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

Abstract

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.

• Authors: Nadeem Irshad, Arif-Ullah Khan, Alamgeer, Salah-Ud-Din Khan, Muhammad Shahid Iqbal
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 139 Pg. 111567 (Jul 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 33848773 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Masson SAS.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antihypertensive Agents
• Antioxidants
• Pyrimidines
• Vasodilator Agents
• Phenylephrine
• Desoxycorticosterone
• Calcium

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antihypertensive Agents (pharmacology, therapeutic use)
• Antioxidants (pharmacology)
• Aorta (drug effects)
• Calcium (pharmacology)
• Desoxycorticosterone
• Female
• Guinea Pigs
• Humans
• Hypertension (chemically induced, drug therapy)
• Kidney Function Tests
• Male
• Mice
• Muscle Contraction (drug effects)
• Muscle, Smooth, Vascular (drug effects)
• Myocardial Contraction (drug effects)
• Phenylephrine (pharmacology)
• Platelet Aggregation (drug effects)
• Pyrimidines (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Vasodilator Agents (pharmacology)