Biomedical subjects

R Sauvé

Publications and source records attributed to R Sauvé.

At least 19 recordsLinked to original sources

PubMed1994

Histamine-evoked Ca2+ oscillations in HeLa cells are sensitive to methylxanthines but insensitive to ryanodine.

The relative contribution of inositol-trisphosphate(InsP3)-sensitive and InsP3-insensitive Ca2+ stores to the agonist-evoked oscillatory release of Ca2+ in HeLa cells was investigated using fura-2 cytosolic Ca2+ measurements and whole-cell recordings of Ca(2+)-activated K+ currents [K(Ca2+)]. The experimental approach chosen consisted in studying the effects on Ca2+ oscillations of a variety of pharmacological agents such as ryanodine, ruthenium red, caffeine and theophylline, which are known to affect the Ca2+ channels responsible for Ca(2+)-induced Ca2+ release (CICR) in excitable cells. The results obtained essentially indicate (a) that neither ryanodine nor ruthenium red affects the generation of periodic K(Ca2+) current pulses in whole-cell experiments, and (b) that histamine-induced Ca2+ oscillations are inhibited by caffeine and theophylline in a dose-dependent manner. However, these methylxanthines were unable, at concentrations ranging from 0.1 mM to 10 mM, either to mobilize Ca2+ from internal stores or to block the initial Ca2+ rise evoked by histamine. In addition, both methylxanthines showed at high concentrations (10-20 mM) a moderate inhibitory action on the production of InsP3 induced by histamine. This effect was not essential to the action of caffeine on the oscillatory release of Ca2+, since an inhibition by caffeine of InsP3-induced Ca2+ oscillations was still observed in whole-cell experiments where the InsP3 concentration was kept constant. The results also show (c) that the application of either caffeine or theophylline during histamine stimulation leads systematically to an increased Ca2+ sequestration in InsP3-sensitive Ca2+ pools, the effect observed with theophylline being stronger than that resulting from the application of caffeine, and finally (d) that the action of caffeine and theophylline is not related to an increase in cAMP concentration since neither forskolin (10-50 microM) nor 8-Br-cAMP (1 mM) caused an inhibition of the InsP3-induced Ca2+ oscillations. It is concluded on the basis of these results that the agonist-evoked Ca2+ oscillations in HeLa cells do not involve directly or indirectly a ryanodine-sensitive Ca(2+)-release channel with CICR properties, but rather arise from a control by Ca2+ of the InsP3 Ca(2+)-release process.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1994

Cardiovascular effects of Buthus martensii (Karsch) scorpion venom.

Buthus martensii (Karsch) (BMK) scorpion envenomation is a common medical problem in China and BMK scorpion has been widely used in traditional Chinese medicine. However, the cardiovascular effects of this venom have not been systematically investigated. In the present study, i.v. BMK venom injection significantly increased the blood pressure in conscious rats in a concentration-dependent manner (ED50 = 59 +/- 12 micrograms/kg). The increase in blood pressure occurred within 1 min of injection of the venom and was sustained for more than 50 min. Heart rate was not changed by the venom in conscious rats. In vitro studies with BMK venom revealed the increase in the force of contraction, without modification of the contraction frequency (within 20 min) of isolated atrial strips. Contractions of isolated arterial strips from aorta, renal and vertebral arteries were also enhanced by BMK venom with a time lag of 8 min between the application of the venom and the initiation of the contraction. Furthermore, BMK venom-induced rises in blood pressure in vivo and increased contraction of isolated vessel strips were inhibited by prazosin and tolazoline, respectively, two alpha 1-adrenergic antagonists. BMK venom alone did not alter intracellular calcium concentrations, [Ca2+]i, in cultured vascular smooth muscle cells and endothelial cells. However, BMK venom significantly increased the metabolism of InsP3 in dispersed cardiac myocytes, indicating a direct effect on cardiac myocytes. These results demonstrate the significant cardiovascular effects of BMK venom, which may be mediated by an alteration in InsP3 in cardiac myocytes but not by [Ca2+]i in vascular smooth muscle cells.

