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The effect of fluvoxamine on ouabain-induced arrhythmia in isolated guinea-pig atria
Pharmacological Research 52 (2005) 151–153
The effect of fluvoxamine on ouabain-induced arrhythmia in isolated guinea-pig atria Abbas Pousti ∗ , Tara Deemyad, Kaveh Brumand, Azam Bakhtiarian Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran Accepted 21 January 2005
Abstract 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 M) caused a dose-dependent decrease in the rate of contractions (7–52%) and in the contractile force (11–57%). Ouabain alone (2 M) produced arrhythmia at 4.6 min and asystole at 17.4 min. Pre-administration of the atria with FLV (32 M) 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. © 2005 Elsevier Ltd. All rights reserved. Keywords: Fluvoxamine; Ouabain; Arrhythmia; Isolated atria
1. Introduction It has been reported that tricyclic antidepressant drugs (TCA), such as imipramine and amitriptyline have a quinidine-like effect on both atrial and ventricular arrhythmia in therapeutic concentration [1,2]. The newer antidepressant compounds, selective serotonin reuptake inhibitor (SSRI) drugs are widely used as antidepressants in treating patients. It is thought that by blocking 5-HT reuptake from nerve terminals and enhancing 5serotonergic transmission which is regarded as primary therapeutic action of these compounds [3]. Recent studies have indicated, however that SSRIs has additional effects that are apparently not related to the inhibition of the neuronal 5-HT reuptake, for example in cardiac and vascular tissue fluoxetine has been reported to block sodium, calcium and potassium channels [4–7]. ∗
Corresponding author. Tel.: +98 216112803; fax: +98 216402569. E-mail address: [email protected] (A. Pousti).
1043-6618/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2005.01.002
In animal study, specially designed to study the cardiac effect of fluvoxamine (FLV), they have found that FLV produced a decrease in heart rate and a related prolongation of the QT-interval. The myocardial contractile force (as measured by left ventricular dp/dt) was decreased slightly by FLV and arrhythmia sporadically at nearly lethal dose [8,9]. In man, FLV also produced a statistically significant slowing of the sinus rate and prolongation the QT interval in relation to the slowing of the heart rate [10]. Although this new antidepressant drug, FLV with high doses has occasionally arrhythmogenic effects, but in our primitive experiments we have found that FLV like fluoxetine and citalopram [11,12] has an antiarrhythmic effect on atria. The primary goal of present study is to elucidate the recently observed important antiarrhythmic activity of this compound in arrhythmia produced by ouabain in isolated guinea-pig atria and discuss the mechanism beyond the phenomenon.
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A. Pousti et al. / Pharmacological Research 52 (2005) 151–153
2. Materials and methods 2.1. Animals Guinea-pig of either sex weighing 450–600 g was anaesthetized by ether and exsanguinated. The heart was rapidly removed; the auricles were dissected from the heart and suspended in a bath containing 50 ml of oxygenated modified Krebs solution at 36–37 ◦ C and pH 7.4. The composition of solution was as follows (mM): NaCl 118.0, KCl 4.7, CaCl2 2.6, MgCl2 1.2, NaH2 PO4 1.0, NaHCO3 25.0, glucose 11.1, EDTA 0.004 and ascorbic acid 0.11. After mounting, the preparation was allowed to stand for 30 min for equilibration. The rate and force of spontaneous contractions were recorded isometrically with a photosensitive transducer on a Beckman RS Dynograph recorder. The diastolic tension on the atrial preparations was adjusted to 0.5 g. Seven atria were used for each experiment. Solutions of drugs were prepared so that a constant volume of 0.5 ml for each dose was added to 50 ml of the bathing fluid [11]. The duration of spontaneous rhythmicity of guinea-pig atrial preparations under our experiments conditions was 25–35 min.
Fig. 2. The mean time of onset of arrhythmia.
2.4. Statistical analysis Results were expressed as mean ± S.E. of seven guineapig atria in each group. Statistical significance was determined by using Student’s t test for paired data. P value <0.05 was considered significant.
