Fisetin, a natural flavonoid found in a variety of vegetables and fruits, has been shown to possess many biological functions. The present study was undertaken to investigate the influence of fisetin on vascular smooth muscle contractility and to determine the mechanism involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Fisetin significantly relaxed fluoride-, thromboxane A2- or phorbol ester-induced vascular contraction suggesting as a possible anti-hypertensive on the agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, fisetin significantly inhibited fluoride-induced increases in pMYPT1 levels and phorbol ester-induced increases in pERK1/2 levels suggesting the mechanism involving the inhibition of Rho-kinase activity and the subsequent phosphorylation of MYPT1 and MEK activity and the subsequent phosphorylation of ERK1/2. This study provides evidence regarding the mechanism underlying the relaxation effect of fisetin on agonist-induced vascular contraction regardless of endothelial function.
Animals ; Fluorides ; Fruit ; Humans ; Isometric Contraction ; Male ; Muscle, Smooth, Vascular ; Nitric Oxide ; Phosphorylation ; Rats ; Relaxation ; rho-Associated Kinases ; Vegetables

Background: Dual-type calcium channel blockers (CCBs), such as efonidipine and cilnidipine, are renoprotective drugs that reportedly reduce proteinuria by dilating afferent and efferent arterioles of the glomerulus. However, studies comparing the effect of dual-type CCB on proteinuria have not been conducted. Therefore, we aimed to compare the effect of dual-type CCB (efonidipine and cilnidipine) usage patterns in hypertensive patients with chronic kidney disease (CKD). Methods: This single-center, retrospective study included 53 patients with CKD who 1) initiated efonidipine or cilnidipine treatment while on a renin-angiotensin system inhibitor and 2) had received efonidipine or cilnidipine for at least one year. We compared usage patterns between the efonidipine and cilnidipine groups during the one-year period and analyzed the following outcomes: urinary protein-to-creatinine ratio, blood pressure, and serum creatinine. Results: The study included 25 patients in the efonidipine group and 28 patients in the cilnidipine group. In both groups, blood pressure and urinary protein-to-creatinine ratios tended to decrease; however, the change during each interval was not significant. Conclusions In patients with CKD who were on renin-angiotensin system inhibitor therapy, the addition of a dual-type CCB (i.e., efonidipine or cilnidipine) tended to reduce proteinuria; however, the change during each interval was not significant.

Background: Dual-type calcium channel blockers (CCBs), such as efonidipine and cilnidipine, are renoprotective drugs that reportedly reduce proteinuria by dilating afferent and efferent arterioles of the glomerulus. However, studies comparing the effect of dual-type CCB on proteinuria have not been conducted. Therefore, we aimed to compare the effect of dual-type CCB (efonidipine and cilnidipine) usage patterns in hypertensive patients with chronic kidney disease (CKD). Methods: This single-center, retrospective study included 53 patients with CKD who 1) initiated efonidipine or cilnidipine treatment while on a renin-angiotensin system inhibitor and 2) had received efonidipine or cilnidipine for at least one year. We compared usage patterns between the efonidipine and cilnidipine groups during the one-year period and analyzed the following outcomes: urinary protein-to-creatinine ratio, blood pressure, and serum creatinine. Results: The study included 25 patients in the efonidipine group and 28 patients in the cilnidipine group. In both groups, blood pressure and urinary protein-to-creatinine ratios tended to decrease; however, the change during each interval was not significant. Conclusions In patients with CKD who were on renin-angiotensin system inhibitor therapy, the addition of a dual-type CCB (i.e., efonidipine or cilnidipine) tended to reduce proteinuria; however, the change during each interval was not significant.