Animals↗

PubMed1994

Analysis of a novel double-barreled anion channel from rat liver rough endoplasmic reticulum.

The presence of anionic channels in stripped rough endoplasmic reticulum membranes isolated from rat hepatocytes was investigated by fusing microsomes from these membranes to a planar lipid bilayer. Several types of anion-selective channels were observed including a voltage-gated Cl- channel, the activity of which appeared in bursts characterized by transitions among three distinct conductance levels of 0 pS (0 level), 160 pS (O1 level), and 320 pS (O2 level), respectively, in 450 mM (cis) 50 mM (trans) KCl conditions. A chi 2 analysis on current records where interburst silent periods were omitted showed that the relative probability of current levels 0 (baseline), O1, and O2 followed a binomial statistic. However, measurements of the conditional probabilities W(level 0 at tau/level O2 at 0) and W(level O2 at tau/level 0 at 0) provided clear evidence of direct transitions between the current levels 0 and O2 without any detectable transitions to the intermediate level O1. It was concluded on the basis of these results that the observed channel was controlled by at least two distinct gating processes, namely 1) a voltage-dependent activation mechanism in which the entire system behaves as two independent monomeric channels of 160 pS with each channel characterized by a simple Open-Closed kinetic, and 2) a slow voltage-dependent process that accounts for both the appearance of silent periods between bursts of channel activity and the transitions between the current levels 0 and O2. Finally, an analysis of the relative probability for the system to be in levels 0, O1, and O2 showed that our results are more compatible with a model in which all the states resulting from the superposition of the two independent monomeric channels have access at different rates to a common inactivated state than with a model where a simple Open-Closed main gate either occludes or exposes simultaneously two independent 160-pS monomers.

Animals↗

PubMed1994

Does halothane interfere with the release, action, or stability of endothelium-derived relaxing factor/nitric oxide?

BACKGROUND: Halothane attenuates endothelium-dependent relaxation. To differentiate halothane's effect on endothelium-derived relaxing factor/nitric oxide (EDRF/NO) production from its effect on nitric oxide action on vascular smooth muscle, halothane's effect on endothelium-dependent relaxation was studied in a bioassay system. METHODS: Indomethacin-treated, bovine aortic endothelial cells (BAEC) grown on microcarrier beads, continuously perfused by oxygenated and carbonated (95% O2, 5% CO2) Krebs-Ringer solution served as nitric oxide donors while an isolated denuded rabbit aortic ring directly superfused by the effluent of the BAEC and precontracted with phenylephrine was used to detect EDRF/NO release. The effect of basal and bradykinin-stimulated EDRF release on the tension of the vascular ring was measured. In the bioassay, it was possible to treat either the vascular denuded ring alone or the vascular ring plus the BAEC with halothane by adding it to the perfusate either upstream or downstream from the BAEC. Halothane (final concentration 2.2%) was added to the perfusate at these two positions, and its effect on the relaxation induced by EDRF/NO was determined. In some experiments, the preparations were treated with hemoglobin or L-monomethyl-L-arginine to attenuate the relaxation induced by the EDRF/NO pathway. Finally, halothane's effect on vascular relaxation induced by an increasing concentration of sodium nitroprusside was measured. Halothane's concentration in the perfusate was determined by gas chromatography using electron capture for anesthetic measurement. RESULTS: EDRF/NO released by the BAEC was responsible for the relaxation of the vascular ring. Halothane added to the perfusate potentiated the tension induced by phenylephrine (7.1 +/- 1.89%) and attenuated the relaxation induced by the release of EDRF/NO. This effect was reversible after discontinuation of halothane. Halothane's effect was present even when the anesthetic was added to the perfusate downstream to the perfusion of the endothelial cells. Halothane had no effect on the vascular relaxation induced by sodium nitroprusside. CONCLUSIONS: The authors' data demonstrate that halothane does not interfere with endothelial cell release of EDRF/NO and its smooth muscle cell relaxation but seems to modify either EDRF/NO half-life or its activated redox form.

