Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathways
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,...
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doaj-4d31227dbdd74d08a6b3e0fb6c68562c2021-06-03T04:54:55ZengElsevierBiomedicine & Pharmacotherapy0753-33222021-07-01139111567Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathwaysNadeem Irshad0Arif-ullah Khan1 Alamgeer2Salah-Ud-Din Khan3Muhammad Shahid Iqbal4Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, PakistanRiphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; Corresponding author.Punjab University College of Pharmacy, University of Punjab, Lahore, PakistanDepartment of Biochemistry, College of Medicine, Imam Mohammad Ibn Saud Univeristy, Riyadh, Saudi ArabiaDepartment of Clinical Pharmacy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj, Saudi ArabiaThis 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.http://www.sciencedirect.com/science/article/pii/S0753332221003528Pyrimidine selected derivativesHypotensiveVasodilationDiureticAntioxidantAnti-inflammatory |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nadeem Irshad Arif-ullah Khan Alamgeer Salah-Ud-Din Khan Muhammad Shahid Iqbal |
spellingShingle |
Nadeem Irshad Arif-ullah Khan Alamgeer Salah-Ud-Din Khan Muhammad Shahid Iqbal Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathways Biomedicine & Pharmacotherapy Pyrimidine selected derivatives Hypotensive Vasodilation Diuretic Antioxidant Anti-inflammatory |
author_facet |
Nadeem Irshad Arif-ullah Khan Alamgeer Salah-Ud-Din Khan Muhammad Shahid Iqbal |
author_sort |
Nadeem Irshad |
title |
Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathways |
title_short |
Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathways |
title_full |
Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathways |
title_fullStr |
Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathways |
title_full_unstemmed |
Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathways |
title_sort |
antihypertensive potential of selected pyrimidine derivatives: explanation of underlying mechanistic pathways |
publisher |
Elsevier |
series |
Biomedicine & Pharmacotherapy |
issn |
0753-3322 |
publishDate |
2021-07-01 |
description |
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. |
topic |
Pyrimidine selected derivatives Hypotensive Vasodilation Diuretic Antioxidant Anti-inflammatory |
url |
http://www.sciencedirect.com/science/article/pii/S0753332221003528 |
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