Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathways

• DOI: 10.1016/j.biopha.2021.111567
• Publication Date: 2021-04-13T18:15:14Z
• Authors: Nadeem Irshad; Arif-ullah Khan; Alamgeer; Salah-Ud-Din Khan; Muhammad Shahid I...
• Keywords: Male; 0303 health sciences; Platelet Aggregation; Anti-Inflammatory Agents, Non-Steroidal; Guinea Pigs; Kidney Function Tests; Myocardial Contraction; Antioxidants; Muscle, Smooth, Vascular; 3. Good health; Mice; Phenylephrine; 03 medical and health sciences; Pyrimidines; Hypertension; Animals; Humans; Calcium; Female; Desoxycorticosterone; Antihypertensive Agents; Aorta; Muscle Contraction

This study was designed to determine the effectiveness of 5-(3-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-5), 5-(4-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-8), 5-(3-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-9) and 5-(4-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-10) against hypertension. In deoxycorticosterone acetate-salt rats, SR-5, SR-8, SR-9, and SR-10 reduced blood pressure and normalized renal functions. In isolated rat aortic rings, SR-5, SR-8, SR-9, and SR-10 relaxed phenylephrine (PE) and K+-induced contractions. The vasodilator effect was endothelium-independent. Test compounds caused a rightward shift of Ca++ and PE concentration-response curves with a reduction of maximum response. SR-5, SR-8, SR-9, and SR-10 inhibited PE peak contractions in a Ca++ free medium. In guinea-pig atria, SR5, SR-8, SR-9, and SR-10 caused a mild-to-moderate inhibition of force and rate of contractions. In the aorta and heart tissues, the test compounds enhanced glutathione-s-transferase, reduced glutathione and catalase levels, improved cellular architecture, and decreased lipid peroxidation and expression of inflammatory markers: cyclooxygenase 2, tumor necrosis factor alpha, phosphorylated c-Jun N-terminal kinase, and phosphorylated-nuclear factor kappa B, evidenced in the immunohistochemistry, enzyme-linked immunosorbent assay, western blot molecular investigations and a decreased mRNA expression of calcium channel in RT-PCR analysis. SR-5, SR-8, SR-9, and SR-10 increased the urinary output in rats and inhibited the human platelet aggregation. This study revealed that SR-5, SR-8, SR-9, and SR-10 possess BP lowering, reno-protective, vasodilatory (mediated via Ca++ antagonist, antioxidant and anti-inflammatory pathways), partial cardio-suppressant, diuretic, and antiplatelet effects, demonstrating their therapeutic potential in hypertension management.