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

Abstract

<b>Background:</b> 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 BK_Ca channels in the vasorelaxant mechanisms of FPD in the rat superior mesenteric artery. <b>Methods:</b> 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 BK_Ca channels. Ion flux (Ca²⁺, K⁺) studies were conducted in aortic smooth muscle cells. Putative targets proteins were determined by <i>in silico</i> docking studies. A safety evaluation of FPD was carried out using Swiss albino mice. <b>Results:</b> 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 BK_Ca channels. FPD further enhanced efflux of K⁺ and inhibited Bay K8644-stimulated Ca²⁺ influx in aortic smooth muscle cells and docked well in an <i>in silico</i> study with the targets. It was well tolerated in the toxicity study. <b>Conclusion:</b> 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 BK_Ca channels as putative targets of vasorelaxation, and was found safe in oral toxicity.