Cromakalim (BRL 34915) restores in vitro the membrane potential of depolarized human skeletal muscle fibres

Spuler, Andreas; Lehmann‐Horn, Frank; Grafe, Peter

doi:10.1007/bf00173587

Cited by 52 publications

(22 citation statements)

References 23 publications

(26 reference statements)

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“…These clinical and laboratory findings suggest the possible involvement of the K ATP channel also in the pathogenesis of human HOPP. This is also supported by the observations that the K + channel openers, cromakalim and pinacidil, are, respectively, capable of repolarizing the skeletal muscle fibers from humans affected by HOPP and restoring the muscle strength in the same patients (18)(19)(20)(21)(22).…”

Section: Introductionsupporting

confidence: 55%

Impairment of skeletal muscle adenosine triphosphate–sensitive K+ channels in patients with hypokalemic periodic paralysis

Tricarico

Servidei²,

Tonali³

et al. 1999

J. Clin. Invest.

100

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The adenosine triphosphate (ATP)-sensitive K + channel (K ATP ) is a metabolically regulated K + channel present in high density in different tissues, including skeletal muscle (1-4). Although in the last few years the role of this type of ion channel in cardiac and pancreatic β cells has been extensively investigated, not much is known about the role of the K ATP channel in the skeletal muscle. A recent report (5) suggested a possible role of this ion channel in muscle disorders related to hypokalemia. For example, we have shown that in the K + -depleted rat (6), in which a chronic hypokalemia was produced by feeding the rats with a K + -free diet, the activity of the sarcolemma K ATP channels is abnormally reduced. In these animals, the in vitro administration of insulin to the muscles abolishes the residual K ATP current and depolarizes the fibers (5). In contrast, in normokalemic rats, the hormone induces stimulation of the sarcolemma K ATP channels and hyperpolarizes the fibers (7,8). Similarly, in humans affected by an inherited muscle disorder known as hypokalemic periodic paralysis (HOPP; ref. 9), insulin produces fiber depolarization and muscle paralysis associated with a fall of the serum K + concentration (from 3.5 to <2 mEq; ref. 9) but produces fiber hyperpolarization in healthy subjects (7,9).Linkage studies have shown that the human HOPP gene maps to chromosome 1q31-32 and is colocalized with the gene encoding the α1 subunit of the skeletal muscle L-type Ca 2+ channel (10-14). Three point mutations were found within the coding sequence of the α1 subunit containing the dihydropyridine (DHP) receptor, resulting in arginine→histidine (R528H, R1239H) and arginine→glycine (R1239G) substitutions (14). However, functional studies have shown that these mutations do not significantly affect the macroscopic L-type Ca 2+ current of myotubes cultured from muscle of patients with HOPP, or the Ca 2+ current carried by channels expressed in the cell line (15-17). It has recently been proposed (17) that factor(s) directly or indirectly related to the DHP mutation play a role in the pathogenesis of HOPP. This poses the question of how the genotype is related to the phenotype of the muscle pathology (16-18). Indeed, although the mutations of the α1 subunit of the Ca 2+ channel have been found in two of three of the patients with HOPP, the link between the mutations of the DHP receptor, the depolarization of the fibers, the characteristic muscle paralysis induced by insulin, and the hypokalemia occurring during the attacks is not yet understood (17, 18). These clinical and laboratory findings suggest the possible involvement of the K ATP channel also in the pathogenesis of human HOPP. This is also supported by the observations that the K + channel openers, cromakalim and pinacidil, are, respectively, capable of repolarizing the skeletal muscle fibers from humans affected by HOPP and restoring the muscle strength in the same patients (18-22). Received for publication July 14, 1998, and accepted in revised form Januar...

