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

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.

Inhibition of KIR2.1 decreases pulmonary artery smooth muscle cell proliferation and migration

“…K + channels are closely related to the proliferation and apoptosis of PASMcs (42). To date, four different types of K + channels have been identified in smooth muscle cells: Voltage-gated K + (Kv) channels (43,44), ATP-sensitive potassium (K ATP ) channels (45), large conductance ca 2+ -activated K + (BK ca) channels (44,46,47) and KIR channels (22,41,48). The contribution of KIR2.1 to proliferation and migration is relatively controversial and may also be dependent on the cell type.…”

A Review of Approaches to the Metallic and Non-Metallic Synthesis of Benzimidazole (BnZ) and Their Derivatives for Biological Efficacy

“…These are able to treat a broad range of disorders, particularly epilepsy, diabetes, and pregnancy. Such derivatives exhibit a variety of bioactivities like antiallergic [ 61 ], antihistamine [ 62 ], anti-ulcerative, antiproliferative [ 63 ], antioxidant [ 64 , 65 ], antifungal, antibacterial, antitubercular [ 66 ], antihypertensive [ 67 ], anti-inflammatory, analgesic, antiamoebic [ 68 ], antitumor [ 69 , 70 , 71 ], antimalarial [ 72 ], and anti-kinase activity [ 73 ]. Several BnZ derivatives are also being investigated as cholinesterase inhibitors and anti-parasitic drugs [ 74 , 75 , 76 , 77 ].…”

An experimental and computational studies, evaluating the in vitro antidiabetic and antioxidant activity, in silico prediction ADMET properties of 5‐chloro‐1H‐benzimidazole and its newly synthesized silver(I) complex

“…It is a structure with various biologically active properties, such as analgesics 2,3 . antiparasitic, 4 antifungals, 5 anticoagulants, anti‐inflammatory agents, 6 antihypertensives, 7 antihistaminic, 8 antimalarial, 9 antitubercular, 10 anti‐HIV, 11 antimicrobial, 12 antiprotozoal, 13 andantiviral, 14 and is also used as a drug‐active ingredient in the field of pharmacology. Various benzimidazole‐based drugs, such as prazole, rabeprazole, and timoprazole, are widely used as proton pump inhibitors in the treatment of ulcers and gastritis 15 .…”