Influence of Mirtazapine on the Hypotensive Activity of Enalapril and Propranolol in Spontaneously Hypertensive Rats

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1 Doi: /j x Blackwell Publishing Ltd Influence of Mirtazapine on the Hypotensive Activity of Enalapril and Propranolol in Spontaneously Hypertensive Rats Dariusz Andrzejczak, Katarzyna Kocon and Remigiusz Zieba Department of Pharmacodynamics, Medical University of Lódz, Lódz, Poland (Received January 17, 2008; Accepted April 28, 2008) Abstract: Mirtazapine is a noradrenergic and specific serotonergic antidepressant. The influence of the drug on the cardiovascular system has not been definitely determined. Therefore, we made an attempt to evaluate the influence of chronic administration of mirtazapine on the hypotensive action of a single administered dose of propranolol and enalapril in spontaneously hypertensive rats. The animals were divided into eight experimental groups. Mirtazapine (5 and 10 mg/kg) was administered intraperitoneally for 14 days. Twenty-four hours after the last administration of the drug, the rats received a single intraperitoneal dose of hypotensive drugs (propranolol 5 mg/kg or enalapril 10 mg/kg) or 1% solution of methylcellulose. Mirtazapine administered chronically did not affect the hypotensive effect of a single dose of propranolol or enalapril in spontaneously hypertensive rats. It seems that mirtazapine could be a useful drug in patients with depression accompanied by hypertension. Author for correspondence: Dariusz Andrzejczak, Department of Pharmacodynamics, Medical University of Lódz, Muszynskiego 1, PL Lódz, Poland (fax , dandrzejczak@ pharm.am.lodz.pl). Mirtazapine (the 6-aza analogue of mianserin) is a noradrenergic and specific serotonergic antidepressant. The pharmacological action of mirtazapine is characterized by antagonism of presynaptic α 2 -adrenoceptors (autoreceptors and heteroreceptors) and postsynaptic blockade of 5-hydroxytryptamine (HT) 2 and 5-HT 3 receptors. Blockade of α 2 -adrenoceptors enhances noradrenergic and serotonergic neurotransmission [1]. Mirtazapine also has indirect 5-HT 1A receptor agonistic properties [2,3]. The drug has a low affinity for α 1 -adrenoceptors and cholinergic and dopaminergic receptors but a high affinity for central and peripheral histamine H 1 receptors [1]. Contrary to tricyclic antidepressants, mirtazapine is thought to exert little effect on the cardiovascular system. Few data specifically demonstrate that mirtazapine has no clinically significant effects on blood pressure or heart rate [1,4,5]. Thus, mirtazapine may be an alternative drug for patients with depression accompanied by hypertension. However, clear evidence is still lacking. There are also no sufficient data that would indicate the obvious interactions between hypotensive drugs and the new antidepressants (including mirtazapine). Both enalapril and propranolol could be used to treat hypertensive patients, while propranolol could also be used to treat patients with cardiac arrhythmias. Additionally, propranolol has a high lipophilicity, with visible central effects. Therefore, the present study was designed to evaluate the influence of chronic administration of mirtazapine on the hypotensive action of a single administered dose of propranolol and enalapril in spontaneously hypertensive rats. A lack of relevant changes in blood pressure level could be very beneficial in the treatment of depression and hypertension. Enalapril, an angiotensin-converting enzyme inhibitor, reduces the circulating and local levels of angiotensin II and increases the concentration of bradykinin [6]. In addition to its systemic activity, the drug may affect inhibition of the central synthesis of angiotensin II and decrease sympathetic nerve activity. In view of the influence of mirtazapine on central α 2 -adrenoceptors and the enhancement of noradrenergic transmission, an interaction between the drugs seems possible. Propranolol can interact with central 5-HT receptors [7,8], while mirtazapine can also block serotonin receptors; thus, the interaction of these drugs with respect to their effect on arterial blood pressure seems possible. Materials and Methods Materials. The following preparations were used in the experiments: mirtazapine (Organon, Oss, The Netherlands), enalapril maleate (Polfa Warszawa S.A., Warsaw, Poland), propranolol hydrochloride (Polfa Warszawa S.A.) and