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Section: Introductionsupporting

confidence: 55%

Impairment of skeletal muscle adenosine triphosphate–sensitive K+ channels in patients with hypokalemic periodic paralysis

Tricarico

Servidei²,

Tonali³

et al. 1999

J. Clin. Invest.

100

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“…In all neurons tested, neither TEA (n = 3) nor 4-AP (n = 3) nor intracellularly injected CsC1 (n=3) affected the cromakalim-evoked hyperpolarization or resistance decrease. Tolbutamide, a blocker of ATP-sensitive potassium channels in peripheral tissue (Trube et al 1986), has been shown to antagonize the action of cromakalim in skeletal muscle (Spuler et al 1989). Since ATP-sensitive potassium channels have been described in CNS neurons (Ashford et al 1988), we tested the effects of tolbutamide on the action of cromakalim on hippocampal CA3 neurons.…”

Section: Effects Of Potassium-channel Blockers On the Action Of Cromamentioning

confidence: 99%

Effects of cromakalim (BRL 34915) on potassium conductances in CA3 neurons of the guinea-pig hippocampus in vitro

Alzheimer

Sutor

Bruggencate

1989

Naunyn-Schmiedeberg's Arch Pharmacol

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Summary. The action of the potassium channel activator, cromakalim (BRL 34915), on membrane potential, input resistance and current-voltage-relationship of CA3 neurons in a slice preparation of the guinea-pig hippocampus was investigated by means of intracellular recordings. In the presence of tetrodotoxin, cromakalim (30-/00 gmol/1) produced a hyperpolarization up to 4 mV associated with a decrease in input resistance up to 10 MOhms. Determination of the equilibrium potential of the cromakalim action revealed that the hyperpolarization is due to the activation of a potassium conductance. This cromakalim-activated potassium conductance was voltage-dependent, i.e. it increased with hyperpolarization. Among a number of potassium channel blockers tested, only Cs + (2 mmol/1) and Ba 2+ (0.5 retool/l) were able to inhibit the cromakalim-induced effects. Simultaneously, both cations suppressed the hyperpolarizing inward rectification (anomalous rectification) in these neurons, indicating that cromakalim activated or potentiated an inwardly rectifying potassium conductance. In addition, cromakalim slightly enhanced both amplitude and duration of afterhyperpolarizations following single calcium-dependent action potentials, suggesting that cromakalim might have a weak facilitatory effect on calcium-dependent potassium conductances.

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“…In concurrent studies, Spuler et al (1989) (Benton & Haylett, 1990 efflux had become relatively steady) the tissue was transferred, at 2 min intervals, through a series of 15 test tubes. Each contained 5 ml of solution which was gassed via the tubular frame with 100% oxygen to provide mixing.…”

Section: Introductionmentioning

confidence: 99%

Effects of cromakalim on the membrane potassium permeability of frog skeletal muscle in vitro

Benton

Haylett

1992

British J Pharmacology

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1 The effects of the potassium channel opener, cromakalim, and its active enantiomer, lemakalim, have been investigated in frog skeletal muscle.2 Cromakalim (30-300 gM) increased 86Rb efflux from muscles loaded with the isotope, hyperpolarized the fibres and reduced membrane resistance. 3 These effects were inhibited by the sulphonylureas, glibenclamide and tolbutamide. The IC50 for glibenclamide inhibition of 86Rb efflux was ca. 8 nM.4 Phentolamine (300 tiM) (which blocks responses to cromakalim in smooth muscle and inhibits ATP-sensitive K+ channels in pancreatic 3-cells) had no effect on the reduction in membrane resistance caused by 100 1M lemakalim.5 Diazoxide (600 gM) had no effect on 86Rb efflux. 6 The similarities of the K+ channel activated by cromakalim in frog skeletal muscle to the channel acted on in smooth muscle and to the ATP-sensitive K+ channel of ,3-cells are discussed.

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Cromakalim (BRL 34915) restores in vitro the membrane potential of depolarized human skeletal muscle fibres

Cited by 52 publications

References 23 publications

Impairment of skeletal muscle adenosine triphosphate–sensitive K+ channels in patients with hypokalemic periodic paralysis

Impairment of skeletal muscle adenosine triphosphate–sensitive K+ channels in patients with hypokalemic periodic paralysis

Effects of cromakalim (BRL 34915) on potassium conductances in CA3 neurons of the guinea-pig hippocampus in vitro

Effects of cromakalim on the membrane potassium permeability of frog skeletal muscle in vitro

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