Some Pharmacological Studies Of Candesartan In Experimental Animals:

Sherif Ahmed El Sayed Shaltoot

Candesartan is a selective AT1 receptor antagonist. On the otherhand, perindopril is an ACE inhibitor.The present work was carried out to screen the pharmacologicaleffects of candesartan and perindopril on isoprenaline-inducedmyocardial infarction and heart failure and STZ-induced diabeticnephropathy. Also, the effects of candesartan and perindopril on isolatedrabbit’s aortic strip and isolated rabbit’s heart were evaluated.Myocardial infarction was experimentally induced by a singlesubcutaneous injection of isoprenaline (500mg/kg). Theelectrocardiograph tracing showed sinus tachycardia with injury currentsin form of highly peaked T-wave, serum creatine phosphokinase (CPKMB)and troponin-I levels increased in rats 4 hours after subcutaneousinjection of isoprenaline. The mean percentage of infarction size percentwas (47.71±2.4%) and histopathological examination of cardiac sectionsof MI group revealed myocyte degeneration and necrosis and interstitialfibrosis.In the present work, it was observed that pre-treatment(10mg/kg/day for 7 days) and post-treatment (10mg/kg) with oralcandesartan decreased significantely the T- wave voltage and levels ofCPK-MB and troponin-I. However, it produced insignificant decease inheart rate. On the other hand, pre-treatment (6mg/kg/day for 7 days) andpost treatment (6mg/kg) with oral perindopril decresed significantely theT- wave voltage and levels of CPK-MB and troponin-I. However, itSummary and Conclusion14 6produced insignificant decease in heart rate. There was significant effectin the pretreated groups and no significant effect between candesartan andperindopril in the pretreated and postreated groups.The degree of cardio-protective effect induced by candesartan andperindopril was evaluated by studying the changes in the severity of thecardiac necrosis evoked by isoprenaline in rats. It was founded thatcandesartan and perindopril pretreatment minimized the infarction sizewith significant decrease in candesartan pre-treatment group. There wasno significant effect of candesartan and perindopril post-treatmentgroups on the infarction size.Heart failure was experimentally induced in rats by a singlesubcutaneous injection of isoprenaline (150mg/kg). After 2 weeks, therewas significant decrease in the systolic and diastolic blood pressure. Also,there was significant increase in the heart rate in comparison with controlgroup.In the present work, it was observed that daily oral administrationof candesartan (10mg/kg/day) and perindopril (6mg/kg/day) for 2 weeksproduced significant reduction in the systolic and diastolic blood pressurewhen compared with control group. In comparison with HF group, itproduced insignificant reduction in SBP and DBP and significantdecrease in HR. There was significant effect in perindopril treated group.Histopathological examination of cardiac sections of control groupshowed no detectable abnormality in cardiac smooth muscle cells.Sections of heart failure group revealed myocyte degeneration andnecrosis and interstitial fibrosis. Candesartan and perindoprilSummary and Conclusion14 7administration effectively decreased these changes with more significanteffect in candesartan treated group.In the present study, diabetic nephropathy wasexperimentally induced in rats by single intraperitoneal injectionof streptozotocin (70mg/kg). Aِfter one month, streptozotocininduced significant increase of fasting blood glucose, serum urea,serum creatinine and 24-hour collected urine albumin in rats andsignificant decrease of creatinine clearance level.Histopathological examination of renal tissues of diabeticnephropathy rats by light microscopy revealed diffuse glomerularsclerotic lesion.It was observed that daily oral administration of candesartan(10mg/kg/day) and perindopril (6mg/kg/day) for 4 weeks producedsignificant reduction in fasting blood glucose, serum urea, serumcreatinine and 24-hour collected urine albumin in rats and significantincrease of creatinine clearance level. There was insignificant differencebetween candesartan and perindopril treated groups except for 24-hourcollected urine albumin, where perindopril was more significant thancandesartan.Regarding histopathological examination of renal tissues, daily oraladministration of candesartan and perindopril revealed mild degenerativechanges and fibrosis compared to untreared rats. Perindopril was moreeffective in improvement of renal tissue than candesartan.Data obtained in the present study pointed out that candesartan ingradually increasing doses (2,4,8,16 and 32/ml bath) produce no effect onthe isolated rabbit’s aortic strip and basal myocardial contractility ofSummary and Conclusion14 8isolated rabbit’s heart. However, it antagonized angiotensin-II inducedcontractions in isolated rabbit’s aortic strip and rabbit’s heart.On the other hand, perindopril in gradually increasing doses(2,4,8,16 and 32/ml bath) produced no effect on the isolated rabbit’saortic strip and basal myocardial contractility of isolated rabbit’s heart.Also, it did not antagoniz angiotensin-II induced contractions in isolatedrabbit’s aortic strip or rabbit’s heart.In conclusion, both candesartan and perindopril havecardioprotective effect against acute MI and HF as well as markednephroprotective effect in diabetic nephropathy with no significantdifference between both drugs. So, the choice of either drug in thesedisease states depend on which of them has low side effects.