scholarly journals Rho-Kinase Inhibition Attenuates Acute Hypoxic Fetoplacental Vasoconstriction in the Rat

2012 ◽  
pp. S43-S48 ◽  
Author(s):  
P. KAFKA ◽  
O. VAJNEROVÁ ◽  
J. HERGET ◽  
V. HAMPL
Keyword(s):  
Calcium Influx ◽  
Acute Hypoxia ◽  
Rho Kinase ◽  
Calcium Sensitization ◽  
Constant Flow Rate ◽  
Vascular Beds ◽  
Kinase Signaling Pathway ◽  
Kinase Pathway ◽  
Hypoxic Gas Mixture

The vessels on the fetal side of the placenta differ from most other vascular beds except the lungs in that they respond to acute hypoxia by vasoconstriction. An essential role of calcium influx in the mechanism of this hypoxic fetoplacental vasoconstriction (HFPV) has been shown previously. That finding does not, however, exclude the possible involvement of other mechanisms of vascular tone regulation. In this study we tested the hypothesis that Rho-kinase-mediated calcium sensitization is involved in HFPV. We used a model of isolated rat placenta dually perfused (from both the maternal and fetal side) with Krebs salt solution saturated with normoxic and hypoxic gas mixture respectively at constant flow rate. Rho-kinase pathway was inhibited by fasudil (10 μM). We found that fasudil reduced basal normoxic fetoplacental vascular resistance and completely prevented HFPV. This suggests that the activity of Rho-kinase signaling pathway is essential for HFPV.

Role of the RhoA/Rho-kinase pathway in the regulation of pulmonary vasoconstrictor function

2010 ◽  
Vol 88 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Bobby D. Nossaman ◽  
Vaughn E. Nossaman ◽  
Subramanyam N. Murthy ◽  
Philip J. Kadowitz
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Calcium Binding ◽  
Rho Kinase ◽  
Smooth Muscle Contraction ◽  
Downstream Effector ◽  
Downstream Effectors ◽  
Vascular Beds ◽  
Kinase Pathway

Calcium is the major intracellular messenger that triggers smooth muscle contraction. The study of calcium-binding proteins, such as calmodulin and its downstream effectors, reveals critical regulation of smooth muscle contraction by protein kinases and phosphatases. Moreover, the small GTP-binding protein RhoA and its downstream effector protein, Rho-kinase, have been shown to play a novel role in the regulation of smooth muscle contraction. Studies have shown that the activation of Rho-kinase is involved in the development of endothelial dysfunction, inflammation, restenosis, and increased vascular tone in a number of cardiovascular disorders. Because inhibitors of this pathway promote vasodilation independent of the mechanism that increases vasoconstrictor tone, it is our hypothesis that Rho-kinase is constitutively active in regulating vasoconstrictor tone in the pulmonary and systemic vascular beds. Studies in the literature suggest that the RhoA/Rho-kinase pathway has an important role in the pathogenesis of pulmonary hypertension.

scholarly journals Rho-kinase inhibition reduces pressure-mediated autoregulatory adjustments in afferent arteriolar diameter

2009 ◽  
Vol 296 (3) ◽  
pp. F590-F597 ◽  
Author(s):  
Edward W. Inscho ◽  
Anthony K. Cook ◽  
R. Clinton Webb ◽  
Li-Ming Jin
Keyword(s):  
Angiotensin Ii ◽  
Calcium Influx ◽  
Rho Kinase ◽  
Receptor Activation ◽  
Kinase Inhibition ◽  
Calcium Sensitization ◽  
Intact Kidney ◽  
Arteriolar Diameter

Preglomerular resistance is regulated by calcium influx- and mobilization-dependent mechanisms; however, the role of Rho-kinase in calcium sensitization in the intact kidney has not been carefully examined. Experiments were performed to test the hypothesis that Rho-kinase inhibition blunts pressure-mediated afferent arteriolar autoregulatory behavior and vasoconstrictor responses evoked by angiotensin II and P2X1 receptor activation. Rat kidneys were studied in vitro using the blood-perfused juxtamedullary nephron technique. Autoregulatory behavior was assessed before and during Rho-kinase inhibition with Y-27632 (1.0 μM; n = 5). Control diameter averaged 14.3 ± 0.8 μm and increased to 18.1 ± 0.9 μm ( P < 0.05) during Y-27632 treatment. In the continued presence of Y-27632, reducing perfusion pressure to 65 mmHg slightly increased diameter to 18.7 ± 1.0 μm. Subsequent pressure increases to 130 and 160 mmHg yielded afferent arteriolar diameters of 17.5 ± 0.8 and 16.6 ± 0.6 μm ( P < 0.05). This 11% decline in diameter is significantly smaller than the 40% decrease obtained in untreated kidneys. The inhibitory effects of Y-27632 on autoregulatory behavior were concentration dependent. Angiotensin II responses were blunted by Y-27632. Angiotensin II (1.0 nM) reduced afferent diameter by 17 ± 1% in untreated arterioles and by 6 ± 2% during exposure to Y-27632. The P2X1 receptor agonist, α, β-methylene ATP, reduced afferent arteriolar diameter by 8 ± 1% but this response was eliminated during exposure to Y-27632. Western blot analysis confirms expression of the Rho-kinase signaling pathway. Thus, Rho-kinase may be important in pressure-mediated autoregulatory adjustments in preglomerular resistance and responsiveness to angiotensin II and autoregulatory P2X1 receptor agonists.