Apigenin, a natural flavonoid found in a variety of vegetables and fruits, has been shown to possess many biological functions. The present study was undertaken to investigate the influence of apigenin on vascular smooth muscle contractility and to determine the mechanism involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Apigenin significantly relaxed fluoride-, thromboxane A2 mimetic- or phorbol ester-induced vascular contraction, which suggests that apigenin could be an anti-hypertensive that reduces agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, apigenin significantly inhibited fluoride-induced increases in pMYPT1 levels and phorbol ester-induced increases in pERK1/2 levels, which suggests the mechanism involving the inhibition of Rho-kinase and MEK activity and the subsequent phosphorylation of MYPT1 and ERK1/2. This study provides evidence regarding the mechanism underlying the relaxation effect of apigenin on agonist-induced vascular contraction regardless of endothelial function.
Animals ; Apigenin* ; Calcium* ; Fluorides ; Fruit ; Humans ; Isometric Contraction ; Male ; Muscle, Smooth, Vascular ; Nitric Oxide ; Phosphorylation ; Rats ; Relaxation ; rho-Associated Kinases ; Thromboxane A2 ; Vegetables

Shikonin, a natural flavonoid found in the roots of Lithospermum erythrorhizon, has been shown to possess many biological functions. The present study was undertaken to investigate the influence of shikonin on vascular smooth muscle contractility and to determine the mechanism involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Shikonin significantly relaxed fluoride-, thromboxane A2- or phorbol ester-induced vascular contraction suggesting as a possible anti-hypertensive on the agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, shikonin significantly inhibited fluoride-induced increases in pMYPT1 levels and phorbol ester-induced increases in pERK1/2 levels suggesting the mechanism involving the inhibition of Rho-kinase activity and the subsequent phosphorylation of MYPT1 and the inhibition of MEK activity and the subsequent phosphorylation of ERK1/2. This study provides evidence regarding the mechanism underlying the relaxation effect of shikonin on agonist-induced vascular contraction regardless of endothelial function.
Animals ; Fluorides ; Humans ; Isometric Contraction ; Lithospermum ; Male ; Muscle, Smooth, Vascular ; Nitric Oxide ; Phosphorylation ; Rats ; Relaxation ; rho-Associated Kinases

The present study was undertaken to investigate the influence of hypothermia on endothelium-independent vascular smooth muscle contractility and to determine the mechanism underlying the relaxation. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Hypothermia significantly inhibited fluoride-, thromboxane A2-, phenylephrine-, and phorbol ester-induced vascular contractions regardless of endothelial nitric oxide synthesis, suggesting that another pathway had a direct effect on vascular smooth muscle. Hypothermia significantly inhibited the fluoride-induced increase in pMYPT1 level and phorbol ester-induced increase in pERK1/2 level, suggesting inhibition of Rho-kinase and MEK activity and subsequent phosphorylation of MYPT1 and ERK1/2. These results suggest that the relaxing effect of moderate hypothermia on agonist-induced vascular contraction regardless of endothelial function involves inhibition of Rho-kinase and MEK activities.
Animals ; Fluorides ; Humans ; Hypothermia* ; Isometric Contraction ; Male ; Muscle, Smooth, Vascular ; Nitric Oxide ; Phosphorylation ; Rats ; Relaxation ; rho-Associated Kinases*

In this study, we investigated the effects of pelargonidin, an anthocyanidin found in many fruits and vegetables, on endothelium-independent vascular contractility to determine the underlying mechanism of relaxation. Isometric contractions of denuded aortic muscles from male rats were recorded, and the data were combined with those obtained in western blot analysis. Pelargonidin significantly inhibited fluoride-, thromboxane A2-, and phorbol ester-induced vascular contractions, regardless of the presence or absence of endothelium, suggesting a direct effect of the compound on vascular smooth muscles via a different pathway. Pelargonidin significantly inhibited the fluoride-dependent increase in the level of myosin phosphatase target subunit 1 (MYPT1) phosphorylation at Thr-855 and the phorbol 12,13-dibutyrate-dependent increase in the level of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation at Thr202/Tyr204, suggesting the inhibition of Rho-kinase and mitogen-activated protein kinase kinase (MEK) activities and subsequent phosphorylation of MYPT1 and ERK1/2. These results suggest that the relaxation effect of pelargonidin on agonist-dependent vascular contractions includes inhibition of Rho-kinase and MEK activities, independent of the endothelial function.
Animals ; Anthocyanins ; Aorta* ; Blotting, Western ; Endothelium* ; Fluorides ; Fruit ; Humans ; Isometric Contraction ; Male ; Muscle, Smooth, Vascular ; Muscles ; Myosin-Light-Chain Phosphatase ; Phosphorylation ; Phosphotransferases ; Protein Kinases ; Rats* ; Relaxation ; rho-Associated Kinases ; Vasoconstriction* ; Vegetables