Inhibition of delayed rectifier K<sup>+</sup>‐current by levcromakalim in single intestinal smooth muscle cells: effects of cations and dependence on K<sup>+</sup>‐flux

McHugh, Damian; Beech, David J.

doi:10.1111/j.1476-5381.1995.tb13239.x

Cited by 15 publications

(13 citation statements)

References 36 publications

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“…On the other hand, they do not beyond all doubts disprove this hypothesis, either. Altogether, the data published on this matter are so far controversial; while Ashcroft et al (1994) studying mouse pancreatic islet cells in the whole-cell configuration could not at all establish inhibition of K v by the K + channel opener, diazoxide, inhibition of K v by levcromakalim was found in our experiments (guinea pig portal vein, single channels in cell-attached patches), in those of Edwards et al (1993;rat portal vein, whole-cell configuration), and in most of the guinea pig intestinal cells studied by McHugh and Beech (1995; whole-cell clamp configuration). In the latter study however, in a number of cells, no inhibition of K v by levcromakalim was observed.…”

Section: Discussioncontrasting

confidence: 61%

“…glibenclamide, Zn 2+ , Ba 2+ , and Rb + , also reversed the effect of levcromakalim on K v . Based on these latter findings, McHugh and Beech (1995) suggested that competition for the same submembraneous reservoir of K + ions might explain the matching of K + membrane currents before and during the presence of the KCO, thereby abandoning the idea of levcromakalim affecting the K v directly or via an intermediate protein.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that the validation of this conversion hypothesis would require one to establish the conductances of single K v and K ATP under comparable conditions (McHugh and Beech 1995), and to observe the interconversion at the single channel level (Henry and Escande 1994); using the patch clamp technique in the cell-attached configuration, we have studied the action of levcromakalim on single K v s in smooth muscle cells from the guinea pig portal vein. It was our aim to investigate whether the conductances of the two channels are similar in size, and to demonstrate the putative conversion of K v into K ATP in the same membrane patches upon addition of the drug.…”

Section: Introductionmentioning

confidence: 99%

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A K+ single channel and whole-cell clamp study on the effects of levcromakalim in guinea pig portal vein cells

Karle

Yao

Kreye

1998

Naunyn-Schmiedeberg's Arch Pharmacol

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Single channel cell-attached patch and whole-cell clamp experiments on the mode of action of the K+ channel opener (KCO), levcromakalim, were performed in guinea pig isolated portal vein cells. At +20 mV (135/23 mM K+ in bath/pipette), 10 microM levcromakalim activated K+ channels with a chord conductance of 23.2 pS (K(KCO)), which were sensitive to the blocker of ATP-dependent K+ channels (K(ATP)), glibenclamide. Voltage steps from -80 mV to +20 mV activated 4-aminopyridine-sensitive K+ channels of 6.5 pS with properties of delayed rectifier K+ channels (Kv). In patches which upon a previous voltage step had revealed the existence of Kv, levcromakalim reduced the open-probability of Kv, but it did not concomitantly activate K(KCO). During the course of the experiments, but unrelated to the presence of levcromakalim, large conductance K+ channels (BK(Ca)) appeared which could be inhibited by iberiotoxin, a selective blocker of BK(Ca), and by the membrane-permeant calcium buffer, BAPTA/AM, but not by glibenclamide. Whole-cell current-voltage (i-V) relations were established in response to voltage ramps from +50 mV to -100 mV; on subtraction of control i-V curves from i-V curves obtained in the presence of 10 microM levcromakalim, the KCO-induced K+ current remained which was proportional to voltage. This is not compatible with the upward-bent curvature predicted by the GHK current equation for purely resistive channels at high [K+]i versus low [K+]o. In conclusion, in the guinea pig portal vein cells, no evidence could be established for the hypotheses that KCOs may act via conversion of Kv to K(ATP) (Beech and Bolton 1989; Edwards et al. 1993) or by activation of BK(Ca) (Balwierczak et al. 1995). In these cells, mild inward rectification of the levcromakalim-induced current was observed which underlines their relationship to K(ATP) in other tissues.

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Section: Discussioncontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A K+ single channel and whole-cell clamp study on the effects of levcromakalim in guinea pig portal vein cells

Karle

Yao

Kreye

1998

Naunyn-Schmiedeberg's Arch Pharmacol

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“…IK v has been characterized in various types of smooth muscle cells, e.g., coronary artery (14), trachea (6,10), portal vein (18) and pulmonary artery smooth muscle cells (19,20,24,27). Delayed rectifier K + channels are pharmacologically blocked by 4-aminopyridine (22), tedisamil (21) and cromakalim (9,15,4). Naturally occurring inhibitors of smooth muscle K v are intracellular Mg 2+ , Ca 2+ (11) and protein kinase C (2).…”

Section: Introductionmentioning

confidence: 99%

Vascular effects of class-III antiarrhythmic drugs: chromanol 293B, but not dofetilide blocks the smooth muscle delayed rectifier K + channel