2.2. Drugs 3. Results The following drugs ouabain and fluvoxamine were purchased from Sigma. Ouabain and fluvoxamine were prepared in distilled water and pH adjusted to 7.3 ± 0.1. 2.3. Experimental plan Group I: 28 atria were examined after a period of 30 min. FLV was added to the bath in doses 8, 16, 32, and 64 M. Only one dose of FLV was added to each atrium. Group II: seven atria were treated with ouabain (2 M) alone after a period of 30 min. Group III: seven atria pretreated with 32 M of FLV for 10 min. Ouabain (2 M) was then added to the bath in the presence of FLV.
Fig. 1. The effect fluvoxamine (8, 16, 32 and 64 M) on guinea-pig isolated atria. Results are mean ± S.E.
Fluvoxamine at a concentration of 8–64 M (n = 28) caused a significant decrease in heart rate (7–52%) and contractile force (11–57%) of the isolated guinea-pig atria in a dose-dependent manner (P < 0.001, Fig. 1). The baseline of the heart rate and length of contractile force of isolated atria before adding the drugs (as a control) were 242 ± 3 min−1 and 14.6 ± 1 mm−1 , respectively. Ouabain alone (2 M) produced arrhythmia after 4.6 min and asystole at 17.4 min (Figs. 2 and 3). Pretreatment with FLV (32 M, n = 7) significantly increased the onset of arrhythmia to 14.6 min (P < 0.001, Fig. 2) and asystole occurred at 58.6 min (P < 0.001, Fig. 3). The pattern of contractile force by FLV + ouabain was more regular than by ouabain alone.
Fig. 3. The mean time of complete atrial block.
A. Pousti et al. / Pharmacological Research 52 (2005) 151–153
4. Discussion In guinea-pig atria in vitro, fluvoxamine (FLV) produced a significant decrease in the rate and force of contractions (P < 0.001). The observed effects were dose-dependent. These effects are similar to those of citalopram (CIT) and fluoxetine (FL) [11,12], suggesting that FLV like other SSRI compounds may inhibit neuronal and cardiac Ca2+ and Na+ channels in addition to the known blockage of the serotonin transporter [13–15]. There are several similarities between these drugs on atria: (1) FLV and two previous drugs have the same effects on contractile force and mean time of asystolia due to ouabain in isolated atria whereas the effects of FLV on the heart rate and duration the onset of arrhythmia due to ouabain were greater than FL and CIT [11,12]. (2) FLV like FL and CIT produced a direct cardiac action probably by inhibiting cardiac Ca2+ and Na+ channels in guinea-pig atria [4,11,13]. The negative inotropic and chronotropic action of FLV in isolated guinea-pig atria were similar to those of observed by other investigators. These authors have also shown FLV produced a decrease in the heart rate and force of contractions in guinea-pig heart [9]. These reports may in part help to explain our results that FLV produces a direct cardiac action probably due to the inhibition of cardiac Ca2+ and Na+ channels in guinea-pig atria. The effect of fluvoxamine on the prevention of ouabaininduced arrhythmia appears to be mediated through the inhibition of ionic current and probably a non-specific effect due to stabilizing action of the membrane as this molecule is lipophilic and bind to the hydrophobic areas of the membranes thus altering the transport [16]. Cardiac glycosides act by inhibition of Na+ –K+ pump. Thus, increasing [Na+ ]i and causing more Ca2+ to enter the cardiac myocytes. Digitalis toxicity appears to be caused by excessive Ca2+ influx into cardiac cells. Both therapeutic and toxic effects of digitalis are due to myocardial Ca2+ loading [17]. FLV through inhibition of Ca2+ and Na+ channels may correct ouabain-induced arrhythmia. Our results suggest that the new generation of antidepressants, FLV may also have antiarrhythmic (class I + IV) as well as proarrhythmic properties [5]. In conclusion the effectiveness of FLV in prevention or delay of ouabain-induced arrhythmia in isolated guinea-pig atria is presumably through a quinidine-like effect on membrane permeability, which corrects the ionic disturbance due to ouabain toxicity.
