scholarly journals Basal and Activated Calcium Sensitization Mediated by RhoA/Rho Kinase Pathway in Rats with Genetic and Salt Hypertension

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Michal Behuliak ◽  
Michal Bencze ◽  
Ivana Vaněčková ◽  
Jaroslav Kuneš ◽  
Josef Zicha
Keyword(s):  
Blood Pressure ◽  
Kinase Inhibitor ◽  
Blood Pressure Response ◽  
Blood Pressure Reduction ◽  
Rho Kinase ◽  
Experimental Hypertension ◽  
Acute Administration ◽  
Calcium Sensitization ◽  
Rho Kinase Inhibitor ◽  
Kinase Pathway

Calcium sensitization mediated by RhoA/Rho kinase pathway can be evaluated either in the absence (basal calcium sensitization) or in the presence of endogenous vasoconstrictor systems (activated calcium sensitization). Our aim was to compare basal and activated calcium sensitization in three forms of experimental hypertension with increased sympathetic tone and enhanced calcium entry—spontaneously hypertensive rats (SHR), heterozygous Ren-2 transgenic rats (TGR), and salt hypertensive Dahl rats. Activated calcium sensitization was determined as blood pressure reduction induced by acute administration of Rho kinase inhibitor fasudil in conscious rats with intact sympathetic nervous system (SNS) and renin-angiotensin system (RAS). Basal calcium sensitization was studied as fasudil-dependent difference in blood pressure response to calcium channel opener BAY K8644 in rats subjected to RAS and SNS blockade. Calcium sensitization was also estimated from reduced development of isolated artery contraction by Rho kinase inhibitor Y-27632. Activated calcium sensitization was enhanced in all three hypertensive models (due to the hyperactivity of vasoconstrictor systems). In contrast, basal calcium sensitization was reduced in SHR and TGR relative to their controls, whereas it was augmented in salt-sensitive Dahl rats relative to their salt-resistant controls. Similar differences in calcium sensitization were seen in femoral arteries of SHR and Dahl rats.

scholarly journals The Interaction of Calcium Entry and Calcium Sensitization in the Control of Vascular Tone and Blood Pressure of Normotensive and Hypertensive Rats

2014 ◽  
pp. S19-S27 ◽  
Author(s):  
J. ZICHA ◽  
M. BEHULIAK ◽  
M. PINTÉROVÁ ◽  
M. BENCZE ◽  
J. KUNEŠ ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Rho Kinase ◽  
Calcium Entry ◽  
Experimental Hypertension ◽  
Hypertensive Rats ◽  
Calcium Sensitization ◽  
Wky Rats ◽  
Kinase Pathway

Increased systemic vascular resistance is responsible for blood pressure (BP) elevation in most forms of human or experimental hypertension. The enhanced contractility of structurally remodeled resistance arterioles is mediated by enhanced calcium entry (through L type voltage-dependent calcium channels – L-VDCC) and/or augmented calcium sensitization (mediated by RhoA/Rho kinase pathway). It is rather difficult to evaluate separately the role of these two pathways in BP control because BP response to the blockade of either pathway is always dependent on the concomitant activity of the complementary pathway. Moreover, vasoconstrictor systems enhance the activity of both pathways, while vasodilators attenuate them. The basal fasudil-sensitive calcium sensitization determined in rats deprived of endogenous renin-angiotensin system (RAS) and sympathetic nervous system (SNS) in which calcium entry was dose-dependently increased by L-VDCC opener BAY K8644, is smaller in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto (WKY) rats. In contrast, if endogenous RAS and SNS were present in intact rats, fasudil caused a greater BP fall in SHR than WKY rats. Our in vivo experiments indicated that the endogenous pressor systems (RAS and SNS) augment calcium sensitization mediated by RhoA/Rho kinase pathway, whereas the endogenous vasodilator systems (such as nitric oxide) attenuate this pathway. However, the modulation of calcium entry and calcium sensitization by nitric oxide is strain-dependent because NO deficiency significantly augments low calcium entry in WKY and low calcium sensitization in SHR. Further in vivo and in vitro experiments should clarify the interrelationships between endogenous vasoactive systems and the contribution of calcium entry and/or calcium sensitization to BP maintenance in various forms of experimental hypertension.

scholarly journals The absence of sympathoexcitation during the development of hypertension in Cyp1a1 Ren-2 transgenic rats

2019 ◽  
pp. 329-334
Author(s):  
J. Zicha ◽  
J. Hojná ◽  
L. Kopkan ◽  
L. Červenka ◽  
I. Vaněčková
Keyword(s):  
Blood Pressure ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Calcium Sensitization ◽  
Sympathetic Vasoconstriction ◽  
Rho Kinase Inhibitor ◽  
Dependent Form