methylcellulose (Sigma, St. Louis, MO, USA). Mirtazapine, enalapril and propranolol were suspended in a 1% aqueous solution of methylcellulose and administered intraperitoneally in a volume of 1 ml per kg of the animal s body weight. The drug doses were selected on the basis of literature review. The doses of pharmaceutical preparations were as follows: 5 or 10 mg/kg for mirtazapine, 10 mg/kg for enalapril, and 5 mg/kg for propranolol. For experiments associated with its antidepressive effects in rats, mirtazapine was usually administered at a dose of 3, 5, 10 or 20 mg/kg once or twice a day for about 2 weeks [9 11]. Animals. The study was performed on 77 spontaneously hypertensive male rats with initial body weights ranging between g, aged weeks, and which had free access to standard feed and water. The animals were housed in standard plastic cages, five animals per cage, at a constant temperature of 22 and under a 12-hr

2 MIRTAZAPINE AND HYPOTENSIVE DRUGS 451 light:dark cycle. All experiments were carried out between 8 a.m. and 3 p.m. All experimental procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals and were approved by the Local Ethics Committee for the Experiments on Animals (no. 5/LB311/2006). Experimental design. The animals were divided into eight experimental groups (8 11 rats in each group) and randomly allocated to every group. The rats received the following doses of preparations: Group 1 (M5): mirtazapine, 5 mg/kg, intraperitoneally daily rats received a single dose of 1% methylcellulose solution (1 ml/kg, intraperitoneally) (n = 8); Group 2 (M10): mirtazapine, 10 mg/kg, intraperitoneally daily rats received a single dose of 1% methylcellulose solution (1 ml/kg, intraperitoneally) (n = 8); Group 3 (E): 1% methylcellulose solution, 1 ml/kg, intraperitoneally daily for 14 days; 24 hr after the last administration of 1% methylcellulose solution; the rats received a single dose of enalapril (10 mg/kg, intraperitoneally) (n = 10); Group 4 (M5+E): mirtazapine, 5 mg/kg, intraperitoneally daily rats received a single dose of enalapril (10 mg/kg, intraperitoneally) (n = 11); Group 5 (M10+E): mirtazapine, 10 mg/kg, intraperitoneally daily for 14 days; 24 hr after the last administration of mirtazapine, the rats received a single dose of enalapril (10 mg/kg, intraperitoneally) (n = 10); Group 6 (P): 1% methylcellulose solution, 1 ml/kg, intraperitoneally daily for 14 days; 24 hr after the last administration of 1% methylcellulose solution, the rats received a single dose of propranolol (5 mg/kg, intraperitoneally) (n = 10); Group 7 (M5+P): mirtazapine, 5 mg/kg, intraperitoneally daily rats received a single dose of propranolol (5 mg/kg, intraperitoneally) (n = 10); and Group 8 (M10+P): mirtazapine, 10 mg/kg, intraperitoneally daily for 14 days; 24 hr after the last administration of mirtazapine, the rats received a single dose of propranolol (5 mg/kg, intraperitoneally) (n = 10). Blood pressure measurement. Systolic, diastolic and mean arterial blood pressure was measured in conscious rats with a manometer manufactured by Letica (Panlab S.L., Barcelona, Spain), using the tail-cuff method. Before the measurements, the animals were placed inside a warming chamber (about 34 ) for 30 min. The aim of this procedure was to calm the rats and dilate the tail blood vessels. Arterial blood pressure measurements were carried out with the use of a special manometer sleeve containing a pulse detector on the tail. Preliminary arterial blood pressure measurements were carried out in order to select rats with stable blood pressure values. Mirtazapine was administered for 14 days. Twenty-four hours after the last administration of the drug, the rats received a single dose of hypotensive drugs (propranolol or enalapril) or 1% methylcellulose solution. Blood pressure was measured directly before and at 30 and 60 min. after the hypotensive drug or 1% methylcellulose solution was administered. At least three measurements were carried out at each time-point. Statistical analysis. Statistical analysis was performed using the Statistica 5.0 program. The normality of distribution was checked by means of Kolmogorov Smirnov test with Lillieforce correction. The statistical evaluation was performed using anova, and post hoc comparisons were performed by means of the Scheffe test. If the data were not normally distributed, statistical evaluation was performed by using an anova (Kruskal Wallis) and