Acknowledgments This work was supported by the Medical School of Tehran University of Medical Sciences; I.R. Iran. We also thank Sob-
153
han factory in Iran for the generous supply of fluvoxamine powder.
References [1] Bigger T, Giardina E, Perel JM, Kantor S, Glassman A. Cardiac antiarrhythmic effect of imipramine HCl. N Engl J Med 1977;266:206–8. [2] Glassman AH, Bigger T. Cardiovascular effects of therapeutic doses of tricyclic antidepressant. Arch Gen Psychiatry 1981;38: 815–20. [3] Ungvari Z, Pacher P, Kecskemeti V, Koller A. Fluoxetine dilates isolated small cerebral arteries of rats and attenuates constrictions to serotonin, norepinephrine, and a voltage-dependent Ca2+ channel opener. Stroke 1999;30:1949–54. [4] Pacher P, Magyar J, Szigligeti P, Banyasz T, Pankucsi C, Korom Z, et al. Electrophysiological effect of fluoxetine in mammalian cardiac tissues. Naunyn Schmiedeberg’s Arch Pharmacol 2000;361(1): 67–73. [5] Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des 2004;10(20):2463–75. [6] Pacher P, Ungvari Z, Kecskemeti V, Koller A. Serotonin reuptake inhibitor, fluoxetine dilated skeletal muscle arterioles. Possible role of altered Ca2+ sensitivity. Br J Pharmacol 1999;127(3): 740–6. [7] Pacher P, Kecskemeti V, Ungvari Z, Korom S, Pankucsi C. Cardiodepressant effects of fluoxetine in isolated heart preparations. Naunyn-Schmeideberg’s Arch Pharmacol 1998;358(Suppl. 2): R641. [8] Wouters W, Deiman W. Acute cardiac effects of fluvoxamine and other antidepressant in conscious rabbits. Arch Int Pharmacodyn Ther 1983;263:197–207. [9] Roos JC. Cardiac effects of antidepressant drugs. A comparison of the tricyclic antidepressant and fluvoxamine. Br J Clin Pharmacol 1983;15:439S–45S. [10] Robinson JF, Doogan DP. A placebo-controlled cardiotoxicity study of antidepressant drugs fluvoxamine and clovoxamine in human volunteers. Br J Clin Pharmacol 1982;14:805–8. [11] Pousti A, Malihi G, Abdollahi M, Toosi ER. The effect of fluoxetine on ouabain-induced arrhythmia in isolated guinea-pig atria. Indian J Pharmacol 2003;35:55–8. [12] Pousti A, Malihi G, Naghibi B. Effect of citalopram on ouabaininduced arrhythmia in isolated guinea-pig atria. Hum Psychopharmacol Clin Exp 2003;18:121–4. [13] Deak F, Laszoczi B, Pacher P, Petheo GL, Kecskemeti V, Spat A. Inhibition of voltage-gated calcium channel by fluoxetine in rat hippocampal pyramidal cells. Neuropharmacology 2000;39(6):1029– 36. [14] Magyar J, Rusznak Z, Harasztosi C, Kortvely A, Pacher P, Banyasz T, et al. Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues. Int J Mol Med 2003;11(4):535–42. [15] Pacher P, Ungvari Z, Nanasi PP, Frust S, Kecskmeti V. Speculation on difference between tricyclic and selective serotonin reuptake inhibitor antidepressant on their cardiac effects. Is there any? Curr Med Chem 1999;6:469–80. [16] Velasco A, Alamo C, Hervas J, Carvajal A. Effect of fluoxetine hydrochloride and fluvoxamine maleate on different preparations of isolated guinea pig and rat organ tissues. Gen Pharmacol 1997;28(4):509–12. [17] Brenner GM. Pharmacology. 1st ed. USA: W.B. Saunders Co.; 2000 [p. 115].
