Effect of chronic hypoxia on agonist-induced tone and calcium signaling in rat pulmonary artery

Bonnet, Sébastien; Belus, Alexandra; Hyvelin, Jean-Marc; Roux, Étienne; Marthan, Roger; Savineau, Jean‐Pierre

doi:10.1152/ajplung.2001.281.1.l193

Cited by 54 publications

(59 citation statements)

References 46 publications

(78 reference statements)

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“…Notably, a recent study demonstrated that the alterations in the protein expression profile after allergen sensitisation and challenge partly correlated with those observed in hypoxia [33], which is known to induce PAH and increased vascular responses to vasoconstrictors [34,35].…”

Section: Discussionmentioning

confidence: 99%

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness

Witzenrath¹

2006

European Respiratory Journal

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Pulmonary arterial vasoconstriction is an important early component of pulmonary hypertension. Inflammatory mechanisms play a prominent role in the pathogenesis of pulmonary hypertension. The present authors investigated the potential role of acute allergic lung inflammation for alterations in pulmonary haemodynamics.BALB/c mice were intraperitoneally sensitised to ovalbumin and challenged by ovalbumin inhalation. Subsequently, lungs were ventilated and perfused ex vivo, and pulmonary arterial pressure (Ppa) was continuously monitored.Isolated perfused lungs of allergen-sensitised and -challenged mice showed five-fold enhanced Ppa responses to serotonin, which is reported to be a significant contributor to pulmonary hypertension in humans. This increase in Ppa was abolished by the serotonin receptor-2A antagonist ketanserin, but not the serotonin receptor-1B antagonist GR127935. Intracellular signalling to serotonin involved phosphatidylcholine-specific phospholipase C and protein kinase C, as well as Rho-kinase, as assessed by employing the specific inhibitors D609, bisindolylmaleimide and Y27632, respectively. In addition to serotonin, impressively enhanced Ppa increases in allergic lungs were also evoked by the thromboxane receptor agonist U46619, angiotensin II and endothelin-1.In conclusion, allergic lung inflammation was accompanied by impressive pulmonary vascular hyperresponsiveness. These results suggest a possible role for allergic inflammation in the development of pulmonary arterial hypertension.

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Section: Discussionmentioning

confidence: 99%

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness

Witzenrath¹

2006

European Respiratory Journal

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“…A cumulative concentration-response curve to sildenafil (0.1 nM-1 M) was then constructed on PE-precontracted PA rings. Because reactivity to agonists is reduced in main PA rings from CH rats (4,5,40), 0.3 and 3 M PE were used to obtain the same value of precontraction in rings from control and CH rats, respectively. Some experiments were also performed in endothelium-denuded rings.…”

