Inhibition of sustained hypoxic vasoconstriction by Y‐27632 in isolated intrapulmonary arteries and perfused lung of the rat

Robertson, Tom; Dipp, Michelle; Ward, Jeremy P. T.; Aaronson, Philip I.; Evans, A. Mark

doi:10.1038/sj.bjp.0703537

Cited by 145 publications

(151 citation statements)

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“…For sustained HPV in particular, a Ca 2+ sensitisation, in addition to an increase in calcium, possibly via activation of Rho-kinase, has been suggested [66][67][68]. A recent point-counterpoint discussion summarised the debate regarding Ca 2+ sensitisation as a further possible mechanism for HPV [69].…”

Section: Signal Transduction and Effector Mechanism: About Contractiomentioning

confidence: 99%

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

Sommer¹,

Dietrich²,

Schermuly³

et al. 2008

Eur Respir J

186

142

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Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is a physiological response to alveolar hypoxia which distributes pulmonary capillary blood flow to alveolar areas of high oxygen partial pressure.Impairment of this mechanism may result in hypoxaemia. Under conditions of chronic hypoxia generalised vasoconstriction of the pulmonary vasculature in concert with hypoxia-induced vascular remodelling leads to pulmonary hypertension. Although the principle of HPV was recognised decades ago, its exact pathway still remains elusive. Neither the oxygen sensing process nor the exact pathway underlying HPV is fully deciphered yet. The effector pathway is suggested to include L-type calcium channels, nonspecific cation channels and voltagedependent potassium channels, whereas mitochondria and nicotinamide adenine dinucleotide phosphate oxidases are discussed as oxygen sensors. Reactive oxygen species, redox couples and adenosine monophosphate-activated kinases are under investigation as mediators of hypoxic pulmonary vasoconstriction. Moreover, the role of calcium sensitisation, intracellular calcium stores and direction of change of reactive oxygen species is still under debate.In this context the present article focuses on the basic mechanisms of hypoxic pulmonary vasoconstriction and also outlines differences in current concepts that have been suggested for the regulation of hypoxic pulmonary vasoconstriction.

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Section: Signal Transduction and Effector Mechanism: About Contractiomentioning

confidence: 99%

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

Sommer¹,

Dietrich²,

Schermuly³

et al. 2008

Eur Respir J

186

142

View full text Add to dashboard Cite

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“…Rho kinase (ROCK) is a family of serine/threonine protein kinases, stimulated by G proteincoupled receptor activation of small plasma membranebound GTP-binding proteins, such as the Rho and Rac family. Relevant to the pathophysiology of myocardial infarction, potent stimuli for ROCK activation include hypoxia (25), pressor mediators such as endothelin-1, angiotensin II, and norepinephrine (29,30), and mitochondrially derived reactive oxygen species (2). In the cardiovascular system, the diverse outcomes of ROCK signaling include effects on cardiac myocyte hypertrophy, vascular smooth muscle tone, and vascular smooth muscle cell proliferation and cell migration (20,15,24).…”

mentioning

confidence: 99%

Rho kinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium

Hamid¹,

Bower²,

Baxter³

2007

American Journal of Physiology-Heart and Circulatory Physiology

104

116

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Hamid SA, Bower HS, Baxter GF. Rho kinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium. Am J Physiol Heart Circ Physiol 292: H2598 -H2606, 2007. First published January 12, 2007; doi:10.1152/ajpheart.01393.2006.-Intracellular signal transduction events in reperfusion following ischemia influence myocardial infarct development. Here we investigate the role of Rho kinase (ROCK) activation as a specific injury signal during reperfusion via attenuation of the reperfusion injury salvage kinase (RISK) pathway phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric oxide (NO) synthase (eNOS). Rat isolated hearts underwent 35 min of left coronary artery occlusion and 120 min of reperfusion. Phosphorylation of the ROCK substrate protein complex ezrin-radixin-moesin, assessed by immunoblotting and immunofluorescence, was used as a marker of ROCK activation. Infarct size was determined by tetrazolium staining, and terminal dUTP nick-end labeling (TUNEL) positivity was used as an index of apoptosis. The ROCK inhibitors fasudil or Y-27632 given 10 min before ischemia until 10 min after reperfusion reduced infarct size (control, 34.1 Ϯ 3.8%; 5 M fasudil, 18.2 Ϯ 3.1%; 0.3 M Y-27632, 19.4 Ϯ 4.4%; 5 M Y-27632, 9.2 Ϯ 2.9%). When 5 M Y-27632 was targeted specifically during early reperfusion, robust infarct limitation was observed (14.2 Ϯ 2.6% vs. control 33.4 Ϯ 4.4%, P Ͻ 0.01). The protective action of Y-27632 given at reperfusion was attenuated by wortmannin (29.2 Ϯ 6.1%) and N -nitro-L-arginine methyl ester (30.4 Ϯ 5.7%), confirming a protective mechanism involving PI3K/Akt/NO. Ezrin-radixin-moesin phosphorylation in risk zone myocardium confirmed early and sustained ROCK activation during reperfusion and its inhibition by Y-27632. Inhibition of ROCK activation at reperfusion reduced the proportion of TUNEL-positive nuclei in the infarcted region. In conclusion, ROCK activation occurs specifically during early reperfusion. Inhibition of ROCK at reperfusion onset limits infarct size through an Akt/eNOS-dependent mechanism, suggesting that ROCK activation at reperfusion may be deleterious through suppression of the RISK pathway. apoptosis; myocardial infarction; nitric oxide DESPITE THE UNQUESTIONED NEED for reperfusion to prevent ischemic necrosis in acute myocardial infarction, there is accumulating experimental evidence that reperfusion is associated with the paradoxical activation of lethal signals that culminate in necrosis/apoptosis. Indeed, recent experimental evidence suggests that reperfusion may contribute to a far greater extent than was previously supposed (8, 9). Whereas this does not detract from the proven therapeutic value of reperfusion, it prompts a reassessment of reperfusion injury and its mechanisms. Rho kinase (ROCK) is a family of serine/threonine protein kinases, stimulated by G proteincoupled receptor activation of small plasma membranebound GTP-binding proteins, such as the Rho and Rac family. Relevant to the pathophysiology of myocardial infarction, pot...