The effect of fluvoxamine on ouabain-induced arrhythmia in isolated guinea-pig atria Abbas Pousti ∗ , Tara Deemyad, Kaveh Brumand, Azam Bakhtiarian Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran Accepted 21 January 2005
Abstract 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 M) caused a dose-dependent decrease in the rate of contractions (7–52%) and in the contractile force (11–57%). Ouabain alone (2 M) produced arrhythmia at 4.6 min and asystole at 17.4 min. Pre-administration of the atria with FLV (32 M) 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. © 2005 Elsevier Ltd. All rights reserved. Keywords: Fluvoxamine; Ouabain; Arrhythmia; Isolated atria
1. Introduction It has been reported that tricyclic antidepressant drugs (TCA), such as imipramine and amitriptyline have a quinidine-like effect on both atrial and ventricular arrhythmia in therapeutic concentration [1,2]. The newer antidepressant compounds, selective serotonin reuptake inhibitor (SSRI) drugs are widely used as antidepressants in treating patients. It is thought that by blocking 5-HT reuptake from nerve terminals and enhancing 5serotonergic transmission which is regarded as primary therapeutic action of these compounds [3]. Recent studies have indicated, however that SSRIs has additional effects that are apparently not related to the inhibition of the neuronal 5-HT reuptake, for example in cardiac and vascular tissue fluoxetine has been reported to block sodium, calcium and potassium channels [4–7]. ∗
Corresponding author. Tel.: +98 216112803; fax: +98 216402569. E-mail address: [email protected] (A. Pousti).
1043-6618/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2005.01.002
In animal study, specially designed to study the cardiac effect of fluvoxamine (FLV), they have found that FLV produced a decrease in heart rate and a related prolongation of the QT-interval. The myocardial contractile force (as measured by left ventricular dp/dt) was decreased slightly by FLV and arrhythmia sporadically at nearly lethal dose [8,9]. In man, FLV also produced a statistically significant slowing of the sinus rate and prolongation the QT interval in relation to the slowing of the heart rate [10]. Although this new antidepressant drug, FLV with high doses has occasionally arrhythmogenic effects, but in our primitive experiments we have found that FLV like fluoxetine and citalopram [11,12] has an antiarrhythmic effect on atria. The primary goal of present study is to elucidate the recently observed important antiarrhythmic activity of this compound in arrhythmia produced by ouabain in isolated guinea-pig atria and discuss the mechanism beyond the phenomenon.
152
A. Pousti et al. / Pharmacological Research 52 (2005) 151–153
2. Materials and methods 2.1. Animals Guinea-pig of either sex weighing 450–600 g was anaesthetized by ether and exsanguinated. The heart was rapidly removed; the auricles were dissected from the heart and suspended in a bath containing 50 ml of oxygenated modified Krebs solution at 36–37 ◦ C and pH 7.4. The composition of solution was as follows (mM): NaCl 118.0, KCl 4.7, CaCl2 2.6, MgCl2 1.2, NaH2 PO4 1.0, NaHCO3 25.0, glucose 11.1, EDTA 0.004 and ascorbic acid 0.11. After mounting, the preparation was allowed to stand for 30 min for equilibration. The rate and force of spontaneous contractions were recorded isometrically with a photosensitive transducer on a Beckman RS Dynograph recorder. The diastolic tension on the atrial preparations was adjusted to 0.5 g. Seven atria were used for each experiment. Solutions of drugs were prepared so that a constant volume of 0.5 ml for each dose was added to 50 ml of the bathing fluid [11]. The duration of spontaneous rhythmicity of guinea-pig atrial preparations under our experiments conditions was 25–35 min.
Fig. 2. The mean time of onset of arrhythmia.
2.4. Statistical analysis Results were expressed as mean ± S.E. of seven guineapig atria in each group. Statistical significance was determined by using Student’s t test for paired data. P value <0.05 was considered significant.
