Possible Cardiovascular Adverse Effects Profile of Acute and Chronic AripiprazoleAdministration, in Comparison to Olanzapine, in Male Wistar Rats: Contribution of Serotonin Receptors

Abstract

Second-generation (atypical)antipsychotics have been substantially used in treatment of psychiatric disorders during the past decade. Although the cardiovascular toxicity of conventional antipsychotics is well-established, the cardiovascular profile of members of the atypical class is a subject of investigation. Some drugs, such as olanzapine, pose known metabolic and cardiovascular risk. On the other hand, the ‘newer’ atypical antipsychotic aripiprazole has been shown to have an adverse effect profile comparable to that of placebo.A significant weight gain on administration of aripiprazole was, however, observed in a long-term double-blind controlled trial. Regarding cardiovascular toxicity, several case reports have linked development of hypertension with commencement of aripiprazole therapy. This adverse effect of the drug was observed from as early as the first dose. Moreover, a 24-month study reported significant increase in both systolic and diastolic blood pressures as well as significant mild increase in QTc interval. Earlier reports, however, tend to associate orthostatic hypotension with the use of antipsychotic drugs. This conflict might echo the lack of systematic evaluation of the comparative safety and tolerability of this agent. Aripiprazole is the first atypical antipsychotic with potent partial agonist activity at D2 and 5-HT1A receptors. Efficacy of aripiprazole, as well as its undesirable effects, is attributed, in part, to its effect on serotonergic receptors. These receptors are involved in either modulation of blood pressure or change in cardiac rhythm, or both. Aim of the Work: The aim is to study the cardiovascular adverse effects upon acute graded dosing and chronic administration of aipiprazole, correlating the outcome effect to serotonergic receptors through using a serotonergic blocker (cyproheptadine) and comparing the outcome results to that of chronically administered olanzapine. Study Design: In the present study, 117 Male Wistar rats were used. They were divided into 12 groups: Animal Groups: I. Acute Study: The acute study consisted of 6 groups, 9 animals each: Group 1: Control vehicle-treated animals, Group 2: ARI-treated group with the dose 1 mg/kg i.p., Group 3: ARI-treated group with the dose 3 mg/kg i.p., Group 4: ARI-treated group with the dose 10 mg/kg i.p., Group 5: Cyproheptadine treated group with the dose 10 mg/kg i.p., Group 6: Cyproheptadine pretreated with the dose of 10 mg/kg i.p., followed by ARI with the dose of 10 mg/kg i.p. The outcome measures were: (a) Systolic blood pressure using the tail-cuff technique 60 and 90 minutes after injection for each animal. (b) ECG was done for each animal after anesthesia and QTc interval was calculated. (c) Invasive blood pressure for measurement of systolic, diastolic and mean BP using P23XL (Viggo Spectramed Inc.) pressure transducerstwo hours after injection for each animal. II. Chronic Study: The chronic study consisted of 6 groups, [group (1) consists of 18 animals, while the other groups consist of 9 animals each]. The drugs were administered daily for 21 days i.p. The volume of injected drugs i.p. was 2 - 3.5 mL/kg. All groups received i.p. injections including either drug treatment or vehicle throughout the experiment. Group 1: Control vehicle-treated group (18 animals), divided into 2 sub-groups: (a) 9 animals treated with 2.5% tween 80 i.p.,(b) 9 animals treated with 0.0001% acetic acid i.p., Group2: OLA-treated group with the dose 10 mg/kg i.p., Group 3: ARI-treated group with the dose 6 mg/kg i.p., Group 4: Cyproheptadine treated group with the dose 10 mg/kg i.p., Group 5: Cyproheptadine pretreated group with the dose of 10 mg/kg i.p., followed by OLA with the dose of 10 mg/kg i.p. , Group 6:Cyproheptadine pretreated group with the dose of 10 mg/kg i.p., followed by ARI treated with the dose of 6 mg/kg i.p. The outcome measures were: • Systolic blood pressure using the tail-cuff technique on the days 1, 7, 14 and 21 of the study. • Body weight using 3-digit electronic balance on the days 1, 7, 14 and 21 of the study. • ECG was done for each animal after anesthesia and QTc interval was calculated. • Evaluation of the ex-vivo aortic reactivity using isolated aortic ring which is then assessed for PHE cumulative dose contraction and ACh cumulative dose relaxation for each animal.

