myocardium, and therefore should be free of the proarrhythmic effects noted for many antiarrhythmic drugs. However, K ATP channels are not located exclusively in the heart (Gribble et al, 1998;Gögelein et al, 1999;Gögelein, 2001). Indeed, glibenclamide blocks both pancreatic K ATP channels and coronary vascular smooth muscle K ATP channels, thereby promoting insulin release and hypoglycemia as well as reducing coronary perfusion (Gögelein et al, 1999;Gögelein, 2001), respectively.…”

“…However, K ATP channels are not located exclusively in the heart (Gribble et al, 1998;Gögelein et al, 1999;Gögelein, 2001). Indeed, glibenclamide blocks both pancreatic K ATP channels and coronary vascular smooth muscle K ATP channels, thereby promoting insulin release and hypoglycemia as well as reducing coronary perfusion (Gögelein et al, 1999;Gögelein, 2001), respectively. These noncardiac actions would limit the antiarrhythmic potential of glibenclamide in the clinic.…”

“…The ATP-sensitive potassium channel consists of a pore-forming subunit coupled to a sulfonylurea receptor (Inagaki et al, 1995;Gögelein et al, 1999;Gögelein, 2001). The functional channel forms as a heterooctomer composed of a tetramer of the pore and four sulfonyl receptor subunits.…”

“…At present, two different pore-forming subunits have been identified, both of which produce an inward rectifier potassium current (Kir 6.1 and Kir 6.2; Liu et al, 2001). Three different sulfonylurea receptor subtypes have been isolated: SUR1 (on pancreatic islet cells), SUR2A (on cardiac tissue), and SUR2B (on vascular smooth muscle) (Gribble et al, 1998;Gögelein et al, 1999;Gögelein, 2001). Thus, six different potassium channel pore and sulfonylurea receptor combinations are possible.…”