2.2. Drugs 3. Results The following drugs ouabain and fluvoxamine were purchased from Sigma. Ouabain and fluvoxamine were prepared in distilled water and pH adjusted to 7.3 ± 0.1. 2.3. Experimental plan Group I: 28 atria were examined after a period of 30 min. FLV was added to the bath in doses 8, 16, 32, and 64 M. Only one dose of FLV was added to each atrium. Group II: seven atria were treated with ouabain (2 M) alone after a period of 30 min. Group III: seven atria pretreated with 32 M of FLV for 10 min. Ouabain (2 M) was then added to the bath in the presence of FLV.
Fig. 1. The effect fluvoxamine (8, 16, 32 and 64 M) on guinea-pig isolated atria. Results are mean ± S.E.
Fluvoxamine at a concentration of 8–64 M (n = 28) caused a significant decrease in heart rate (7–52%) and contractile force (11–57%) of the isolated guinea-pig atria in a dose-dependent manner (P < 0.001, Fig. 1). The baseline of the heart rate and length of contractile force of isolated atria before adding the drugs (as a control) were 242 ± 3 min−1 and 14.6 ± 1 mm−1 , respectively. Ouabain alone (2 M) produced arrhythmia after 4.6 min and asystole at 17.4 min (Figs. 2 and 3). Pretreatment with FLV (32 M, n = 7) significantly increased the onset of arrhythmia to 14.6 min (P < 0.001, Fig. 2) and asystole occurred at 58.6 min (P < 0.001, Fig. 3). The pattern of contractile force by FLV + ouabain was more regular than by ouabain alone.
Fig. 3. The mean time of complete atrial block.
A. Pousti et al. / Pharmacological Research 52 (2005) 151–153
4. Discussion In guinea-pig atria in vitro, fluvoxamine (FLV) produced a significant decrease in the rate and force of contractions (P < 0.001). The observed effects were dose-dependent. These effects are similar to those of citalopram (CIT) and fluoxetine (FL) [11,12], suggesting that FLV like other SSRI compounds may inhibit neuronal and cardiac Ca2+ and Na+ channels in addition to the known blockage of the serotonin transporter [13–15]. There are several similarities between these drugs on atria: (1) FLV and two previous drugs have the same effects on contractile force and mean time of asystolia due to ouabain in isolated atria whereas the effects of FLV on the heart rate and duration the onset of arrhythmia due to ouabain were greater than FL and CIT [11,12]. (2) FLV like FL and CIT produced a direct cardiac action probably by inhibiting cardiac Ca2+ and Na+ channels in guinea-pig atria [4,11,13]. The negative inotropic and chronotropic action of FLV in isolated guinea-pig atria were similar to those of observed by other investigators. These authors have also shown FLV produced a decrease in the heart rate and force of contractions in guinea-pig heart [9]. These reports may in part help to explain our results that FLV produces a direct cardiac action probably due to the inhibition of cardiac Ca2+ and Na+ channels in guinea-pig atria. The effect of fluvoxamine on the prevention of ouabaininduced arrhythmia appears to be mediated through the inhibition of ionic current and probably a non-specific effect due to stabilizing action of the membrane as this molecule is lipophilic and bind to the hydrophobic areas of the membranes thus altering the transport [16]. Cardiac glycosides act by inhibition of Na+ –K+ pump. Thus, increasing [Na+ ]i and causing more Ca2+ to enter the cardiac myocytes. Digitalis toxicity appears to be caused by excessive Ca2+ influx into cardiac cells. Both therapeutic and toxic effects of digitalis are due to myocardial Ca2+ loading [17]. FLV through inhibition of Ca2+ and Na+ channels may correct ouabain-induced arrhythmia. Our results suggest that the new generation of antidepressants, FLV may also have antiarrhythmic (class I + IV) as well as proarrhythmic properties [5]. In conclusion the effectiveness of FLV in prevention or delay of ouabain-induced arrhythmia in isolated guinea-pig atria is presumably through a quinidine-like effect on membrane permeability, which corrects the ionic disturbance due to ouabain toxicity.