Animals↗

PubMed1994

Effects of Buthus martensii Karsch scorpion venom on the release of noradrenaline from in vitro and in vivo rat preparations.

The aim of this study was to test the neuronal effects of the Chinese Buthus martensii Karsch (BMK) scorpion venom in vivo and in vitro in order to understand the mechanism involved in the cardiovascular pressor effect of this venom. In conscious unrestrained rats, administration of 100 micrograms/kg i.v. BMK venom induced an increase in blood pressure, which was associated with a significant increase in plasma noradrenaline. In isolated atria, BMK also induced an increase in the stimulation-induced release of [3H]noradrenaline in a dose-dependent manner. The modulatory effect of agents acting at sympathetic prejunctional adrenoceptors on [3H]noradrenaline release was not altered by BMK venom administration. Finally, it was observed that 100 micrograms/mL BMK venom increased the intracellular calcium concentration in acutely dissociated sympathetic neurons from adult rat superior cervical ganglion. This action appeared to be mainly due to an influx of extracellular calcium. BMK venom induced a small rise in intracellular calcium in the absence of external calcium, indicating that it may also mobilize calcium from intracellular stores. The results observed in this study suggest that BMK venom may induce pressor responses by releasing noradrenaline from the sympathetic nerve terminals and that activation of neuronal calcium channels may be involved in that process.

Animals↗

PubMed1993

The vasorelaxant effect of deuterium oxide is secondary to calcium-induced liberation of nitric oxide by endothelial cells.

OBJECTIVE: To test the hypothesis that deuterium oxide (D2O) might induce endothelium-dependent and nitric oxide-mediated vasodilation by altering intracellular calcium concentration ([Ca2+]i) in vascular endothelial cells. DESIGN: The endothelium-dependent and nitric oxide-mediated regulation of vascular tone by D2O was first examined in perfused rat mesenteric arterial beds. Direct effects of D2O on [Ca2+]i in cultured vascular endothelial cells were then examined in order to elucidate a cellular mechanism for D2O-induced vasodilation. METHODS: Vascular reactivity was assayed by measuring the perfusion pressure of isolated rat mesenteric arterial beds. [Ca2+]i in cultured bovine and rat vascular endothelial cells was measured with the fura-2 fluorescence technique. RESULTS: D2O relaxed precontracted rat mesenteric arterial beds with an intact endothelium. This effect of D2O was either inhibited by N omega-nitro-L- arginine (a nitric oxide synthase inhibitor) or eliminated by the removal of endothelium. In cultured bovine aortic, rat aortic, and rat tail artery endothelial cells, D2O induced a biphasic increase in [Ca2+]i, with a characteristic initial transient increase followed by various patterns of sustained [Ca2+]i increase. The sustained phase was entirely dependent on the extracellular calcium entry. CONCLUSIONS: A direct effect of D2O on [Ca2+]i in vascular endothelial cells may be responsible for the endothelium-dependent, presumably nitric oxide-mediated, vasodilation induced by D2O in precontracted vessels. From these results new mechanisms can be explored for the antihypertensive effect of D2O and new avenues can be developed to study the functional integrity of the endothelium-dependent regulation of the vascular tone.

Animals↗

PubMed1992

Incorporation into a planar lipid bilayer of K channels from the luminal membrane of rabbit proximal tubule.

