Effect of telmisartan, perindopril or both on vascular changes induced by chronic blockade of no synthesis

ABSTRACT

Modulation of the renin-angiotensin system is a prime strategy for the management of cardiovascular diseases. Recently, there is a growing interest in combining ACEIs and ARBs to improve the therapeutic efficacy. In the present study, we used the model of chronic NO synthesis inhibition to investigate the effects of ARBs and ACEIs; on hypertention and blood vessel changes induced by chronic administration of L-NAME, The beneficial vascular effects of the ARB, telmisartan or the ACEI, perindopril; were compared with those of their combined administration. Sixty adult male Wistar rats, were used and divided into five groups of 12 animals each, to receive either placebo [untreated standard chow and drinking water], L-NAME [1mg/ml], L-NAME + telmisartan [0.1 mg/ml], L-NAME + perindopril [0.01mg/ml], or L-NAME + combination of both telmisartan [0.1mg/ml] and perindopril [0.01mg/ml]; for eight weeks. Rats from the different groups were subjected to measurement of systolic blood pressure and heart rate, at weeks 0, 1, 4 and 8 of treatment, using the tail-cuff method. At end of the study period, all animals were sacrificed and the whole length of aorta is excised and used for pharmacological and histopathological examination. Results showed that, chronic treatment with L-NAME produced progressive rise in arterial blood pressure throughout the study. The hypertension induced by L-NAME was associated with significant endothelial dysfunction manifested by altered vascular responsiveness, with exaggeration of the aortic contractile response to phenylephrine [shift to the left of dose-response curve and significantly reduced EC50] and inhibition of the vasorelaxant effect of acetylcholine. Also, L-NAME administration for eight weeks leads to marked pathologic vascular changes in the form of intimal thickening and inflammatory changes in the media of aortic segments. Treatment with either telmisartan or perindopril concurrently with L-NAME leads to significant attenuation of the L-NAME-induced hypertension and vascular changes. They produced comparable reduction in the elevated blood pressure; normalization of the vascular responsiveness to phenyIephrine and acetylcholine; together with reduction of the aortic pathologic changes induced by chronic L-NAME administration. The combination of both telmisartan and perindopril produced more marked reduction of blood pressure than either agent alone, but with similar reduction of vascular changes in this experimental rat model. Thus, ARBs provide equivalent therapeutic alternatives to ACEIs in treatment of cardiovascular diseases. The combination of both classes may not add more benefits in preventing vascular changes, but can produce more hypotensive effect than either agent alone