Acknowledgments This work was supported by the Medical School of Tehran University of Medical Sciences; I.R. Iran. We also thank Sob-
153
han factory in Iran for the generous supply of fluvoxamine powder.
References [1] Bigger T, Giardina E, Perel JM, Kantor S, Glassman A. Cardiac antiarrhythmic effect of imipramine HCl. N Engl J Med 1977;266:206–8. [2] Glassman AH, Bigger T. Cardiovascular effects of therapeutic doses of tricyclic antidepressant. Arch Gen Psychiatry 1981;38: 815–20. [3] Ungvari Z, Pacher P, Kecskemeti V, Koller A. Fluoxetine dilates isolated small cerebral arteries of rats and attenuates constrictions to serotonin, norepinephrine, and a voltage-dependent Ca2+ channel opener. Stroke 1999;30:1949–54. [4] Pacher P, Magyar J, Szigligeti P, Banyasz T, Pankucsi C, Korom Z, et al. Electrophysiological effect of fluoxetine in mammalian cardiac tissues. Naunyn Schmiedeberg’s Arch Pharmacol 2000;361(1): 67–73. [5] Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des 2004;10(20):2463–75. [6] Pacher P, Ungvari Z, Kecskemeti V, Koller A. Serotonin reuptake inhibitor, fluoxetine dilated skeletal muscle arterioles. Possible role of altered Ca2+ sensitivity. Br J Pharmacol 1999;127(3): 740–6. [7] Pacher P, Kecskemeti V, Ungvari Z, Korom S, Pankucsi C. Cardiodepressant effects of fluoxetine in isolated heart preparations. Naunyn-Schmeideberg’s Arch Pharmacol 1998;358(Suppl. 2): R641. [8] Wouters W, Deiman W. Acute cardiac effects of fluvoxamine and other antidepressant in conscious rabbits. Arch Int Pharmacodyn Ther 1983;263:197–207. [9] Roos JC. Cardiac effects of antidepressant drugs. A comparison of the tricyclic antidepressant and fluvoxamine. Br J Clin Pharmacol 1983;15:439S–45S. [10] Robinson JF, Doogan DP. A placebo-controlled cardiotoxicity study of antidepressant drugs fluvoxamine and clovoxamine in human volunteers. Br J Clin Pharmacol 1982;14:805–8. [11] Pousti A, Malihi G, Abdollahi M, Toosi ER. The effect of fluoxetine on ouabain-induced arrhythmia in isolated guinea-pig atria. Indian J Pharmacol 2003;35:55–8. [12] Pousti A, Malihi G, Naghibi B. Effect of citalopram on ouabaininduced arrhythmia in isolated guinea-pig atria. Hum Psychopharmacol Clin Exp 2003;18:121–4. [13] Deak F, Laszoczi B, Pacher P, Petheo GL, Kecskemeti V, Spat A. Inhibition of voltage-gated calcium channel by fluoxetine in rat hippocampal pyramidal cells. Neuropharmacology 2000;39(6):1029– 36. [14] Magyar J, Rusznak Z, Harasztosi C, Kortvely A, Pacher P, Banyasz T, et al. Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues. Int J Mol Med 2003;11(4):535–42. [15] Pacher P, Ungvari Z, Nanasi PP, Frust S, Kecskmeti V. Speculation on difference between tricyclic and selective serotonin reuptake inhibitor antidepressant on their cardiac effects. Is there any? Curr Med Chem 1999;6:469–80. [16] Velasco A, Alamo C, Hervas J, Carvajal A. Effect of fluoxetine hydrochloride and fluvoxamine maleate on different preparations of isolated guinea pig and rat organ tissues. Gen Pharmacol 1997;28(4):509–12. [17] Brenner GM. Pharmacology. 1st ed. USA: W.B. Saunders Co.; 2000 [p. 115].