The insertion of mouse renin gene (Ren-2) into the genome of normotensive rats causes a spontaneous rise of blood pressure (BP), leading to an angiotensin II (Ang II)-dependent form of hypertension in transgenic (mRen-2)27 rats (TGR). However, enhanced sympathetic BP component was demonstrated in heterozygous TGR aged 20 weeks. In the present study we used another model, i.e. Cyp1a1-Ren-2 transgenic rats (iTGR) in which hypertension can be induced by natural xenobiotic indole-3 carbinol (I3C) added to the diet. We investigated whether the development of high blood pressure (BP) in 5-month-old iTGR animals fed I3C diet for 10 days is solely due to enhanced Ang II-dependent vasoconstriction or whether enhanced sympathetic vasoconstriction also participates in BP maintenance in this form of hypertension. Using acute sequential blockade of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and NO synthase (NOS) we have demonstrated that the observed gradual increase of BP in iTGR fed I3C diet was entirely due to the augmentation of Ang II-dependent BP component without significant changes of sympathetic BP component. Thus, the hypertension in iTGR resembles to that of homozygous TGR in which high BP was entirely dependent on Ang II-dependent vasoconstriction. Moreover, our measurements of acute BP response to Rho kinase inhibitor fasudil in animals subjected to a combined blockade of RAS, SNS and NOS indicated the attenuation of basal calcium sensitization in both iTGR and homozygous TGR.

RhoA-Rho kinase mediates synergistic ET-1 and phenylephrine contraction of rat corpus cavernosum

2003 ◽  
Vol 285 (5) ◽  
pp. R1145-R1152 ◽  
Author(s):  
Christopher J. Wingard ◽  
Shahid Husain ◽  
Jan Williams ◽  
Sharita James
Keyword(s):  
Kinase Inhibitor ◽  
Corpus Cavernosum ◽  
Rho Kinase ◽  
Stress Generation ◽  
Combined Stress ◽  
Fourfold Increase ◽  
Rho Kinase Inhibitor ◽  
Tissue Homogenates ◽  
Dose Dependent ◽  
Kinase Pathway

Maintenance of the detumescent state of the penis is believed to involve the actions of several vasoconstrictors. However, our mechanistic understanding of any synergistic vasoconstrictor influences is extremely limited. We tested the hypothesis that a vasoconstrictor combination of endothelin (ET-1) and phenylephrine (PE) augments the constrictor responses in rat corporal cavernosal tissues by a mechanism involving the RhoA-Rho kinase pathway. Independently, ET-1 (1 nM-30 μM) and PE (100 nM-100 μM) both caused dose-dependent contractions of isolated rat cavernosal tissues. In combination, ET-1 (30 nM) augmented the contractile effect of PE and shifted the calculated EC50 for PE (90 ± 12 to 45 ± 5 μM). The active stress generated by cavernosal strips during the ET-1 + PE combined stimulation (4.9 ± 0.2 mN/mm2) was greater than the combined stress generated with ET-1 (0.4 ± 0.1 mN/mm2) or PE (3.3 ± 0.2 mN/mm2) stimulations alone. Blockade of ETA receptors (30 nM; A-127722) reversed the augmented stress generation and the Rho-kinase inhibitor Y-27632 differentially and dose-dependently relaxed the tissue. The combined constrictor effect was associated with a fourfold increase of RhoA in the membrane faction of the tissue homogenates. We conclude that the ET-1 + PE combination potentiate vasoconstriction through mutual activation of the RhoA-Rho kinase pathway. The interactions of these agonists likely play important roles in the maintenance of the flaccid state and contribute to some forms of erectile dysfunction.

scholarly journals Sex differences in the enhanced responsiveness to acute angiotensin II in growth-restricted rats: role of fasudil, a Rho kinase inhibitor

2013 ◽  
Vol 304 (7) ◽  
pp. F900-F907 ◽  
Author(s):  
Norma B. Ojeda ◽  
Thomas P. Royals ◽  
Barbara T. Alexander
Keyword(s):  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Angiotensin Ii ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Ang Ii ◽  
Intact Male ◽  
Rho Kinase Inhibitor