The presence of ionic channels at the apical membrane of rabbit proximal tubule cells was investigated by fusion of brush-border membrane vesicles (BBMV) with a planar lipid bilayer (PE/PC, 1:1). The BBMV obtained from native membranes showed poor fusogenic properties. The probability of vesicles fusion with a planar bilayer was, however, enhanced by preincubating the BBMV with liposomes made of azolectin. We report here the presence in BBMV preparations of two K(+)-selective channels of 65 pS and 40 pS, respectively, in asymmetrical 200 parallel 50 mM KCl solutions. The channel of 65 pS appeared highly selective to K+ over Na+ and Cl- ions, while the 40 pS channel discriminated poorly between K+ and Na+ with a permeability ratio PK/PNa = 4. The open probability Po of both channels was found to be voltage-independent within the potential range -60 mV to +60 mV. These K+ channels may be related to channels identified using other methods.

Animals↗

PubMed1992

A patch-clamp study of the Ca2+ mobilization from internal stores in bovine aortic endothelial cells. I. Effects of caffeine on intracellular Ca2+ stores.

The effects of agents known to interfere with Ca2+ release processes of endoplasmic reticulum were investigated in bradykinin (BK)-stimulated bovine aortic endothelial cells (BAE cells), via the activation of Ca(2+)-activated potassium channels [K(Ca2+) channels]. In cell-attached patch experiments, the external application of caffeine (1 mM) caused a brief activation of K(Ca2+) channels in Ca(2+)-free and Ca(2+)-containing external solutions. The application of BK (10 nM) during cell stimulation by caffeine (1-20 mM) invariably led to a drastic channel activation which was maintained during a recording period longer than that observed in caffeine-free conditions. In addition, the cell exposure to caffeine (20 mM) during the BK stimulation enhanced systematically the channel activation process. Since a rapid inhibition of BK-evoked channel activity was also produced by removing caffeine from the bath medium, it is proposed that the sustained single-channel response recorded in the concomitant presence of both agents was due to their synergic action on internal stores and/or the external Ca2+ entry pathway resulting in an increased [Ca2+]i. In addition, the local anesthetic, procaine, depressed the initial BK-induced K(Ca2+) channel activity and completely blocked the secondary phase of the channel activation process related to the external Ca2+ influx into stimulated cells. In contrast, this blocking effect of procaine was not observed on the initial caffeine-elicited channel activity and could not suppress the external Ca(2+)-dependent phase of this channel activation process. Our results confirm the existence of at least two pharmacologically distinct types of Ca(2+)-release from internal stores in BAE cells: an inositol 1,4,5-triphosphate (InsP3)-dependent and a caffeine-induced Ca(2+)-release process.

Animals↗

PubMed1992

A patch-clamp study of the Ca2+ mobilization from internal stores in bovine aortic endothelial cells. II. Effects of thapsigargin on the cellular Ca2+ homeostasis.

Evidence was provided, in the preceding paper (Thuringer & Sauvé, 1992), that the external Ca(2+)-dependent phase of the Ca2+ signals evoked by bradykinin (BK) or caffeine in bovine aortic endothelial cells (BAE), differ in their respective sensitivity to procaine. To examine whether the emptying of the InsP3-sensitive Ca2+ store is the signal for activating the agonist-evoked Ca2+ entry, we have investigated the effects of thapsigargin (TSG), a known inhibitor of the microsomal Ca(2+)-ATPase activity in a variety of cell types, via the activity of calcium-activated potassium channels [K(Ca2+) channels]. In cell-attached experiments, the external application of TSG caused a sustained or oscillatory activation of K(Ca2+) channels depending on both the cells and doses tested. The TSG-evoked channel activity could be reversibly blocked by removing extracellular Ca2+, and strongly decreased by adding 10 mM procaine to the bath medium. In Ca(2+)-free external conditions, TSG did not promote an apparent Ca2+ discharge from internal stores but prevented in a dose- and time-dependent manner the subsequent agonist-evoked channel activity related to the release of internally sequestered Ca2+. These results confirm that TSG and BK release Ca2+ from the same internal stores but with different kinetics. Because the channel response to caffeine was found to be poorly sensitive to procaine, in contrast to that evoked by BK and TSG, it may be concluded that both BK and TSG activate the same Ca2+ entry pathway. Therefore, the emptying of the InsP3-sensitive Ca2+ store is likely to be the main signal for activating the agonist-evoked Ca2+ entry in BAE cells.

