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

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 channels in the vasorelaxant mechanisms of FPD in the rat superior mesenteric artery. 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 channels. Ion flux (Ca, K) studies were conducted in aortic smooth muscle cells. Putative targets proteins were determined by docking studies. A safety evaluation of FPD was carried out using Swiss albino mice. 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 channels. FPD further enhanced efflux of K and inhibited Bay K8644-stimulated Ca influx in aortic smooth muscle cells and docked well in an study with the targets. It was well tolerated in the toxicity study. The present study reports the antihypertensive activity of novel AT-1 receptor blocker FPD at 50 and 100 mg kg with cGMP, L-type calcium channels, and BK channels as putative targets of vasorelaxation, and was found safe in oral toxicity.