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“…pulmonary circulation; arteries; hypoxia THE MECHANISM(S) UNDERLYING hypoxic pulmonary vasoconstriction (HPV), a unique and vital homeostatic mechanism that matches ventilation to perfusion in the event of localized alveolar hypoxia (32), remain unresolved. Because HPV can be observed in isolated pulmonary arteries (8,10,18,22,24,25), the oxygen sensor and subsequent constrictor mechanism(s) must reside in either the smooth muscle, endothelium, or both. In rat intrapulmonary arteries (IPA), the response to acute hypoxia, usually in the presence of a small degree of agonist-induced tone, is biphasic in nature (9,10,18,19,(22)(23)(24)(25)(26), consisting of an initial transient rise in tension (phase I) superimposed on a more slowly developing sustained constriction (phase II).…”

mentioning

confidence: 99%

Ca²⁺ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent

Robertson

Aaronson

Ward

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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Robertson, Tom P., Philip I. Aaronson, and Jeremy P. T. Ward. Ca 2ϩ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent. Am J Physiol Lung Cell Mol Physiol 284: L1121-L1126, 2003. First published February 28, 2003 10.1152/ajplung.00422. 2002The main aim of this study was to determine the effects of endothelium removal on tension and intracellular Ca 2ϩ ([Ca 2ϩ ]i) during hypoxic pulmonary vasoconstriction (HPV) in rat isolated intrapulmonary arteries (IPA). Rat IPA and mesenteric arteries (MA) were mounted on myographs and loaded with the Ca 2ϩ -sensitive fluorophore fura PE-3. Arteries were precontracted with prostaglandin F 2␣, and the effects of hypoxia were examined. HPV in isolated IPA consisted of a transient constriction superimposed on a second sustained phase. Only the latter phase was abolished by endothelial denudation. However, removal of the endothelium had no effect on [Ca 2ϩ ]i at any point during HPV. The endothelin-1 antagonists BQ-123 and BQ-788 did not affect HPV, although constriction induced by 100 nM endothelin-1 was abolished. In MA, hypoxia induced an initial transient rise in tension and [Ca 2ϩ ]i, followed by vasodilatation and a fall in [Ca 2ϩ ]i to (but not below) prehypoxic levels. These results are consistent with sustained HPV being mediated by an endothelium-derived constrictor factor that is distinct from endothelin-1 and that elicits vasoconstriction via Ca 2ϩ sensitization. pulmonary circulation; arteries; hypoxia THE MECHANISM(S) UNDERLYING hypoxic pulmonary vasoconstriction (HPV), a unique and vital homeostatic mechanism that matches ventilation to perfusion in the event of localized alveolar hypoxia (32), remain unresolved. Because HPV can be observed in isolated pulmonary arteries (8,10,18,22,24,25), the oxygen sensor and subsequent constrictor mechanism(s) must reside in either the smooth muscle, endothelium, or both. In rat intrapulmonary arteries (IPA), the response to acute hypoxia, usually in the presence of a small degree of agonist-induced tone, is biphasic in nature (9,10,18,19,(22)(23)(24)(25)(26), consisting of an initial transient rise in tension (phase I) superimposed on a more slowly developing sustained constriction (phase II). Under similar experimental conditions, an almost identical transient phase I constriction has been observed in a variety of isolated systemic arteries (6, 22, 37), whereas the second phase of the response in systemic arteries to hypoxia is vasodilatation (22). Because the phase II constriction is peculiar to pulmonary arteries, we have argued that phase II is the more physiologically important process for sustained HPV (2, 33). In support of this contention, we have reported that the selective Rho kinase antagonist Y-27632 inhibited the hypoxic pressor response in perfused rat lungs yet only inhibited the second phase of HPV in rat isolated arteries (25).We have reported that the sustained phase II constriction of HPV is endothelium dependent (22). This is in agreement with other reports th...

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Inhibition of sustained hypoxic vasoconstriction by Y‐27632 in isolated intrapulmonary arteries and perfused lung of the rat

Cited by 145 publications

References 17 publications

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

Rho kinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium

Ca²⁺ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent

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Inhibition of sustained hypoxic vasoconstriction by Y‐27632 in isolated intrapulmonary arteries and perfused lung of the rat

Cited by 145 publications

References 17 publications

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

Rho kinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium

Ca2+ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent

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Ca²⁺ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent