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Antidepressant Activity of Fosinopril, Ramipril and Losartan, but Not of Lisinopril in Depressive Paradigms of Albino Rats and Mice

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Antidepressant Activity of Fosinopril, Ramipril and Losartan, but Not of Lisinopril in Depressive Paradigms of Albino Rats and Mice Indian Journal of Experimental Biology Vol. 46, March 2008, pp. 180-184 Antidepressant activity of fosinopril, ramipril and losartan, but not of lisinopril in depressive paradigms of albino rats and mice Veena Nayak & P A Patil* Department of Pharmacology & Pharmacotherapeutics, J.N.Medical College, Belgaum 590 010, India Received 15 January 2007; revised 15 January 2008 Fosinopril, ramipril and losartan significantly decreased the duration (sec) of immobility in forced swim test and were comparable to amitriptyline. The duration of immobility were significantly decreased in fosinopril, ramipril and losartan in the tail suspension test and were comparable to amitriptyline. Only losartan significantly increased the rearing number of entries, time spent (sec) in open arm and in light area in comparison to control animals. Fosinopril and ramipril and not lisinopril showed significant antidepressant activity while losartan showed a significant antidepressant and anxiolytic activity. Present findings suggest that these drugs could be better antihypertensives in hypertensive patients with co- morbidity like depression or anxiety. Keywords: Anxiety, Depression, Fosinopril, Lisinopril, Losartan, Ramipril Physiological depression and anxiety when become possess antidepressant and anxiolytic activity like severe and chronic lead to a variety of psychiatric captopril and enalapril. A report regarding quinapril13 disorders. Quite often such mood disorders could be indicates that all ACE inhibitors may not share secondary to a number of cardiovascular and antidepressant and anxiolytic activity and such endocrinal disorders1,2 requiring treatment with two activities are not probed with other ACE inhibitors drugs, one for physical or metabolic and the other for used clinically. It is therefore planned to investigate associated mental disorder. Logically, a single drug the effect of widely used, chemically heterogeneous that can control the physical and associated mental ACE inhibitors14 with varying lipophilicity15 viz. illness would be an ideal agent for the treatment of fosinopril, ramipril and lisinopril for their such co morbid conditions. antidepressant and anxiolytic activity in male Wistar Interestingly, angiotensin converting enzyme (ACE) rats and Swiss mice. inhibitors like captopril3, perindopril4 and ceronapril5 have been reported to possess antidepressant activity in Materials and Methods experimental animals. Similarly losartan, an Animals—Male adult Wistar rats and Swiss mice, angiotensin II receptor blocker has also been reported weighing between 150-250 g and 20-30 g to possess antidepressant activity in experimental respectively, were obtained from the central animal animals6. Moreover captopril7, 8 and enalapril8 have house of the institute and were kept in the laboratory been reported to control not only blood pressure but for about 10 days in 12:12 hr L:D cycle. Throughout also improve the depressed mood and cognition in the experiment the animals were fed with laboratory hypertensive patients. In addition captopril9,10, chow (Amrut Brand) and water ad libitum. Animals enalapril11 and losartan11,12 have been shown receiving alprazolam orally were fasted overnight experimentally to exert anxiolytic activity both in prior to the day of experiment and experiments were normotensive and hypertensive rats. conducted between 09.00-14.00 hrs. Due to the common mechanism of action, other The study was approved by Institutional Animal ACE inhibitors used clinically could be expected to Ethical Committee formed as per the guidelines of CPCSEA, New Delhi. _________ Drugs and doses—Amitriptyline (Inj. Typtin, Sterfil *Correspondent author: Labs Ltd), alprazolam (Tablets Alprax, Torrent Ltd), Phone: 0831-2473777 Ext: 1828 Fax: 91-0831-470759 lisinopril (Tablets Lipril, Lupin Ltd) and losartan E-mail: [email protected] (Tablets Angizaar, Carsynoa, Microlabs) were NAYAK & PATIL: ANTIDEPRESSANT ACTIVITY OF ACE INHIBITORS 181 purchased locally. Fosinopril and ramipril were The plus maze apparatus consists of two open obtained as generous gift samples from Cipla Ltd. (50 × 10 cm) and two side-closed arms (50 × 10 × Rat and mice equivalent doses in mg/kg body 40 cm) without roof, elevated 50 cm from the floor. weight of clinical doses were calculated as mg/kg The pretreated animals were placed individually for body weight with the help of the table cited earlier16 5 min at the center of the elevated plus maze facing and were 27.0 for amitriptyline (AMT), 0.045 for the head towards an open arm. The number of entries alprazolam (AZM), 1.8 for fosinopril (FSL), 0.23 for into the open or closed arm and the time spent in each ramipril (RML), 1.8 for lisinopril (LSL), 10.0 for arm