This study tested the hypothesis that Rho kinase contributes to the enhanced pressor response to acute angiotensin II in intact male growth-restricted and gonadectomized female growth-restricted rats. Mean arterial pressure (MAP) and renal function were determined in conscious animals pretreated with enalapril (250 mg/l in drinking water) for 1 wk to block the endogenous renin-angiotensin system and normalize blood pressure (baseline). Blood pressure and renal hemodynamics did not differ at baseline. Acute Ang II (100 ng·kg−1·min−1) induced a greater increase in MAP and renal vascular resistance and enhanced reduction in glomerular filtration rate in intact male growth-restricted rats compared with intact male controls ( P < 0.05). Cotreatment with the Rho kinase inhibitor fasudil (33 μg·kg−1·min−1) significantly attenuated these hemodynamic changes ( P < 0.05), but it did not abolish the differential increase in blood pressure above baseline, suggesting that the impact of intrauterine growth restriction on blood pressure in intact male growth-restricted rats is independent of Rho kinase. Gonadectomy in conjunction with fasudil returned blood pressure back to baseline in male growth-restricted rats, and yet glomerular filtration rate remained significantly reduced ( P < 0.05). Thus, these data suggest a role for enhanced renal sensitivity to acute Ang II in the developmental programming of hypertension in male growth-restricted rats. However, inhibition of Rho kinase had no effect on the basal or enhanced increase in blood pressure induced by acute Ang II in the gonadectomized female growth-restricted rat. Therefore, these studies suggest that Rho kinase inhibition exerts a sex-specific effect on blood pressure sensitivity to acute Ang II in growth-restricted rats.

scholarly journals Effect of Rho-kinase inhibition on vasoconstriction in the penile circulation

2001 ◽  
Vol 91 (3) ◽  
pp. 1269-1273 ◽  
Author(s):  
Thomas M. Mills ◽  
Kanchan Chitaley ◽  
Christopher J. Wingard ◽  
Ronald W. Lewis ◽  
R. Clinton Webb
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Nature Medicine ◽  
Rho Kinase ◽  
Vasodilatory Effect ◽  
Rho Kinase Inhibitor ◽  
Erectile Response ◽  
Kinase Pathway

A recent report from this laboratory (Chitaley K, Wingard C, Webb R, Branam H, Stopper V, Lewis R, and Mills T. Nature Medicine 7: 119–122, 2001) showed that inhibition of Rho-kinase increased the erectile response (intracavernosal pressure and mean arterial pressure) by a process that does not require nitric oxide or cGMP. The present study investigated whether vasoconstrictor agents, which are active in the penis, act via the Rho-kinase pathway. Western analysis revealed RhoA and Rho-kinase protein in the penis. Treatment with the selective Rho-kinase inhibitor Y-27632 significantly increased the magnitude of the erectile response. Intracavernous administration of endothelin-1 (ET-1; 50 pmol) or methoxamine (10 μg/kg) reduced the erectile response to autonomic stimulation. If Y-27632 was given before ET-1 or methoxamine, the vasoconstrictor effect was reduced, and intracavernosal pressure and mean arterial pressure remained elevated. However, when given after methoxamine, Y-27632 had a reduced vasodilatory effect, and Y-27632 had no vasodilatory effect when given after ET-1. These findings suggest that ET-1 and methoxamine increase Rho-kinase activity in the cavernous circulation and support the hypothesis that the vasoconstriction that maintains the penis in the nonerect state is mediated, in part, by the Rho-kinase pathway.

Abstract 4461: Rho-kinase Pathway Plays an Important Role in the Pathogenesis of Coronary Hyperconstricting Responses Induced by Drug-Eluting Stent

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takashi Shiroto ◽  
Satoshi Yasuda ◽  
Ryuji Tsuburaya ◽  
Yoshitaka Ito ◽  
Hatsue Ishibashi-Ueda ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Bare Metal Stent ◽  
Drug Eluting Stent ◽  
Rho Kinase Inhibitor ◽  
Drug Eluting ◽  
Kinase Expression ◽  
Kinase Pathway

It has recently been reported that coronary vasoconstricting responses are enhanced at the edge of coronary segment implanted with drug-eluting stent (DES) as compared with bare-metal stent (BMS) in humans. We have previously demonstrated in animal models and humans that activation of Rho-kinase plays a key role in the molecular mechanism of coronary vasospasm. In this study, we thus examined whether Rho-kinase pathway also is involved in the DES-induced coronary hyperconstriction in vitro and in vivo. In cultured human coronary vascular smooth muscle cells, paclitaxel (10 –1000 nM, comparable tissue concentrations in humans, 24 hours) concentration-dependently up-regulated Rho-kinase expression (n=9) and increased Rho-kinase activity (10 nM, n=6). In a porcine model in vivo, DES (Taxus ™ ) and BMS (Express ™ ) were randomly implanted in the left anterior descending and circumflex coronary arteries (n=5). Four weeks after the implantation, coronary vasoconstricting responses to serotonin (5-HT, 50 and 100 μg/kg, IC) were significantly enhanced at the DES site compared with the BMS site (DES −52±4 vs. BMS −31±5%, P<0.01), and the enhanced responses were prevented by hydroxyfasudil (HF, 90 and 300 μg/kg, IC), a selective Rho-kinase inhibitor ( Figure A ). The same in vivo findings also were noted in another comparison between DES (Cypher ™ ) and BMS (Velocity ™ ) (DES −62±3% vs. BMS −41±3%, n=6, P<0.01) ( Figure B ). Histological analysis showed microthrombus formation only at the DES site. These results suggest that Rho-kinase pathway also plays an important pathogenetic role in the DES-induced coronary hyperconstricting responses.