Karle

Bauer

Weretka

et al. 2002

Basic Research in Cardiology

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Chromanol 293B and dofetilide are inhibitors of IKs and IKr, i.e., of the slow and the rapid component of the delayed rectifier potassium current. The specificity of these drugs was tested by investigating their effects on the delayed rectifier potassium current in vascular smooth muscle, regulating the tone of blood vessels. Using depolarizing step protocols with asymmetrical potassium concentrations (135/4.5 mM K+ in pipette/bath), voltage-dependent K+ currents (IKv) of enzymatically dispersed guinea pig portal vein cells were studied in the whole-cell patch-clamp technique. Peak currents were obtained within 20 ms (at +50 mV) after activation. During a 10 s test pulse to +60 mV, these currents exhibited a relatively fast inactivation with time constants of 384 ms (Tfast) and 4505 ms (Tslow). Dofetilide was totally ineffective in modulating currents; in contrast, after application of chromanol 293B, a steady-state block of IKv developed within 135 s. The block was concentration-dependent with an IC50 of 7.4 microM. Chromanol did not produce any shift in the normalized steady-state activation and inactivation curves and the recovery from inactivation was not significantly changed. Chromanol 293B similarly inhibited delayed rectifier K+ channels whether in their closed or open state, and produced an "apparent" acceleration of inactivation, i.e., the drug accelerated the faster time constant of inactivation during a 10 s test pulse from 384 ms (control) to 149 ms (100 microM chromanol). In recent studies, chromanol was described as a specific blocker of slowly activating delayed rectifier potassium channels (IKs) in cardiomyocytes. The results of this study, however, extend the inhibitory spectrum of the drug and demonstrate block of closed and open state delayed rectifier K+ currents in portal vein vascular smooth muscle. Such a block could possibly contribute to the generation of portal hypertension.

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“…Potassium channel openers relax various gastrointestinal smooth muscles including ileum [7,8], stomach [9,10], and colon [11]. They have also been shown to activate glibenclamide-sensitive K + currents in single cells from colon [11] and ileum [12]. Recently the potassium channel opener cromakalim has been shown to possess antiulcer activity in various experimental gastroduodenal ulcer models [13].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Effects of Nicorandil on Experimentally Induced Gastric Ulcers

Patel¹,

Santani²,

Goswami³

2001

Pharmacology

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The present study was designed to evaluate the effects of a potassium channel opener, nicorandil, and to elucidate its possible mechanism of action in aspirin plus pylorus ligation induced and ethanol-induced gastric ulcers in rats. In an attempt to ascertain the involvement of K_ATP channels in the modulation of gastric ulcers, the effects of nicorandil alone as well as in the presence of the K_ATP channel blocker glibenclamide were studied. Nicorandil and glibenclamide were administered orally at a dose of 2 mg/kg throughout the study. Nicorandil showed significant protection in all the selected models that was evident from a significant reduction in the ulcer index. The results of nicorandil treatment were comparable with those of cimetidine treatment in both models. Glibenclamide was found to inhibit this effect of nicorandil. Further, glibenclamide showed proulcerogenic potential in ethanol and aspirin plus pylorus ligation models. In the aspirin plus pylorus ligation model, nicorandil showed a significant reduction in total acidity, pepsin activity, and protein content and a significant rise in mucin activity. The effect of nicorandil was also studied on gastric mucosal blood flow (GMBF). The GMBF was found to be more increased in the test group than in the control group, indicating enhancement of GMBF by nicorandil. Glibenclamide reversed this effect of nicorandil as well. It is concluded from our study that nicorandil possesses antiulcer activity in the models employed in the present study. This may be attributed to the opening of K_ATP channels, inhibition of acid secretion, enhancement of mucin activity, and improvement in GMBF.

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Inhibition of delayed rectifier K⁺‐current by levcromakalim in single intestinal smooth muscle cells: effects of cations and dependence on K⁺‐flux

Cited by 15 publications

References 36 publications

A K+ single channel and whole-cell clamp study on the effects of levcromakalim in guinea pig portal vein cells

A K+ single channel and whole-cell clamp study on the effects of levcromakalim in guinea pig portal vein cells

Vascular effects of class-III antiarrhythmic drugs: chromanol 293B, but not dofetilide blocks the smooth muscle delayed rectifier K + channel

Evaluation of the Effects of Nicorandil on Experimentally Induced Gastric Ulcers

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Inhibition of delayed rectifier K+‐current by levcromakalim in single intestinal smooth muscle cells: effects of cations and dependence on K+‐flux

Cited by 15 publications

References 36 publications

A K+ single channel and whole-cell clamp study on the effects of levcromakalim in guinea pig portal vein cells

A K+ single channel and whole-cell clamp study on the effects of levcromakalim in guinea pig portal vein cells

Vascular effects of class-III antiarrhythmic drugs: chromanol 293B, but not dofetilide blocks the smooth muscle delayed rectifier K + channel

Evaluation of the Effects of Nicorandil on Experimentally Induced Gastric Ulcers

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Inhibition of delayed rectifier K⁺‐current by levcromakalim in single intestinal smooth muscle cells: effects of cations and dependence on K⁺‐flux