Chronic hypoxia-induced spontaneous and rhythmic contractions in the rat main pulmonary artery

Bonnet, Sébastien; Hyvelin, Jean-Marc; Bonnet, Pierre; Marthan, Roger; Savineau, Jean‐Pierre

doi:10.1152/ajplung.2001.281.1.l183

Cited by 30 publications

(44 citation statements)

References 29 publications

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“…The vasoconstriction was not due to the inhibition of EDHF activity, because neither agent inhibited the EDHF-mediated vasodilation, and charybdotoxin plus apamin did not elicit the response. In contrast to its vasoconstrictor effect in perfused hypertensive lungs, 18␣-glycyrrhetinic acid inhibits spontaneous contractions and causes relaxation of hypertensive main pulmonary arteries from chronically hypoxic rats (4).…”

Section: Discussionmentioning

confidence: 94%

EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs

Morio

Carter

Oka

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs. Am J Physiol Heart Circ Physiol 284: H1762-H1770, 2003. First published January 9, 2003 10.1152/ajpheart.00831.2002The role of endothelium-derived hyperpolarizing factor (EDHF) in regulating the pulmonary circulation and the participation of cytochrome P-450 (CYP450) activity and gap junction intercellular communication in EDHF-mediated pulmonary vasodilation are unclear. We tested whether tonic EDHF activity regulated pulmonary vascular tone and examined the mechanism of EDHF-mediated pulmonary vasodilation induced by thapsigargin in salt solution-perfused normotensive and hypoxia-induced hypertensive rat lungs. After blockade of both cyclooxygenase and nitric oxide synthase, inhibition of EDHF with charybdotoxin plus apamin did not affect either normotensive or hypertensive vascular tone or acute hypoxic vasoconstriction but abolished thapsigargin vasodilation in both groups of lungs. The CYP450 inhibitors 7-ethoxyresorufin and sulfaphenazole and the gap junction inhibitor palmitoleic acid, but not 18␣-glycyrrhetinic acid, inhibited thapsigargin vasodilation in normotensive lungs. None of these agents inhibited the vasodilation in hypertensive lungs. Thus tonic EDHF activity does not regulate either normotensive or hypertensive pulmonary vascular tone or acute hypoxic vasoconstriction. Whereas thapsigargin-induced EDHF-mediated vasodilation in normotensive rat lungs involves CYP450 activity and might act through gap junctions, the mechanism of vasodilation is apparently different in hypertensive lungs. pulmonary vasoregulation; pulmonary hypertension; endothelium-derived hyperpolarizing factor; cytochrome P-

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Section: Discussionmentioning

confidence: 94%

EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs

Morio

Carter

Oka

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…The rhythmic contraction of pulmonary artery was reported in different types of PAH models in rats, which is induced by either chronic hypoxia (18) or MCT (7), as well as a 4-day-organoid culture of pulmonary artery in vitro (19). The ionic mechanism for developing rhythmic contraction has been explained by membrane depolarization activating L-type calcium channels, which is balanced by calcium-activated potassium channel activity (19) and also by calcium-induced calcium release (7,18).…”

Section: Discussionmentioning

confidence: 99%

“…The ionic mechanism for developing rhythmic contraction has been explained by membrane depolarization activating L-type calcium channels, which is balanced by calcium-activated potassium channel activity (19) and also by calcium-induced calcium release (7,18). In addition, we previously suggested that PGH 2 might be involved in the stretch-induced rhythmic contraction of pulmonary arteries of MCT-PHR, because indomethacin and the PGH 2 /thromboxane A 2 receptor antagonist ), which were expressed in the bathing solution containing 100 μM of RGD-peptide.…”

Section: Discussionmentioning

confidence: 99%

Role of Secretory Phospholipase A2 in Rhythmic Contraction of Pulmonary Arteries of Rats With Monocrotaline-Induced Pulmonary Arterial Hypertension

et al. 2012

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Abstract. Excessive stretching of the vascular wall in accordance with pulmonary arterial hypertension (PAH) induces a variety of pathogenic cellular events in the pulmonary arteries. We previously reported that indoxam, a selective inhibitor for secretory phospholipase A 2 (sPLA 2 ), blocked the stretch-induced contraction of rabbit pulmonary arteries by inhibition of untransformed prostaglandin H 2 (PGH 2 ) production. The present study was undertaken to investigate involvement of sPLA 2 and untransformed PGH 2 in the enhanced contractility of pulmonary arteries of experimental PAH in rats. Among all the known isoforms of sPLA 2 , sPLA 2 -X transcript was most significantly augmented in the pulmonary arteries of rats with monocrotaline-induced pulmonary hypertension (MCT-PHR). The pulmonary arteries of MCT-PHR frequently showed two types of spontaneous contraction in response to stretch; 27% showed rhythmic contraction, which was sensitive to indoxam and SC-560 (selective COX-1 inhibitor), but less sensitive to NS-398 (selective COX-2 inhibitor); and 47% showed sustained incremental tension (tonic contraction), which was insensitive to indoxam and SC-560, but sensitive to NS-398 and was attenuated to 45% of the control. Only the rhythmically contracting pulmonary arteries of MCT-PHR produced a substantial amount of untransformed PGH 2 , which was abolished by indoxam. These results suggest that sPLA 2 -mediated PGH 2 synthesis plays an important role in the rhythmic contraction of pulmonary arteries of MCT-PHR.

