The effect of paroxetine on ouabain-induced toxicity in isolated guinea pig atria.

It has been reported that selective serotonin reuptake inhibitors (SSRIs) possess some cardiac effects. In the present study we have investigated the effect of paroxetine (PX), a potent SSRI agent, on spontaneously as well as ouabain-induced arrhythmia beating isolated guinea-pig atria. The Guinea-pig heart was rapidly removed; the auricles were dissected out in oxygenated modified Krebs solution. The rate and force of spontaneous contractions were recorded isometrically with a photosensitive transducer. PX (1-16 µg/ml) caused a dose-dependent decrease in the rate of contractions (14-70%) and contractile force (8-16%). Ouabain alone (1.2 µg/ml) produced arrhythmia at 7.2 ± 1.5 min and asystole at 20.1 ± 3.1 min. Pretreatment with PX (4 µg/ml) significantly increased the time of arrhythmia onset to 19.8 min. In addition, PX prolonged the duration of action beating from 20.1 ± 3.1 min to 43.1± 2.6 and delayed the occurrence of asystole. The pattern of contractile force by PX + ouabain treatment was more regular than that observed after administration of ouabain alone. The above findings may the probably be due to the inhibition of cardiac Na(+) and Ca(2+) channels or autonomic nervous system. Results also suggest that PX may reduce the membrane conductance through inhibition of ionic channels to prevent ouabain-induced arrhythmia.

Effect of sertraline on ouabain-induced arrhythmia in isolated guinea-pig atria.

BACKGROUND: The effect of sertraline a selective serotonin reuptake inhibitor antidepressant was studied on ouabain-induced toxicity (arrhythmia) in spontaneously beating isolated guinea-pig atria. METHODS: The guinea-pig atrium was dissected out and suspended in modified Krebs solution under physiological conditions. Drugs were added into solutions. The changes in rate and force of contractions were measured using a physiograph. RESULTS: Sertraline (2-16 microg/mL) caused a dose-dependent decrease in the rate of contractions (17-46%) and in the contractile force (26-48%). Ouabain alone (1.2 microg/mL) produced arrhythmia at 7.8 min and asystole at 22 min. Pre- administration of the atria with sertraline (8 microg/mL) significantly increased the time required to produce arrhythmia by ouabain to 20.5 min, prolonged the beating of atria to more than 64.5 min and delayed the occurrence of asystolia. The pattern of contractile force induced by sertraline + ouabain was more regular than that produced by ouabain alone. CONCLUSIONS: These findings indicate that sertraline produces direct cardiac action, probably due to the inhibition of cardiac Na(+) and Ca(2+) channels. Our results suggest that sertraline may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain-induced arrhythmia.

A preliminary study on the interaction of fluvoxamine and adenosine receptor on isolated Guinea-pig atria.

Fluvoxamine (FLV), a selective serotonin reuptake inhibitor (SSRI) antidepressant, caused a dose-dependent decrease in rate and contractile force of the isolated guinea-pig atria. These effects significantly blocked by DPCPX, a specific A(1) receptor antagonist. Theophylline, an A(1)/A(2A) receptor antagonist, also prevented the inotropic and chronotropic effect of FLV. The atrium was dissected out and suspended in modified Krebs solution under physiologic conditions. Drug was added to the solution. The changes in rate and contractions were measured using a physiograph. The data indicate that DPCPX and theophylline prevent the inotropic and chronotropic effects of FLV on atria, but these effects were not prevented by atropine and DMPX, an A(2) receptor antagonist. Adenosine A(1) receptor blockade attenuates FLV effects in isolated guinea-pig atria.

Involvement of adenosine in the effect of fluoxetine on isolated guinea-pig atria.

The effect of fluoxetine (FL) a selective serotonin reuptake inhibitor antidepressant was studied on the rate and force of contractions of isolated guinea-pig atria. FL (2-16 microg/ml) caused a decrease in the rate (13-45%) and contractile force (41-53%) of isolated guinea-pig atria in a dose-dependent manner. These negative inotropic and chronotropic effect of FL (4 microg/ml) were not prevented by atropine (1 microg/ml) and 3,7-dimethyl-1-propargylxanthine (DMPX; 1.5 microg/ml), an adenosine A(2) receptor antagonist, but 1,3-dipropargyl-8-cyclopentylxanthine (DPCPX;12 microg/ml), a specific adenosine A(1) receptor antagonist significantly blocked these effects (P < 0.001) and theophylline (30 microg/ml) a non- selective adenosine A(1)/A(2A) receptor antagonist also prevented the inotropic and chronotropic effects of FL. These results suggest that the negative chronotropic and inotropic effect of FL on isolated guinea-pig atria is probably mediated through an inhibition of the reuptake of adenosine or the A(1) receptor mechanism.

The effect of fluvoxamine on ouabain-induced arrhythmia in isolated guinea-pig atria.

