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 (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 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 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.

Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2), downstream to p38MAPK (p38mitogen-activated protein kinase), regulates cellular inflammation and proliferation. So far, the role of MK2 has been studied in many cardiovascular diseases, but it remains unexplored in pulmonary hypertension (PH). Therefore, to investigate the role of MK2 in the PH pathogenesis, human pulmonary artery smooth muscle cells were exposed to hypoxia (1% O ₂ ) for 72 hours, and MK2 was inhibited by siRNA. We observed significantly increased MK2 expression, inflammatory cytokines, proliferation, mitochondrial dysfunction, and apoptosis resistance in hypoxic human pulmonary artery smooth muscle cells, which were reversed by treatment with MK2 siRNA. For in vivo studies, male Sprague Dawley rats were treated with monocrotaline (60 mg/kg, SC, once) to induce PH. To inhibit MK2, a peptide MMI-0100 (40 μg/kg, IP daily, 5 weeks for preventive and 3 weeks for curative study) was administered. MMI-0100 treatment decreased right ventricle pressure and hypertrophy, hallmarks of PH, in both preventive and curative study. MMI-0100-treated rats showed better cardiac functions as revealed by 2-dimensional echocardiography study. Furthermore, MMI-0100 reversed pulmonary vascular remodeling and improved pulmonary vascular relaxation in monocrotaline-treated rats. Finally, the above results were confirmed in MK2 knockout mice. MK2 knockout mice, received 600 mg/kg monocrotaline, subcutaneous weekly for 5 weeks, failed to develop PH and showed no increase in right ventricle pressure and hypertrophy. This study, therefore, proved that MK2 is involved in PH, and its inhibition may be a novel target for PH treatment.