Mann Whitney U test. Differences were considered significant when P < Table 1. Influence of the repeated administration of mirtazapine at doses of 5 and 10 mg/kg and a single administration of enalapril (10 mg/kg) and propranolol (5 mg/kg). Group 0 min. 30 min. 60 min. E ± ± ± 22 P5 345 ± ± ± 15 1 M5+E 348 ± ± ± 28 M10+E 325 ± ± ± 25 M5+P 349 ± ± ± 12 1 M10+P 335 ± ± ± 28 Results Spontaneously hypertensive rats selected for the experiments had initial arterial blood pressure values as follows: systolic pressure 234 ± 12 mmhg; diastolic pressure 138 ± 10 mmhg; and mean pressure 170 ± 9 mmhg. The heart rate values before and after hypotensive drug administration are presented in table 1. Effects of the repeated administration of mirtazapine. Mirtazapine at a dose of 5 mg/kg (M5) administered for 14 days only decreased diastolic blood pressure (119 ± 9 mmhg versus 138 ± 10 mmhg), and at the dose of 10 mg/kg (M10), it only decreased mean blood pressure (158 ± 9 mmhg versus 167 ± 6 mmhg) in comparison with the baseline values. Effects of a single dose of enalapril. In rats receiving methylcellulose for 14 days, enalapril at a single dose of 10 mg/kg (E) significantly decreased systolic, diastolic and mean blood pressure (without a significant change in heart rate) at both 30 and 60 min. after the drug injection. Effects of repeated administration of mirtazapine and a single dose of enalapril. Mirtazapine at doses of 5 or 10 mg/kg, administered for 14 days, did not alter the effects of an acute enalapril dose (M5+E or M10+E) in comparison with the group of rats receiving enalapril alone (E) at both 30 and 60 min. after the drug injection. The results are shown in fig. 1. A single dose of enalapril administered after repeated dosing (14 days) of mirtazapine in doses of 5 and 10 mg/kg did not change heart rate at both 30 and 60 min. after the drug injection (table 1). Effects of a single dose of propranolol. Heart rate (beat per min.) after the drug administration Each parameter is presented as the mean and standard deviation (S.D.). 1 P < 0.05 in comparison with baseline values (0 min.). Group abbreviations are presented in Materials and Methods, Experimental Design. In rats receiving methylcellulose for 14 days, a single dose of propranolol (5 mg/kg) (P) significantly decreased heart rate

3 452 DARIUSZ ANDRZEJCZAK ET AL. Fig. 1. The influence of the repeated administration of mirtazapine at doses of 5 and 10 mg/kg and a single administration of enalapril at a dose of 10 mg/kg on arterial blood pressure in spontaneously hypertensive rats. Each parameter is presented as the mean and standard deviation (S.D.). E, hypertensive rats receiving methylcellulose for 14 days and a single administration of enalapril; M5 + E, hypertensive rats receiving mirtazapine (5 mg/kg) for 14 days and a single administration of enalapril; M10 + E, hypertensive rats receiving mirtazapine (10 mg/kg) for 14 days and a single administration of enalapril. and systolic and mean blood pressure at both 30 and 60 min. after the drug injection in comparison with the baseline value. Effects of repeated administration of mirtazapine and a single dose of propranolol. A single dose of propranolol administered after repeated dosing (14 days) of mirtazapine at a dose of 5 or 10 mg/kg (M5+P or M10+P) caused no significant changes in blood pressure values (systolic, diastolic and mean) in comparison with the group of rats receiving methylcellulose (14 days) and a single dose of propranolol (P) at both 30 and 60 min. after propranolol injection. The results are shown in fig. 2. A single dose of propranolol administered after repeated dosing of mirtazapine significantly decreased heart rate at both 30 and 60 min. (mirtazapine 5 mg/kg) and at 30 min. (mirtazapine 10 mg/kg) after the drug injection (table 1). Fig. 2. The influence of the repeated administration of mirtazapine at doses of 5 and 10 mg/kg and a single administration of propranolol at a dose of 5 mg/kg on arterial blood pressure in spontaneously hypertensive rats. Each parameter is presented as the mean and standard deviation (S.D.). P, hypertensive rats receiving methylcellulose for 14 days and a single administration of propranolol; M5 + P, hypertensive rats receiving mirtazapine (5 mg/kg) for 14 days and a single administration of propranolol, M10 + P, hypertensive rats receiving mirtazapine (10 mg/kg) for 14 days and a single administration of propranolol.