Animals↗

PubMed1992

Effect of thapsigargin and caffeine on Ca2+ homeostasis in HeLa cells: implications for histamine-induced Ca2+ oscillations.

Several studies have already established that the stimulation of H1 receptors by exogenous histamine induces intracellular Ca2+ oscillations in HeLa cells. The molecular mechanism underlying this oscillatory process remains, however, unclear. A series of fura-2 experiments was undertaken in which the nature of the Ca2+ pools involved in the histamine-induced Ca2+ oscillations was investigated using the tumour promoter agent thapsigargin (TG) and the Ca(2+)-induced Ca(2+)-release promoter, caffeine. The results obtained indicate first that TG causes a gradual increase in cytosolic Ca2+ without inducing internal Ca2+ oscillations, and second that TG and histamine share common internal Ca2+ storage sites. The latter conclusion was derived from experiments performed in the absence of external Ca2+, where the addition of TG before histamine resulted in a total inhibition of the Ca2+ response linked to H1 receptor stimulation, whereas the addition of histamine before TG decreased by more than 90% the TG-induced Ca2+ release. Finally; TG was found to inhibit irreversibly histamine-induced Ca2+ oscillations when added to the bathing medium during the oscillatory process. The effect of caffeine at concentrations ranging from 1 mM to 10 mM on intracellular Ca2+ homeostasis was also investigated. The results obtained show that caffeine does not affect systematically the internal Ca2+ concentration in resting and TG-stimulated HeLa cells, but increases the Ca2+ sequestration ability of inositol-trisphosphate (InsP3)-related Ca2+ stores.(ABSTRACT TRUNCATED AT 250 WORDS)

Caffeine↗

PubMed1991

Membrane transport models with fast and slow reactions: general analytical solution for a single relaxation.

Membrane transport models are usually expressed on the basis of chemical kinetics. The states of a transporter are related by rate constants, and the time-dependent changes of these states are given by linear differential equations of first order. To calculate the time-dependent transport equation, it is necessary to solve a system of differential equations which does not have a general analytical solution if there are more than five states. Since transport measurements in a complex system rarely provide all the time constants because some of them are too rapid, it is more appropriate to obtain approximate analytical solutions, assuming that there are fast and slow reaction steps. The states of the fast steps are related by equilibrium constants, thus permitting the elimination of their differential equations and leaving only those for the slow steps. With a system having only two slow steps, a single differential equation is obtained and the state equations have a single relaxation. Initial conditions for the slow reactions are determined after the perturbation which redistribute the states related by fast reactions. Current and zero-trans uptake equations are calculated. Curve fitting programs can be used to implement the general procedure and obtain the model parameters.

Animals↗

PubMed1991

Modulation by extracellular pH of bradykinin-evoked activation of Ca(2+)-activated K+ channels in endothelial cells.

We used the patch-clamp technique to investigate, via the activation of Ca(2+)-activated potassium channels [K(Ca2+)channels], the effects of extracellular pH (pHo) on the bradykinin (BK)-stimulated rise in cytosolic Ca2+ concentration in bovine aortic endothelial cells (BAE). In cell-attached experiments, the external application of BK caused a transient activation of the K(Ca2+) channels. Increasing pHo from 7.3 to 9 maintained the channel activity, which was not inhibited by withdrawing the agonist. The channel-activation process could be blocked either by removing external Ca2+ or by depolarizing the cells with a high-K+ external solution. These results indicate that the Ca2+ influx triggered by BK contributes in maintaining the agonist-evoked response in high pHo. Changes in pHo produced a slight increase in the intracellular pH (pHi) measured fluorimetrically with the H+ indicator dye 2',7-bis(carboxyethyl)5(6')-carboxyfluorescein. However, increasing pHi by the external application of NH4Cl at physiological pHo caused a rapid decline and not an increase in the K(Ca2+) channel activity triggered by BK. In fura-2-loaded cells, alkaline pHo had no effect on the time course of the Ca2+ response to BK in external Ca(2+)-free conditions, suggesting that the Ca2+ extrusion process is not affected by pHo. Our results suggest that the BK-evoked Ca2+ influx, which is required to reload internal Ca2+ stores, is controlled by a mechanism depending on extracellular H+.

