Potassium channel modulators: scientific applications and therapeutic promise

Robertson, David W.; Steinberg, Mitchell I.

doi:10.1021/jm00168a001

Cited by 220 publications

(120 citation statements)

References 20 publications

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“…In guinea-pig isolated trachea, SCA40 was able to inhibit completely the contractions induced by a low concentration of KCI (20mM); in contrast, contractions induced by 80 mM KCI were only partially inhibited by SCA40 (Laurent et al, 1993). Such a pharmacological profile has been described for K+-channel openers (Hamilton et al, 1986;Robertson & Steinberg, 1990). With high K+ concentrations the potassium equilibrium potential is such that the hyperpolarization induced by K+-channel openers is too weak to close voltage-operated Ca2+-channels.…”

Section: Rat Thoracic Aorta Studiesmentioning

confidence: 80%

Cardiovascular effects of SCA40, a novel potassium channel opener, in rats

Michel

Laurent

Bompart

et al. 1993

British J Pharmacology

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1 Experiments have been performed to investigate the cardiovascular actions in the rat of SCA40, a novel potassium channel opener which is a potent relaxant of guinea-pig airway smooth muscle in vivo and in vitro.2 SCA40 (0.01-30 JM) caused a complete and concentration-dependent relaxation of rat isolated thoracic aorta contracted with 20 mM KCI but failed to inhibit completely the spasmogenic effects of 80 mM KCI.3 The ATP-sensitive K'-channel blocker, glibenclamide (3 JAM), failed to antagonize the relaxant action of SCA40 on 20 mM KCl-contracted rat isolated thoracic aorta. 4 SCA40 (0.001-100 JM) had dual effects on rat isolated atria. At low concentrations, SCA40 produced a concentration-dependent decrease in the rate and force of contractions. At higher concentrations (greater than I JM) SCA40 induced concentration-dependent increases of atrial rate and force.5 In vivo, in normotensive Wistar rats, SCA40 elicited a dose-dependent (1-100 fg kg-') decrease in mean arterial pressure which was accompanied by a moderate dose-dependent increase in heart rate. SCA40 (100 tg kg-') had a slightly greater hypotensive effect than cromakalim (100 ig kg-') but the duration of the hypotension was longer with cromakalim than with SCA40. 6 The hypotensive effect of SCA40 was not reduced by propranolol, atropine, NG-nitro-L-arginine methyl ester (L-NAME) or glibenclamide. 7 It is concluded that the mechanism by which SCA40 relaxes vascular smooth muscle in vitro and in vivo involves activation of K+-channels distinct from glibenclamide-sensitive ATP-sensitive K+-channels.

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Section: Rat Thoracic Aorta Studiesmentioning

confidence: 80%

Cardiovascular effects of SCA40, a novel potassium channel opener, in rats

Michel

Laurent

Bompart

et al. 1993

British J Pharmacology

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“…54 " 59 However, there is not a consensus regarding the specific channel type (or types) that are opened by these drugs. Glibenclamide is a specific blocker of K ATP current in ^-pancreatic and cardiac cells 61 -63 ' 74 and is therefore often used as a pharmacological probe to determine if a given PCO acts by activation of K ATP channels.…”

Section: Mechanism Of Action In Smooth Muscle Cellsmentioning

confidence: 99%

Modulation of potassium channels by antiarrhythmic and antihypertensive drugs.

Sanguinetti

1992

Hypertension

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Agents that modulate cardiac and smooth muscle K+ channels have stimulated considerable interest in recent years because of their therapeutic potential in a number of cardiovascular diseases. Foremost among these drugs are the so-called Class III antiarrhythmic agents, which act by prolonging cardiac action potentials, and K+ channel openers, which hyperpolarize and thereby relax smooth muscle cells. Many of the newly developed Class III antiarrhythmic agents probably act by specific block of one subtype of delayed rectifier K+ current, IKr, whereas other agents block more than one type of cardiac K+ current. Much controversy exists over the specific type of K+ channel (or channels) in smooth muscle that are activated by the K+ channel openers. Both groups of K+ channel modulators have great therapeutic promise, but the Class III antiarrhythmic agents may suffer from a side-effect that is directly linked to their specific mechanism of action.

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“…In addition to ATP, channel opening can be inhibited pharmacologically by the application of sulphonylureas such as glibenclamide (Sturgess et al, 1985). Channel opening can be stimulated by ADP (Dunne & Petersen, 1986;Kakei et al, 1986) and pharmacologically by potassium channel openers (KCOs) such as pinacidil (Robertson & Steinberg, 1990). Both sulphonylureas and KCOs have been shown to interact with specific regions of the SUR subunit of the channel (Ashfield et al, 1999;Uhde et al, 1999;Babenko et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of the subtype‐selective inhibition of cloned K_ATP channels by PNU‐37883A

Kovalev

Quayle

Kamishima

et al. 2004

British J Pharmacology

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1 In this study, we have used Kir6.1/Kir6.2 chimeric proteins and current recordings to investigate the molecular basis of PNU-37883A inhibition of cloned K ATP channels. 2 Rat Kir6.1, Kir6.2 and Kir6.1/Kir6.2 chimeras were co-expressed with either SUR2B or SUR1, following RNA injection into Xenopus oocytes, and fractional inhibition of K ATP currents by 10 mM PNU-37883A reported. 3 Channels containing Kir6.1/SUR2B were more sensitive to inhibition by PNU-37883A than those containing Kir6.2/SUR2B (mean fractional inhibition: 0.70, cf. 0.07). 4 On expression with SUR2B, a chimeric channel with the Kir6.1 pore and the Kir6.2 amino-and carboxy-terminal domains was PNU-37883A insensitive (0.06). A chimera with the Kir6.1 carboxyterminus and Kir6.2 amino-terminus and pore was inhibited (0.48). These results, and those obtained with other chimeras, suggest that the C-terminus is an important determinant of PNU-37883A inhibition of Kir6.1. Similar results were seen when constructs were co-expressed with SUR1. Further chimeric constructs localised PNU-37883A sensitivity to an 81 amino-acid residue section in the Kir6.1 carboxy-terminus. 5 Our data show that structural differences between Kir6.1 and Kir6.2 are important in determining sensitivity to PNU-37883A. This compound may prove useful in probing the structural and functional differences between the two channel subtypes.

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Potassium channel modulators: scientific applications and therapeutic promise

Cited by 220 publications

References 20 publications

Cardiovascular effects of SCA40, a novel potassium channel opener, in rats

Cardiovascular effects of SCA40, a novel potassium channel opener, in rats

Modulation of potassium channels by antiarrhythmic and antihypertensive drugs.

Molecular analysis of the subtype‐selective inhibition of cloned K_ATP channels by PNU‐37883A

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Potassium channel modulators: scientific applications and therapeutic promise

Cited by 220 publications

References 20 publications

Cardiovascular effects of SCA40, a novel potassium channel opener, in rats

Cardiovascular effects of SCA40, a novel potassium channel opener, in rats

Modulation of potassium channels by antiarrhythmic and antihypertensive drugs.

Molecular analysis of the subtype‐selective inhibition of cloned KATP channels by PNU‐37883A

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Molecular analysis of the subtype‐selective inhibition of cloned K_ATP channels by PNU‐37883A