Endothelin-1-induced contraction in veins is independent of hydrogen peroxide

2005 ◽  
Vol 289 (3) ◽  
pp. H1115-H1122 ◽  
Author(s):  
Keshari Thakali ◽  
Stacie L. Demel ◽  
Gregory D. Fink ◽  
Stephanie W. Watts
Keyword(s):  
Vascular Tone ◽  
Kinase Inhibitor ◽  
Vena Cava ◽  
Rho Kinase ◽  
Oxygen Species ◽  
Endothelin 1 ◽  
Rho Kinase Inhibitor ◽  
Rat Thoracic Aorta ◽  
Vascular Beds ◽  
Kinase Pathway

Reactive oxygen species (ROS), such as superoxide and H2O2, are capable of modifying vascular tone, although the response to ROS can vary qualitatively among vascular beds, experimental procedures, and species. Endothelin-1 (ET-1) induces superoxide production, which can be dismutated to H2O2. The RhoA/Rho kinase pathway partially mediates ET-1-induced contraction and recently was implicated in superoxide-induced contraction. We hypothesized that H2O2, not superoxide, mediates venous ET-1-induced contraction. Rat thoracic aorta and vena cava contracted to exogenously added H2O2 (1 μM–1 mM) [maximum aortic contraction = 10 ± 3% of phenylephrine (10 μM) contraction; maximum venous contraction = 85 ± 13% of norepinephrine (10 μM) contraction]. (+)-( R)- trans-4-(1-aminoethyl- N-4-pyridil)cyclohexanecarboxamide dihydrochloride (Y-27632, 10 μM), a Rho kinase inhibitor, significantly reduced venous H2O2-induced contraction (15 ± 1% of control maximum) and reduced maximum ET-1-induced contraction by 59 ± 1%. However, neither the H2O2 scavenger catalase (100 and 2,000 U/ml) nor cell permeable polyethylene glycol-catalase (163 and 326 U/ml) reduced ET-1-induced contraction in the vena cava. The catalase inhibitor 3-aminotriazole (3-AT) also had no effect on maximal venous ET-1-induced contraction. Basal H2O2 levels were three times higher in the vena cava than in the aorta (vena cava, 0.74 ± 0.09 nmol H2O2/mg protein; aorta, 0.24 ± 0.05 nmol H2O2/mg protein). ET-1 (100 nM) increased H2O2 in the vena cava but not in the aorta (vena cava, 154.10 ± 17.29% of control H2O2; aorta, 83.72 ± 20.20%). Antagonism of either ETA or ETB receptors with the use of atrasentan (30 nM) or BQ-788 (100 nM), respectively, reduced ET-1 (100 nM)-induced increases in venous H2O2. In summary, ET-1 increased H2O2 in veins but not arteries, and venous ET-1-induced H2O2 production was independent of the contractile properties of ET-1.

Mechanical Stress Induces Osteopontin via ATP/P2Y1 in Periodontal Cells

2008 ◽  
Vol 87 (6) ◽  
pp. 564-568 ◽  
Author(s):  
S. Wongkhantee ◽  
T. Yongchaitrakul ◽  
P. Pavasant
Keyword(s):  
Mechanical Stress ◽  
Alveolar Bone ◽  
Kinase Inhibitor ◽  
Inductive Effect ◽  
Rho Kinase ◽  
Chain Reaction ◽  
Kinase Activation ◽  
Rho Kinase Inhibitor ◽  
Polymerase Chain ◽  
Kinase Pathway

Our previous study showed that mechanical stress induced the expression of osteopontin (OPN) in human periodontal ligament (HPDL) cells through the Rho kinase pathway. The increase of OPN expression via Rho kinase has been demonstrated to be triggered by nucleotide. Therefore, we hypothesized that nucleotides, particularly adenosine triphosphate (ATP), participated in the stress-induced OPN expression in HPDL cells. In the present study, the roles of ATP and P2Y1 purinoceptor were examined. Reverse-transcription polymerase chain-reaction and Western blot analysis revealed that the stress-induced ATP exerted its stimulatory effect on OPN expression. The inductive effect was attenuated by apyrase and completely inhibited by the Rho kinase inhibitor, as well as by the P2Y1 antagonist. We here propose that stress induces release of ATP, which in turn mediates Rho kinase activation through the P2Y1 receptor, resulting in the up-regulation of OPN. Stress-induced ATP could play a significant role in alveolar bone resorption.

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