The effect of fluvoxamine (FLV) a selective serotonin reuptake inhibitor agent was studied on ouabain-induced arrhythmia in spontaneously beating isolated guinea-pig atria. FLV (8-64 microM) caused a dose-dependent decrease in the rate of contractions (7-52%) and in the contractile force (11-57%). Ouabain alone (2 microM) produced arrhythmia at 4.6 min and asystole at 17.4 min. Pre-administration of the atria with FLV (32 microM) significantly increased the time required to produce arrhythmia by ouabain to 14.6 min, prolonged the beating of atria to more than 58.6 min and delayed the occurrence of asystolia. The pattern of contractile force induced by FLV+ouabain was more regular than that produced by ouabain alone. These findings indicate that FLV produces direct cardiac action, probably due to the inhibition of cardiac Na+ and Ca2+ channels. Our results suggest that FLV may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain-induced arrhythmia.

Effects of diltiazem or verapamil on calcium uptake and release from chicken skeletal muscle sarcoplasmic reticulum.

The purpose of this study was to determine the effects of 2 Ca2+ channel blockers, verapamil and diltiazem, on calcium loading (active Ca2+ uptake) and the following Ca2+ release induced by silver ion (Ag+) and Ca2+ from the membrane of heavy sarcoplasmic reticulum (SR) of chicken skeletal muscle. A fluorescent probe technique was employed to determine the calcium movement through the SR. Pretreatment of the medium with diltiazem and verapamil resulted in a significant decrease in the active Ca2+ uptake, with IC50 of about 290 micromol/L for verapamil and 260 micromol/L for diltiazem. Inhibition of Ca2+ uptake was not due to the development of a substantial drug-dependent leak of Ca2+ from the SR. It might, in part, have been mediated by a direct inhibitory effect of these drugs on the Ca2+ ATPase activity of the SR Ca2+ pump. We confirmed that Ca2+ channel blockers, administered after SR Ca2+ loading and before induction of Ca2+ release, caused a dose-dependent inhibition of both Ca2+- and Ag+-induced Ca2+ release rate. Moreover, if Ca2+ channel blockers were administered prior to SR Ca2+ loading, in spite of Ca2+ uptake inhibition the same reduction in Ca2+- and Ag+-induced Ca2+ release rate was seen. We showed that the inhibition of Ag+-induced Ca2+ release by L-channel blockers is more sensitive than Ca2+-induced Ca2+ release inhibition, so the IC50 for Ag+- and Ca2+-induced Ca2+ release was about 100 and 310 micromol/L for verapamil and 79 and 330 micromol/L for diltiazem, respectively. Our results support the evidence that Ca2+ channel blockers affect muscle microsome of chicken skeletal muscle by 2 independent mechanisms: first, reduction of Ca2+ uptake rate and Ca2+-ATPase activity inhibition, and second, inhibition of both Ag+- and Ca2+-induced Ca2+ release by Ca2+ release channels. These findings confirm the direct effect of Ca2+ channel blockers on calcium release channels. Our results suggest that even if the SR is incompletely preloaded with Ca2+ because of inhibition of Ca2+ uptake by verapamil and diltiazem, no impairment in Ca2+ release occurs.

Mechanism of inhibitory effect of citalopram on isolated guinea-pig atria in relation to adenosine receptor.

The effect of citalopram (CTP), a selective serotonin reuptake inhibitor antidepressant was studied on the rate and force of contractions of isolated guinea-pig atria. CTP (2-32 microg/ml) caused a dose-dependent decrease in the contractile force (7%-62%) and in the rate of contractions (11%-72%). These negative inotropic and chronotropic effects of CTP (8 microg/ml) were not prevented by atropine (1 microg/ml) and 3,7 dimethyl-1-propargylxanthine (DMPX; 1.5 microg/ml), an adenosine A(2) receptor antagonist, but 1,3 dipropargyl-8-cyclopentylxanthine (DPCPX; 12 microg/ml), a specific adenosine A(1) receptor antagonist significantly blocked these effects (p < 0.001) and theophylline (30 microg/ml) a non-selective adenosine A(1)/A(2A) receptor antagonist also prevented the inotropic and chronotropic effects of CTP. These results suggest that the negative inotropic and chronotropic effect of CTP on isolated guinea-pig atria is probably mediated through an inhibition of the uptake of adenosine or the A(1) receptor mechanism.

Effect of citalopram on ouabain-induced arrhythmia in isolated guinea-pig atria.

The effect of citalopram (CTP) a selective serotonin reuptake inhibitor agent was studied on ouabain-induced arrhythmia in spontaneously beating isolated guinea-pig atria. CTP (2-32 microg/ml) produced a dose-dependent decrease in the force of contractions (7-62%), and in the rate of contractions (11-72%). Pre-administration of the atria with CTP inhibited the ouabain-induced arrhythmia in isolated atria. Ouabain alone (1.2 microg/ml) produced arrhythmia at 4.5 min, and asystole at 20.7 min. Pretreatment with CTP (8 microg/ml) significantly increased the time of onset of arrhythmia to 9.5 min. In addition CTP prolonged the beating of atria (survival time) to more than 56 min, and inhibited the occurrence of asystole. These findings indicate that CTP produces direct cardiac action, probably due to the inhibition of cardiac Na(+) and Ca(2+) channels. Moreover our results suggest that CTP may reduce the membrane conductance through inhibition of ionic channels which decrease ouabain-induced arrhythmia.