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“…Isometric Contraction Measurement. Isometric contractions were measured in rings from IPAs that were mounted in vertical 5-ml organ baths of a computerized isolated organ bath system (IOX, EMKA Technologies, Paris) as described (17). Baths were filled with Krebs-Henseleit solution (composition in mM: 118.4 NaCl͞4.7 KCl͞2.5 CaCl 2 ͞1.2 MgSO 4 ͞1.2 KH 2 PO 4 ͞25 NaHCO 3 ͞ 11.1 D-glucose, pH 7.4) maintained at 37°C and bubbled with a 95% O 2 ͞5% CO 2 gas mixture.…”

Section: Methodsmentioning

confidence: 99%

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

Bonnet

Roque

Bégueret

et al. 2003

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

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127

121

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Pulmonary artery (PA) hypertension was studied in a chronic hypoxic-pulmonary hypertension model (7-21 days) in the rat. Increase in PA pressure (measured by catheterism), cardiac right ventricle hypertrophy (determined by echocardiography), and PA remodeling (evaluated by histology) were almost entirely prevented after oral dehydroepiandrosterone (DHEA) administration (30 mg͞kg every alternate day). Furthermore, in hypertensive rats, oral administration, or intravascular injection (into the jugular vein) of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA reduced the level of intracellular calcium (measured by microspectrofluorimetry). The effect of DHEA appears to involve a large conductance Ca 2؉ -activated potassium channel (BK Ca)-dependent stimulatory mechanism, at both function and expression levels (isometric contraction and Western blot), via a redox-dependent pathway. Voltage-gated potassium (Kv) channels also may be involved because the antagonist 4-amino-pyridine blocked part of the DHEA effect. The possible pathophysiological and therapeutic significance of the results is discussed.hypoxia ͉ potassium channels E xposure of animals to chronic hypoxia leads to the development of chronic hypoxic-pulmonary hypertension (CH-PHT). In human beings CH-PHT is frequently associated with severe pulmonary diseases. CH-PHT involve pulmonary arterial vasoconstriction and remodeling (1). Although the endothelium is involved in the pathogenesis of CH-PHT, the role of vascular smooth muscle cells (SMCs) is increasingly recognized (2).Both the contractile status and the proliferative status of SMCs are regulated by the levels of intracellular Ca 2ϩ ([Ca 2ϩ ] i ). The [Ca 2ϩ ] i levels are determined in part by the influx of Ca 2ϩ through the voltage-gated, L-type Ca 2ϩ channels. In pulmonary artery (PA) SMCs, the membrane potential is regulated by large conductance Ca 2ϩ -activated channels (BK Ca ) (3) and voltagegated K ϩ channels (Kv), including shaker family Kv (4, 5). K channel (BK Ca and Kv) function and expression are downregulated with development and maintenance of CH-PHT (6, 7). CH reduces K current density in PASMCs, resulting in a state of depolarization (8, 9), followed by elevation of [Ca 2ϩ ] i , which induces contraction and proliferation (10).The mechanism for K channel down-regulation is unclear, but recent work suggests that it is related to the altered redox state induced by CH (8). Lungs of rats with CH-PHT are in a more reduced redox state than those of normoxic controls, as indicated by increased levels of reduced glutathione (8). A reduced redox state has potential for both short-term effects through modulation of K ϩ channels function (11) and long-term effects by activating several oxygen-responsive genes including hypoxiainducible factor (HIF) (12).We sought to enhance expression and function of BK Ca by using DHEA, a BK Ca opener in hypoxic human pulmonary cells (13), which can shift the redox balance toward an oxidized state leading to both BK Ca and Kv activatio...

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Chronic hypoxia-induced spontaneous and rhythmic contractions in the rat main pulmonary artery

Cited by 30 publications

References 29 publications

EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs

EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs

Role of Secretory Phospholipase A2 in Rhythmic Contraction of Pulmonary Arteries of Rats With Monocrotaline-Induced Pulmonary Arterial Hypertension

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

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