were recorded. At the same time, number of rears losartan (LTN); while the corresponding doses for in the open arm was recorded. mice were 7.8 for AMT, 0.52 for FSL, 0.06 for RML, The percentage of the number of entries (against 0.52 for LSL, and 2.88 for LTN. All the drugs except the total number of entries both in open and closed AZM were dissolved in distilled water while AZM arms) and time spent in the open arm were calculated was suspended in 2% gum acacia. All drugs were for each group. Similarly mean number of rears freshly prepared and were administered in a single ip (standing on the hind limbs) for each group was dose in the volume of 0.5 ml to groups of mice (n=6, calculated. in each) and 1.0 ml to groups of rats (n=6, in each), d) Light–dark arena20: It consists of a wooden box while alprazolam suspension was given orally in the (50 × 30 × 35cm) placed on a table, 1m above floor volume of 1 ml to the rats. Equal volumes of either level. A partition with a gap of 7.5 × 7.5cm at the gum acacia 2% suspension or normal saline were centre of its lower border was fixed to separate 2/5th of administered through corresponding route to the the base from the remaining 3/5th . The smaller 2/5th control group. chamber was painted black and the other one (3/5th of Behavioral studies—a) Antidepressant activity the base) was painted white on all four sides . The studies were carried out in rats using forced swim test chamber painted black was illuminated with red light 17 paradigm as described earlier. while the other chamber was brightly illuminated with Briefly, male adult rats weighing 160-180 g were a 100 W light source located 17 cm above the box. plunged into a vertical plexiglass cylinder (40 cm Pretreated rats were placed in the centre of the bright height 18 cm diam) containing 15 cm of water column area. The number of rearings, entries into and time maintained at 25°C and left there for 5 min. The spent in light area were recorded over a period of duration of immobility in seconds as indicated by the 5 min. The mean number entries and rears and animal floating motionless in the water making only percentage of time spent were calculated for each those movements necessary to keep its head above group. water was noted. Animals were trained for 15 min, 24 The effect of all the drugs used in the present study, hours prior to the experiment. After the experiment, on locomotor activity was tested using the animals were then allowed to dry for 15 min actophotometer (M/S INCO) before returning to their individual cages. Group Statistical analysis—The results were analyzed by mean of immobility time was calculated in treated and one-way ANOVA followed by Dunnet’s test using control animals. Graph pad prism software and P ≤ 0.05 was b) Tail suspension test was carried out in mice as considered significant. 18 described earlier . The mouse pretreated with drug/vehicle was Results suspended from the hook hanging at the center of a Forced swim test and tail suspension test—The horizontal rod placed on 2 metallic stands kept 35 cm mean duration of immobility in the FSL, RML and apart. An adhesive tape stuck 2 cm proximal to the LTN treated groups were significantly (P≤0.01, tail tip was used to suspend the animal through the ≤0.05) reduced as compared to that of the control hook hanging about 35 cm distance from the ground. group and was comparable to that of AMT. However Immobility time in seconds was recorded by assessing LSL failed to show antidepressant activity in both the motionless hanging of the mice over a period of paradigms (Table 1). 6 min. Elevated plus maze—The mean number of entries c) Anxiolytic activity was studied using elevated into the open arm in the control and treated groups plus maze as described earlier19. though did not significantly differ, the mean of 182 INDIAN J EXP BIOL, MARCH 2008 percentage entries into open arm was significantly Locomotor activity—The locomotor activity in the increased in the LTN (P≤0.05) and AZM (P≤0.01) AZM (15.17±1.16) treated group was significantly treated animals. Similarly the mean number of rears (P<0.05) decreased in comparison to control group and percentage of time spent in the open arm was (21.83±1.22). There was no significant change in the significantly increased in the LTN (P≤0.05) and AZM locomotor activity in the AMT (21.17±1.42), FSL (P≤0.01) treated animals (Table 2). (22±1.18), RML (21.50±1.99), LSL (19.83±1.74) and Light dark arena—The mean number of rears and LTN (20±2.38) treated groups was observed. percentage of time spent in the light area in the LTN and AZM treated group was significantly increased Discussion (P<0.05, ≤0.01) when compared to that of control The findings of the present study in both the group (Table 2). models of depression viz. forced swim test and tail suspension test clearly indicate that FSL, RML and Table 1—Effect of various treatments on depression paradigms [Values are mean ± SE from 6 animals in each group] LTN have significant antidepressant activity, comparable to that of AMT.
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