scholarly journals Role of mineralocorticoid receptor/Rho/Rho-kinase pathway in obesity-related renal injury

2011 ◽  
Vol 36 (8) ◽  
pp. 1062-1071 ◽  
Author(s):  
H Tokuyama ◽  
S Wakino ◽  
Y Hara ◽  
N Washida ◽  
K Fujimura ◽  
...  
Keyword(s):  
Renal Injury ◽  
Mineralocorticoid Receptor ◽  
Rho Kinase ◽  
Kinase Pathway

scholarly journals Developmental changes in contractile responses to cholinergic stimuli: role of calcium sensitization and related pathways

2017 ◽  
Vol 313 (2) ◽  
pp. F370-F377
Author(s):  
Young Jae Im ◽  
Jung Keun Lee ◽  
Sun Hee Lee ◽  
Seung-June Oh ◽  
Kwanjin Park
Keyword(s):  
Contractile Response ◽  
Rho Kinase ◽  
Calcium Sensitivity ◽  
Developmental Changes ◽  
Cholinergic Stimulation ◽  
Contractile Responses ◽  
Calcium Sensitization ◽  
Kinase C ◽  
External Calcium

This study was performed to analyze the developmental changes in bladder response to cholinergic stimulation in detail, highlighting calcium sensitization (CS) and its related pathways. Rats were divided into three groups in accordance with reported time of developmental milestones (newborns, days 1–4; youngsters, days 5–14; and grown-ups, days 15–28). Following cholinergic stimulation (carbachol, 5 µM), the contractile response to detrusor was analyzed with respect to three phases (initial phasic, tonic, and superimposed phasic contractions). Contractile responses were analyzed by their dynamic and kinetic aspects. The responses were further compared in varying external calcium concentrations and in the presence of inhibitors of protein kinase C (PKC) and Rho kinase (ROCK), which are involved in CS. The responses of newborns contrasted with the others by their short and brisk initial phasic contractions, prominent tonic contractions, and delayed participation of irregular superimposed phasic contractions. With development, phasic contractions became prominent, and tonic contractions diminished. These developmental changes in phasic contractions were reproduced when exposed to increasing calcium concentrations. Application of specific inhibitors and molecular phasic analysis revealed that PKC was functional in tonic contractions of the newborns, whereas ROCK took over its role with development. Within a few days of birth, rats’ bladders experienced drastic changes in contractile mechanisms. This included dominance of phasic contractions over tonic contractions due to increased calcium dependence and the maturational shift of the calcium sensitivity mechanism from PKC to ROCK.

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.

Critical role of the Rho-kinase pathway in TGF-β2-dependent collagen gel contraction by retinal pigment epithelial cells

2006 ◽  
Vol 82 (5) ◽  
pp. 849-859 ◽  
Author(s):  
Muneki Miura ◽  
Yasuaki Hata ◽  
Kumiko Hirayama ◽  
Takeshi Kita ◽  
Yoshihiro Noda ◽  
...  
Keyword(s):  
Retinal Pigment Epithelial ◽  
Retinal Pigment ◽  
Critical Role ◽  
Rho Kinase ◽  
Collagen Gel ◽  
Retinal Pigment Epithelial Cells ◽  
Collagen Gel Contraction ◽  
Kinase Pathway ◽  
Pigment Epithelial Cells

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.

Effect of changes in pH on wall tension in isolated rat pulmonary artery: role of the RhoA/Rho-kinase pathway

2004 ◽  
Vol 287 (4) ◽  
pp. L673-L684 ◽  
Author(s):  
Jean-Marc Hyvelin ◽  
Clare O’Connor ◽  
Paul McLoughlin
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Kinase Inhibitor ◽  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Systemic Circulation ◽  
Pulmonary Vasculature ◽  
Tension Development ◽  
Kinase Pathway

Pulmonary arteries (PA) are resistant to the vasodilator effects of extracellular acidosis in systemic vessels; the mechanism underlying this difference between systemic and pulmonary circulations has not been elucidated. We hypothesized that RhoA/Rho-kinase-mediated Ca2+ sensitization pathway played a greater role in tension development in pulmonary than in systemic vascular smooth muscle and that this pathway was insensitive to acidosis. In arterial rings contracted with the α1-agonist phenylephrine (PE), the Rho-kinase inhibitor Y-27632 (≤3 μM) induced greater relaxation in precontracted PA rings than in aortic rings. In PA rings stimulated by PE, the activation of RhoA was greater than in aorta. Normocapnic acidosis (NA) induced a smaller relaxation in precontracted PA than in aorta. However, in the presence of nifedipine and thapsigargin, when PE-induced contraction was predominantly mediated by Rho-kinase, the relaxant effect of NA was reduced and similar in both vessel types. Furthermore, in the presence of Y-27632, NA induced a greater relaxation in both PA and aorta, which was similar in both vessels. Finally, in α-toxin-permeabilized smooth muscle, PE-induced contraction at constant Ca2+ activity was inhibited by Y-27632 and unaffected by acidosis. These results indicate that Ca2+ sensitization induced by the RhoA/Rho-kinase pathway played a greater role in agonist-induced vascular smooth muscle contraction in PA than in aorta and that tension mediated by this pathway was insensitive to acidosis. The predominant role of the RhoA/Rho-kinase pathway in the pulmonary vasculature may account for the resistance of this circulation to the vasodilator effect of acidosis observed in the systemic circulation.

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