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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 BK Ca  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 BK Ca  channels. Ion flux (Ca 2+ , 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 BK Ca  channels. FPD further enhanced efflux of K +  and inhibited Bay K8644-stimulated Ca 2+  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 BK Ca  channels as putative targets of vasorelaxation, and was found safe in oral toxicity.

frontiers in pharmacology

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