Drug Design, Development and Therapy (Apr 2016)
Effects of a novel ACE inhibitor, 3-(3-thienyl)-L-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in L-NAME-induced hypertensive rats
Abstract
Mahesh Kumar Seth,1–3 M Ejaz Hussain,2 Santosh Pasha,1 Mohammad Fahim3 1Peptide Synthesis Laboratory, CSIR, Institute of Genomics and Integrative Biology, Delhi, India; 2Centre for Physiotherapy and Rehabilitation Sciences, Jamia Millia Islamia, New Delhi, India; 3Department of Physiology, Jamia Hamdard Deemed University, New Delhi, India Abstract: Nitric oxide (NO) is a widespread biological mediator involved in many physiological and pathological processes, eg, in the regulation of vascular tone and hypertension. Chronic inhibition of NO synthase by NG-nitro-L-arginine methyl ester (ʟ-NAME) hydrochloride results in the development of hypertension accompanied by an increase in vascular responsiveness to adrenergic stimuli. Recently, we developed a novel sulfur-containing angiotensin-converting enzyme inhibitor: 3-(3-thienyl)-ʟ-alanyl-ornithyl-proline (TOP). Our previous studies indicated a superior nature of the molecule as an antihypertensive agent in spontaneously hypertensive rats (showing the involvement of renin–angiotensin–aldosterone system) in comparison to captopril. The aim of the present study was to investigate the effect of TOP on NO pathway in ʟ-NAME-induced hypertensive rats, and captopril was included as the standard treatment group. Treatment with both TOP (20 mg/kg) and captopril (40 mg/kg) prevented the development of hypertension in ʟ-NAME model, but TOP showed better restoration of NO and normal levels of angiotensin-converting enzyme. In addition, in vitro vasorelaxation assay showed an improvement in endothelium-dependent vasodilation in both the cases. Further, the biochemical (malondialdehyde, alanine aminotransferase, and aspartate aminotransferase) and the histopathological effects of TOP on rat liver tissues revealed a protective nature of TOP in comparison to captopril in the ʟ-NAME model. In conclusion, TOP at 50% lesser dose than captopril was found to be better in the ʟ-NAME model. Keywords: nitric oxide, ACE inhibitor
