Antihypertensive Effect of a Novel Angiotensin II Receptor Blocker Fluorophenyl Benzimidazole: Contribution of cGMP, Voltage-dependent Calcium Channels, and BKCa Channels to Vasorelaxant Mechanisms.

Amit Kumar Verma,Hina Iqbal,Kashif Hanif,Sarfaraz Alam,Debabrata Chanda,Feroz Khan,Mohammad Shafiq,Divya Mishra,Pankaj Yadav,Arvind Singh Negi

doi:10.3389/fphar.2021.611109

Abstract

Background: The current study presents the novel angiotensin II receptor blocker fluorophenyl benzimidazole (FPD) as an antihypertensive agent in the SHR model of hypertension. We investigated the role of cGMP, voltage-dependent L-type calcium channels, and BKCa channels in the vasorelaxant mechanisms of FPD in the rat superior mesenteric artery. Methods: The antihypertensive effect of FPD was examined using an invasive technique measuring blood pressure in SHR animals. Using a myograph, tension measurement was completed in the superior mesenteric artery to elucidate the mechanisms of vasorelaxation involving AT1 receptors, the NO/cGMP pathway, L-type calcium channels, and BKCa channels. Ion flux (Ca2+, K+) studies were conducted in aortic smooth muscle cells. Putative targets proteins were determined by in silico docking studies. A safety evaluation of FPD was carried out using Swiss albino mice. Results: FPD significantly decreased blood pressure in SHR. It relaxed superior mesenteric arteries in a concentration-dependent manner and significantly inhibited angiotensin II-induced contraction. The relaxation response was also mediated by an increase in tissue cGMP levels, inhibition of L-type calcium channels, and the opening of BKCa channels. FPD further enhanced efflux of K+ and inhibited Bay K8644-stimulated Ca2+ influx in aortic smooth muscle cells and docked well in an in silico study with the targets. It was well tolerated in the toxicity study. Conclusion: The present study reports the antihypertensive activity of novel AT-1 receptor blocker FPD at 50 and 100 mg kg−1 with cGMP, L-type calcium channels, and BKCa channels as putative targets of vasorelaxation, and was found safe in oral toxicity.

Highlights

Non-communicable diseases are the leading cause of death in the developed and developing world
All the compounds chosen for the study relaxed the U46199 (100 nM) pre-contracted rat superior mesenteric artery at 10 μM considering acetylcholine-induced (10 μM) vasorelaxation as standard (Table 1)
A further three compounds showing Emax > 70% were chosen for the concentration-dependent relaxation (Supplementary Figure S2)

Summary

Introduction

Non-communicable diseases are the leading cause of death in the developed and developing world. Telmisartan, candesartan, and azilsartan have emerged from this class of compounds as clinical drugs acting through the angiotensin receptor blockade (AT1). In spite of the vast number of studies on benzimidazoles and angiotensin receptor blockers (ARBs), literature on the role of these classes of compounds on VDCC and potassium channel functioning pertaining to vasorelaxation in conduit and resistance arteries and antihypertensive activity has been very limited. All the 2-arylbenzimidazole derivatives were evaluated for vasorelaxation and the most potent molecule, fluorophenyl benzimidazole was studied for antihypertensive activity and elucidation of its mechanism of action through blocking the AT1 receptor, cGMP buildup, and modulation of the BKCa channel and VDCC function. The current study presents the novel angiotensin II receptor blocker fluorophenyl benzimidazole (FPD) as an antihypertensive agent in the SHR model of hypertension. We investigated the role of cGMP, voltage-dependent L-type calcium channels, and BKCa channels in the vasorelaxant mechanisms of FPD in the rat superior mesenteric artery

Methods

Results

Discussion

Conclusion