Section: Methodsmentioning

confidence: 99%

Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats

Pauvert

Bonnet²,

Rousseau³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pauvert, Olivier, Sébastien Bonnet, Eric Rousseau, Roger Marthan, and Jean-Pierre Savineau. Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 287: L577-L583, 2004. First published May 21, 2004 10.1152/ajplung.00449.2003.-Sildenafil, a potent type 5 nucleotide-dependent phosphodiesterase (PDE) inhibitor, has been recently proposed as a therapeutic tool to treat or prevent pulmonary artery hypertension (PAHT). We thus studied the effect of sildenafil on both the calcium signaling of isolated pulmonary artery smooth muscle cells (PASMCs) and the reactivity of pulmonary artery (PA) obtained from chronic hypoxia (CH)-induced pulmonary hypertensive rats compared with control (normoxic) rats. CH rats were maintained in an hypobaric chamber (50.5 kPa) for 3 wk leading to full development of PAHT. Intracellular calcium concentration ([Ca 2ϩ ]i) was measured in PASMCs loaded with the calcium fluorophore indo 1. Unlike in control rats, sildenafil (10 -100 nM) decreased the resting [Ca 2ϩ ]i value in PASMCs obtained from CH rats. In PASMCs from both control and CH rats, sildenafil concentration dependently inhibited the [Ca 2ϩ ]i response induced by G-coupled membrane receptor agonists such as angiotensin II and phenylephrine but had no effect on the amplitude of the [Ca 2ϩ ]i response induced by caffeine. Sildenafil (0.1 nM-1 M) concentration dependently reduced basal PA tone that is present in CH rats and relaxed PA rings precontracted with phenylephrine in both control and CH rats. These data show that sildenafil is a potent pulmonary artery relaxant in CH rats and that it normalizes CH-induced increases in resting [Ca 2ϩ ]i and basal tone. Consequently, pharmacological inhibition of sildenafil-sensitive PDE5 downregulates the Ca 2ϩ signaling pathway involved in this model of pulmonary hypertension. pulmonary hypertension; vascular smooth muscle; phosphodiesterase 5; pulmonary vasodilator INTRACELLULAR CYCLIC NUCLEOTIDE [cAMP and guanosine 3Ј,5Ј-cyclic monophosphate (cGMP)] concentration is implicated in the control of the vascular smooth muscle tone including in the pulmonary artery (PA) (3, 9). Agents elevating cAMP or cGMP concentration relax precontracted PA (35,36,38). For instance, the endothelium-derived factor nitric oxide (NO) induces a dose-dependent increase in cGMP concentration and a step-wise relaxation of PA (30,45). In smooth muscle cells, concentration of cGMP is mainly dependent on the balance between the production by guanylate cyclase and the degradation by phosphodiesterases (PDEs), which represent the unique degradation pathway for these intracellular compounds (34, 44). As a consequence, PDE activity is also implicated in the control of smooth muscle tone, and PDE inhibition relaxes smooth muscle (21,41,46). In PA from rats and humans, four types of PDE (PDE1, 3, 4, and 5) have been identified (23,31,34,36). Hence, the pharmacological modulation of PDE activity (e.g., using selective PDE inhibitor...

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“…For example, the down-regulation of Kv1.5 will lead to PASMC depolarization and opening of L-type Ca 2ϩ channels and will sustain the increase in [Ca 2ϩ ] i and thus NFAT activation. The increase in PASMC [Ca 2ϩ ] i might also be promoted by other possibly primary PASMC abnormalities, like the dys-regulated serotonin transporter, up-regulation of TRP channels (37), or decreased SERCA activity (38). Activation of NFAT will complete a reinforcing positive-feedback loop with the down-regulation of Kv1.5 and may explain why the phenotype is preserved in PASMC in culture, in the absence of endothelium-derived or circulating factors.…”

Section: Mitochondria and Pahmentioning

confidence: 99%

The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted

Bonnet

Rochefort

Sutendra

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

328

391

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In pulmonary arterial hypertension (PAH), antiapoptotic, proliferative, and inflammatory diatheses converge to create an obstructive vasculopathy. A selective down-regulation of the Kv channel Kv1.5 has been described in human and animal PAH. The resultant increase in intracellular free Ca 2؉ ([Ca 2؉ ]i) and K ؉ ([K ؉ ]i) concentrations explains the pulmonary artery smooth muscle cell (PASMC) contraction, proliferation and resistance to apoptosis. The recently described PASMC hyperpolarized mitochondria and increased bcl-2 levels also contribute to apoptosis resistance in PAH. The cause of the Kv1.5, mitochondrial, and inflammatory abnormalities remains unknown. We hypothesized that these abnormalities can be explained in part by an activation of NFAT (nuclear factor of activated T cells), a Ca 2؉ / calcineurin-sensitive transcription factor. We studied PASMC and lungs from six patients with and four without PAH and blood from 23 PAH patients and 10 healthy volunteers.

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Effect of chronic hypoxia on agonist-induced tone and calcium signaling in rat pulmonary artery

Cited by 54 publications

References 46 publications

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness

Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats

The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted

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