Voltage‐independent calcium entry in hypoxic pulmonary vasoconstriction of intrapulmonary arteries of the rat

Robertson, Tom; Hague, Dominic; Aaronson, Philip I.; Ward, Jeremy P. T.

doi:10.1111/j.1469-7793.2000.t01-1-00669.x

Cited by 160 publications

(209 citation statements)

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“…9). This may in turn promote calcium influx because of the subsequent activation of the store refilling current (43). These findings (43) and our own (11), do not support the view (2-8) that phase 1 of HPV in isolated vessels is mediated by Ca 2ϩ influx through voltage-gated Ca 2ϩ channels.…”

Section: Discussioncontrasting

confidence: 52%

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ADP-ribosyl Cyclase and Cyclic ADP-ribose Hydrolase Act as a Redox Sensor

Wilson

Dipp

Thomas

et al. 2001

Journal of Biological Chemistry

120

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Hypoxic pulmonary vasoconstriction is unique to pulmonary arteries and serves to match lung perfusion to ventilation. However, in disease states this process can promote hypoxic pulmonary hypertension. Hypoxic pulmonary vasoconstriction is associated with increased NADH levels in pulmonary artery smooth muscle and with intracellular Ca 2؉ release from ryanodine-sensitive stores. Because cyclic ADP-ribose (cADPR) regulates ryanodine receptors and is synthesized from ␤-NAD ؉ , we investigated the regulation by ␤-NADH of cADPR synthesis and metabolism and the role of cADPR in hypoxic pulmonary vasoconstriction. Significantly higher rates of cADPR synthesis occurred in smooth muscle homogenates of pulmonary arteries, compared with homogenates of systemic arteries. When the ␤-NAD ؉ :␤-NADH ratio was reduced, the net amount of cADPR accumulated increased. This was due, at least in part, to the inhibition of cADPR hydrolase by ␤-NADH. Furthermore, hypoxia induced a 10-fold increase in cADPR levels in pulmonary artery smooth muscle, and a membrane-permeant cADPR antagonist, 8-bromocADPR, abolished hypoxic pulmonary vasoconstriction in pulmonary artery rings. We propose that the cellular redox state may be coupled via an increase in ␤-NADH levels to enhanced cADPR synthesis, activation of ryanodine receptors, and sarcoplasmic reticulum Ca 2؉ release. This redox-sensing pathway may offer new therapeutic targets for hypoxic pulmonary hypertension.Since it was first described over 50 years ago, hypoxic pulmonary vasoconstriction (HPV) 1 has been recognized as the critical and distinguishing characteristic of the blood vessels of the lung (1). Thus, in marked contrast to systemic arteries, which dilate in response to hypoxia, pulmonary arteries constrict. Physiologically, HPV contributes to the matching of lung perfusion and ventilation. However, when alveolar hypoxia is global, as it is in disease states such as cystic fibrosis, emphysema, and mountain sickness, it results in pulmonary hypertension, which can ultimately lead to right heart failure. Unfortunately, the precise mechanisms that underpin HPV remain to be identified, and current therapies for hypoxic pulmonary hypertension are poor.Certain key characteristics of HPV have been described. In isolated pulmonary arteries, HPV is biphasic. An initial transient constriction (phase 1) is followed by a slowly developing, sustained phase of constriction (phase 2). It is widely thought that the first phase of constriction is initiated by a reduction in membrane K ϩ conductance in pulmonary artery smooth muscle cells (2-4), membrane depolarization, and Ca 2ϩ influx through voltage-gated Ca 2ϩ channels (5-8). Phase 2 of the constriction is tonic and may depend on the release of a vasoconstrictor from the endothelium, which sensitizes the contractile apparatus to Ca 2ϩ (9, 10). Our recent findings (11) do not support the above hypothesis. They suggest that hypoxia may, by activating a mechanism intrinsic to pulmonary artery smooth muscle cells, induce intracellular Ca 2ϩ rele...