Animals↗

PubMed1990

Single-channel and Fura-2 analysis of internal Ca2+ oscillations in HeLa cells: contribution of the receptor-evoked Ca2+ influx and effect of internal pH.

Patch-clamp and Fura-2 experiments were performed in order to investigate the calcium oscillations due to H1 receptor stimulation in HeLa cells. The cytosolic calcium fluctuations occurring directly at the plasma membrane inner face were detected by measuring the activity of calcium-dependent potassium channels. This method also allowed measurement of changes in intracellular potential using as indicator the amplitude of the channel current jump. The average internal calcium concentration was obtained from Fura-2 experiments carried out at either the single-cell level or from a small population of cells in monolayer. The results indicate that the internal calcium oscillations in HeLa cells arise from a biphasic process with an initial phase independent of the presence of external calcium. External calcium was found, however, to become essential once the regular oscillatory process has been established. Removing external calcium after this initial phase produced a rapid decay in the burst frequency and eventually a complete abolition of the oscillations. In addition, the calcium oscillations occurring during the external-calcium-dependent phase could be blocked by calcium entry blockers such as Co2+ or La3+, or abolished by perfusing the external medium with a high-K+ solution. Experiments were also performed in which the cell internal pH (pHi) was changed by removing the external bicarbonate or by adding NH4Cl to the bathing solution. The results obtained under these conditions indicate that an increase in internal pH abolishes selectively the appearance of calcium spikes without increasing the basal calcium level, while a cellular acidification maintains or stimulates the calcium oscillatory process. It was also observed that the inhibitory effect of alkaline pH was independent of external calcium, and that calcium oscillations could always be seen at alkaline pH during the initial phase of histamine stimulation. On the basis of these results, it is proposed that the internal calcium oscillations in HeLa cells depend on the release of calcium from internal pools, which are reloaded via a pH-dependent mechanism. Part of the calcium sequestration occurring during the oscillatory process would be carried out, however, by pH-insensitive calcium compartments.

Benzofurans↗

PubMed1990

Hypotonic shock activates a maxi K+ channel in primary cultured proximal tubule cells.

The nature and function of the ionic channels at the apical membrane of primary cultured proximal tubule cells (PT) was investigated by use of the extracellular patch-clamp method. Several types of ionic channels were observed, including a calcium-dependent K+ channel of 206 pS in symmetrical 162 mM KCl activated at depolarizing potentials [maxi K+(Ca2+)]. Whole cell experiments were also carried out that clearly indicated that the PT cells respond to a hypotonic shock by activating electroconductive pathways. This response consisted of an initial hyperpolarization (from -47 to -58 mV, SD = 3, n = 4), followed by a strong depolarization (to -23 mV, SD = 4, n = 4). Furthermore, it was found in cell-attached experiments that the maxi K+(Ca2+) channel becomes activated during the hypotonic challenge. The activation process required external Ca2+, although some residual single-channel activity was measured in the absence of extracellular calcium (n = 3). On the basis of these results, it is concluded that the volume regulation process in PT cells in response to a hypotonic shock involves an influx of calcium from the external medium, which in turn triggers the opening of apical maxi K+(Ca2+) channels.

Animals↗

PubMed1990

Single-channel analysis of the electrical response of bovine aortic endothelial cells to bradykinin stimulation: contribution of a Ca2(+)-dependent K+ channel.

The contribution of Ca2(+)-dependent K+ [K(Ca2+)] channels to the electrical response of cultured bovine aortic endothelial cells following bradykinin stimulation was investigated using the patch-clamp method in the cell-attached configuration. Results indicate (1) that bradykinin activates a voltage-insensitive K(Ca2+) channel of 40 pS in 150 mmol/l KCl through a second messenger mechanism; (2) that the time-course of the K(Ca2+) channel activation process corresponds to the time-dependent changes in cytosolic Ca2+ triggered by bradykinin; and (3) that there is a direct correlation between the cellular hyperpolarization induced by bradykinin and the activation of the K(Ca2+) channels. It is proposed that the hyperpolarization of bovine aortic endothelial cells following bradykinin stimulation is a result of the activation of K(Ca2+) channels, and not of a modification in the gating behaviour of an inward rectifying K+ channel (lk1) that is also observed in these cells. A more negative membrane potential may, in turn, enhance the Ca2+ influx involved in the bradykinin-induced Ca2+ signalling process.

Animals↗

PubMed1988

Intracellular bretylium blocks Na+ and K+ currents in heart cells.

The effects of intracellular and extracellular application of bretylium tosylate on outward potassium current and fast inward Na+ current have been studied in single ventricular cells of chick embryo (18-day-old) using the whole-cell voltage clamp technique. Extracellular superfusion with bretylium (3 x 10(-4) M) decreased the K+ current (IK) whereas the fast INa remained unaffected. Introducing bretylium intracellularly also decreased IK, but rapidly inhibited the fast INa. The addition of 3 x 10(-4) M bretylium to the superfusion medium in the presence of intracellular bretylium further decreased IK and caused the fast inward sodium current (INa) to recover. The decrease of IK by bretylium may account for the antifibrillatory properties of this drug in heart.

Animals↗

PubMed1988

Bethanidine increased Na+ and Ca2+ currents and caused a positive inotropic effect in heart cells.

The effects of bethanidine sulphate, a pharmacological analog of the cardiac antibrillatory drug, bretylium tosylate, were studied on action potentials (APs) and K+, Na+, and Ca2+ currents of single cultured embryonic chick heart cells using the whole-cell current clamp and voltage clamp technique. Extracellular application of bethanidine (3 X 10(-4) M) increased the overshoot and the duration of the APs and greatly decreased the outward K+ current (IK) and potentiated the inward fast Na+ currents (INa) and the inward slow calcium current (ICa). However, intracellular introduction of bethanidine (10(-4) M) blocked INa. In isolated atria of rat, bethanidine increased the force of contraction in a dose-dependent manner. These findings suggest that when applied extracellularly, bethanidine exerts a potentiating effect on the myocardial fast Na+ current and slow Ca2+ current and an inhibitory effect of IK. The positive inotropic effect of bethanidine could be due, at least in part, to an increase of Ca2+ influx via the slow Ca2+ channel and the Na-Ca exchange. It is suggested that the decrease of IK by bethanidine may account for its antifibrillatory action.

Action Potentials↗

PubMed1988

Bethanidine increases one type of potassium current and relaxes aortic muscle.

Using a whole-cell voltage-clamp technique, we identified two time- and voltage-dependent K+ currents: an early outward rectifier and a delayed outward rectifier in single vascular smooth muscle cells of rabbit aorta in culture. About 90% of the single cells tested showed a predominant delayed outward K+ current type. Both K+ currents were decreased by tetraethylammonium. In contrast, bethanidine sulphate (10(-4)M), a pharmacological analog of the cardiac antifibrillatory drug, bretylium tosylate, decreased the early outward K+ current, increased the delayed rectifier K+ current type, and hyperpolarized the resting membrane potential. Bethanidine was found to relax vascular smooth muscle. The vasodilatory effect of bethanidine is associated with the activation of a K+ current that is probably involved in keeping the membrane potential at the resting state, thereby depressing the excitability of the aortic vascular smooth muscle.

Animals↗