4 MIRTAZAPINE AND HYPOTENSIVE DRUGS 453 Discussion Mirtazapine is effective and well tolerated in the treatment of depression. As a new antidepressant, the drug is characterized by a better safety profile than tricyclic antidepressants. Therefore, it could be used to treat patients with depression and hypertension [12]. No clinically significant changes in blood pressure have been determined in most of the previous studies including clinical trials comparing efficacy of mirtazapine with other antidepressants [1,4,13,14]. In our study in spontaneously hypertensive rats, it was observed that mirtazapine, both at 5 and 10 mg/kg doses, administered for 14 days did not significantly affect arterial blood pressure. Only a slight decrease in diastolic (at the lower dose) and mean blood pressure (at the higher dose) was observed. This slight blood pressure decrease by mirtazapine could be explained by weak α 1 -adrenoceptor antagonist properties. However, De Boer et al. [15] noticed that its affinity for central and peripheral α 1 -adrenergic receptors is about 30 times lower as compared to central presynaptic α 2 - adrenoceptors (autoreceptors). Moreover, the equal affinity of mirtazapine for peripheral α 1 - and α 2 -adrenoceptors may prevent prominent cardiovascular side-effects. Mirtazapine could also affect blood pressure by its interaction with 5-HT receptors, although the results of its effects on serotonin levels could be very complex. It is important to note that the role of serotonergic pathways in the regulation of blood pressure has not been fully elucidated. Depending on the animal species, the serotonin administration site in the central nervous system and the anaesthetic status, either an increase or a decrease in blood pressure can be observed [16 20]. Most of the previous studies have validated the cardiovascular safety of mirtazapine treatment in patients with depression, although drug drug interactions have not been studied systematically. There is scarce literature data concerning the possible interactions of mirtazapine, especially with hypotensive drugs. The most commonly known interaction is antagonism to clonidine, because mirtazapine enhances noradrenergic transmission by its antagonistic effect on α 2 - adrenoceptors [21,22]. The present study has not demonstrated any effect of chronic administration of mirtazapine on the hypotensive action of a single dose of enalapril. This confirms our observations of blood pressure after multiple doses of mirtazapine in spontaneously hypertensive rats. Theoretically, enhancement of noradrenergic transmission by mirtazapine could counteract the effects of an angiotensin-converting enzyme inhibitor on central and peripheral sympathetic function. However, blockade of α 1 -adrenoceptors by mirtazapine could potentiate the hypotensive effect of this drug, although mirtazapine does have a moderate influence on these receptors. Angiotensin-converting enzyme inhibitors are not involved in significant cytochrome P450-mediated interactions with other drugs [23]. Thus, it also appears that no relevant interaction between mirtazapine and enalapril could be found in long-term studies. In our study, mirtazapine administered in multiple doses did not significantly affect the hypotensive activity of a single dose of propranolol. Only a slight, non-significant tendency to lower blood pressure values was observed. Propranolol is a β-adrenoceptor antagonist with a high lipophilicity with central effects that may also be responsible for its hypotensive effect. Klevans et al. [24] have established that propranolol, administered centrally, may cause a decrease in blood pressure, accompanied by attenuation of sympathetic nerve activity. Jones and Tackett [8] have also shown that ventriculocisternal perfusion of propranolol decreases serotonin turnover in adult mongrel dogs. However, in our studies, mirtazapine administration did not significantly change the hypotensive effect of this β-adrenoceptor antagonist. In longterm studies, there may be an interaction between mirtazapine and propranolol in cytochrome P450 enzymes [25,26]. However, Störmer et al. [27] suggest that mirtazapine has a rather low risk for any cytochrome P450 enzyme interactions with other drugs. An important limitation of our study is the lack of long-term antihypertensive treatment. We think that the action of mirtazapine in long-term studies with enalapril and propranolol may not be significantly altered. However, this interaction cannot be excluded in renal or liver failure. In conclusion, mirtazapine did not influence the hypotensive activity of enalapril and propranolol in spontaneously hypertensive rats. 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