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Section: Discussioncontrasting

confidence: 52%

“…Recent investigations have suggested that phase 1 of HPV may result from an initial fall in ATP levels and inhibition of the SR Ca 2ϩ ATPase, leading to an increase in the net efflux of Ca 2ϩ from the SR (Ref. 43 and Fig. 9).…”

Section: Discussionmentioning

confidence: 99%

ADP-ribosyl Cyclase and Cyclic ADP-ribose Hydrolase Act as a Redox Sensor

Wilson

Dipp

Thomas

et al. 2001

Journal of Biological Chemistry

120

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“…Hypoxia causes intracellular Ca 2+ increase, reaching maximum level in 1-2 min, and this is sustained during hypoxia, reversing on return to normoxia (Robertson et al, 2000). Urena et al (1996) found that in conduit pulmonary artery smooth muscle cell, hypoxia reduced basal intracellular Ca 2+ and decreased Ca 2+ spikes (Urena et al, 1996), consistent with the lack of significant HPV in conduit pulmonary arteries (Archer et al, 1996).…”

Section: Potassium Channelssupporting

confidence: 64%

Hypoxic Pulmonary Arterial Hypertension in the Chicken Model

Hernández¹,

Sandino²

2011

Pulmonary Hypertension - From Bench Research to Clinical Challenges

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“…Calcium accumulation occurs by release from intracellular stores such as the sarcoplasmic reticulum or influx through voltage-dependent channels. Investigators have shown that blocking calcium channels (2,10,22), depletion of intracellular calcium stores (6,8,9,22), and removing extracellular calcium (10, 13) inhibit hypoxic contraction, whereas calcium agonists potentiate HPV (24). Thus we speculate that the downstream events in PKC activation during hypoxia involve calcium influx and subsequent smooth muscle contraction.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Tsai¹,

Wang²,

Pitcher³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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. Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C. Am J Physiol Lung Cell Mol Physiol 287: L1215-L1219, 2004. First published August 20, 2004 doi:10.1152/ ajplung.00179.2004.-Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. Concomitant production of proinflammatory mediators during hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the PKC inhibitors calphostin C or chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator thymeleatoxin for 60 min. After hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to mRNA analysis for TNF-␣ and IL-1␤ via RT-PCR. Our results showed that, in isolated pulmonary arteries, hypoxia caused a biphasic contraction and increased expression of TNF-␣ and IL-1␤ mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-␣ and IL-1␤ mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application. hypoxia; pulmonary hypertension; inflammation; tumor necrosis factor HYPOXIA FREQUENTLY OCCURS in conjunction with inflammatory conditions such as the acute respiratory distress syndrome or severe pulmonary infection. In the absence of infection, an inflammatory response may occur following acute injuries such as ischemia-reperfusion and hypoxia (4, 17). Although much data exist regarding the systemic release of proinflammatory cytokines following acute injury, little is known about the local tissue production of inflammatory cytokines. It is now known that cardiomyocytes generate an intense inflammatory response following acute ischemia-reperfusion injury (14), and these inflammatory mediators contribute to myocardial dysfunction. Therefore, it is possible that hypoxia may stimulate inflammatory cytokine expression from the pulmonary artery (PA) tissue itself.The signaling pathways involved in generating an acute inflammatory response involve mediators such as protein kinase C (PKC). PKC is a regulatory enzyme activated by numerous effectors, growth factors, hormones, and ne...

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Voltage‐independent calcium entry in hypoxic pulmonary vasoconstriction of intrapulmonary arteries of the rat

Cited by 160 publications

References 48 publications

ADP-ribosyl Cyclase and Cyclic ADP-ribose Hydrolase Act as a Redox Sensor

ADP-ribosyl Cyclase and Cyclic ADP-ribose Hydrolase Act as a Redox Sensor

Hypoxic Pulmonary Arterial Hypertension in the Chicken Model

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

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