The Results Could Be Summarized as Follows: (I) Acute Study Results: (a) Blood Pressure Measurements: There is significant elevation in systolic (non-invasive) BP and in mean (invasive) BPon acute administration of ARI in the dose of 3 mg/kg and 10 mg/kg in male Wistar rats which was more significant with ARI 10 mg/kg and this elevation was reversed by combined administration of CYP with ARI. (b) QTc Interval Measurement: There is a significant prolongation of QTc interval (s) on acute administration of ARI in male Wistar rats. The prolongation was reversed by administration of CYP with ARI. (II) Chronic Study Results: (a) Blood Pressure Measurement: At the end of the 3weeks there was significant increase in the percent change of the systolic (non-invasive) blood pressure in male Wistar rats on chronic administration of OLA (10 mg/kg), ARI (6 mg/kg), combined CYP (10 mg/kg) + OLA (10mg/kg) and combined CYP (10 mg/kg) +ARI (6 mg/kg) in comparison to the control group but the percent of change was less with the CYP+ARI in comparison to CYP+OLA. Also there was insignificant change between OLA and CYP+OLA groups; on the other hand there was a significant difference between ARI and CYP+ARI group which means that the effect of OLA was not reversed with combined administration with CYP while the effect of ARI was partially reversed with combined administration with CYP. (c) Body Weight Measurement: There was a noticeable increase in BW in the ARI, CYP and combined ARI+CYP groups by time through the duration of the experiment. But on comparing the percent of change in body weight to the control group, there insignificant difference from ARI, OLA and CYP+ARI while there was significant increase in the percent change of body weight in the CYP group and significant decrease in the CYP+OLA group. (d) QTcInterval Measurement: There was insignificant prolongation of QTc interval on chronic administration of OLA, ARI, CYP, combined CYP+OLA and combined CYP+ARI in male Wistar rats in comparison to the control group.

(e) Ex-Vivo Aortic Reactivity: There is insignificant effect on Emax of phenylephrine induced contraction of isolated aorta (gm) on chronic administration of OLA (10 mg/kg), ARI (6 mg/kg), CYP (10 mg/kg), combined CYP (10 mg/kg) + OLA (10 mg/kg) and combined CYP (10 mg/kg) + ARI (6 mg/kg) in male Wistar rats. There was a significant decrease in the EC50 and obvious shift to the left in the phenylephrine dose-response curve of the isolated aorta on chronic administration of OLA, ARI and combined CYP+OLA in male Wistar rats in comparison to the control group. While there was a significant increase in the EC50 and obvious shift to the right in the phenylephrine dose-response curve of the isolated aorta on chronic administration of combined CYP+ARI, which shows that the effect of OLA on the EC50 was not reversed by blocking of the 5HT receptors while the effect of ARI was reversed. There was a significant reduction in the percent of ACh induced relaxation after contraction with submaximal dose of phenylephrine of Isolated Aorta on chronic administration of OLA, ARI and combined CYP+OLA in male Wistar rats in comparison to the control group. While combined chronic administration of CYP+ARI showed insignificant reduction in the percent of ACh induced relaxation after contraction with submaximal dose of phenylephrine of Isolated Aorta in comparison to the control group, which shows that the effect of OLA on the percent of relaxation was not reversed by blocking of the 5HT receptors while the effect of ARI was reversed. These Ex-vivo results signify that serotonin receptors may be responsible for the hyper-responsiveness and reduced relaxation of the aortic ring in case of chronic administration aripiprazole but not in olanzapine.