Endothelin ETA- and ETB-Receptor-Mediated Vasoconstriction in Rat Pulmonary Arteries and Arterioles

MacLean, Margaret R.; McCulloch, Kirsty; Baird, Michael G.

doi:10.1097/00005344-199405000-00022

Cited by 110 publications

(82 citation statements)

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“…In the human pulmonary artery, the ET A receptors have been found to predominate in arteries from 0.5 to Ͼ8 mm in diameter, although the number of ET B receptors increases with decreasing arterial diameter (3). These data correlate well with contraction assays showing that ET-1-induced contraction of rat proximal arteries is dependent on ET A receptors, whereas in human and rat distal arteries of 150-250 m in diameter, ET B is responsible (27,28). The present study indicates that both receptors are present on normal sheep PLVSMC and that both receptors regulate expression of ppET-1.…”

Section: Discussionsupporting

confidence: 64%

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

Chen

Balyakina

Lawrence³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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-We examined the hypothesis that the potent vasoconstrictor endothelin (ET)-1 regulates both its own production and production of the vasodilator prostaglandins PGE 2 and prostacyclin in sheep peripheral lung vascular smooth muscle cells (PLVSMC). Confluent layers of PLVSMC were exposed to 10 nM ET-1; expression of the prepro (pp)-ET-1, cyclooxygenase (COX)-1, and COX-2 genes was examined by RT-PCR and Western analysis. Intracellular levels of ET-1 were measured by ELISA with and without addition of the protein synthesis inhibitor brefeldin A (50 g/ml). Prostaglandin levels were measured by gas chromatography-mass spectrometry. Through use of ET A and ETB antagonists (BQ-610 and BQ-788, respectively), the contribution of the ET receptors to COX-1 and -2 expression and ppET-1 gene expression was examined. The contribution of phosphorylated p38 and p44/42 MAPK on COX-1 and COX-2 expression was also examined with MAPK inhibitors (p38, SB-203580 and p44/ 42, PD-98056). ET-1 resulted in transient increases in ppET-1, COX-1, and COX-2 gene and protein expression and release of 6-keto-PGF1␣ and PGE2 (P Ͻ 0.05). Both internalization of ET-1 and synthesis of new peptide contributed to an increase in intracellular ET-1 (P Ͻ 0.05). Although increased ppET-1 was regulated by both ETA and ETB, COX-2 expression was upregulated only by ETA; COX-1 expression was unaffected by either antagonist. ET-1 treatment resulted in transient phosphorylation of p38 and p44/42 MAPK; inhibitors of these MAPKs suppressed expression of COX-2 but not COX-1. Our data indicate that local production of ET-1 regulates COX-2 by activation of the ETA receptor and phosphorylation of p38 and p44/42 MAPK in PLVSMC.prostacyclin; prostaglandin E2; endothelin receptors

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Section: Discussionsupporting

confidence: 64%

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

Chen

Balyakina

Lawrence³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The physiological effect of ET-1 is complex, depending on the dose, the initial blood pressure and the type of vascular bed [26,27]. ET-1 induces pulmonary vasoconstriction by activation of both ET-A and ET-B receptors whereas it induces transient vasorelaxation exclusively by activation of ET-B receptors [28,29]. Vasodilatation is partly due to a release of NO [30], prostacyclin [31] and EDHF [32].…”

Section: Discussionmentioning

confidence: 99%

Maturational changes of endothelial vasoactive factors and pulmonary vascular tone at birth

Lévy¹,

Souil²,

Sabry³

et al. 2000

Eur Respir J

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The aim of this study was to determine which endothelial factors were involved in the decrease of pulmonary vascular resistance at birth, and how they changed with maturation.Response of intrapulmonary artery rings precontracted with prostaglandin F 2a were studied from piglets aged <2 h, 2±3 day, 10 day and adult pigs for pharmacological responses to acetylcholine (ACh) and cromakalim (CMK) in the presence and the absence of the nitric oxide synthase (NOS) inhibitor, N v -nitro-L-arginine (L-NA), the adenosine triphosphate sensitive potassium (KATP) channel blocker, glibenclamide and the endothelin (ET)-A receptor antagonist, BQ123. In situ hybridization and immunochemistry studies were performed in lung tissues of the same animals in order to determine the expression of NOS and ET.There was a small contractile effect of ACh in the newborn. Relaxation to ACh, which was blocked by L-NA and reduced by glibenclamide, only appeared from the age of 3 days. The significantly greater relaxation to CMK in rings without endothelium (p<0.05) was abolished by BQ123 in the newborn, and then disappeared by 2 days of age. Glibenclamide had a greater inhibitory effect on relaxation induced by CMK at 10 days than in the newborn and 2 days old piglets. NOS expression was low in pulmonary arteries of the newborn and increased by 2 days of age whereas the converse was seen with ET expression.It is concluded that: 1) relaxant response to acetylcholine was absent at birth and appeared at 2 days; 2) the reduced relaxant response to cromakalin in rings with endothelium at birth could be blocked by BQ123; and 3) the expression of endothelin decreased whereas the expression of nitric oxide synthase increased from birth to 2 days of age. Eur Respir J 2000; 15: 158±165. Pulmonary arterial pressure and resistance are high at birth, and decrease rapidly thereafter due to structural [1±3] and functional [4,5] changes. The underlying mechanisms of these modifications are not fully understood, but nitric oxide (NO) is known to play a role. NO [6±8] is released from the lungs of foetal and newborn animals [5,9,10]. It reduces basal tone in utero and contributes to the postnatal fall in pulmonary vascular resistance. However, endothelium-dependent relaxation to various agonists is either absent [11] or very weak [12] until the third day after birth. Then it rapidly increases during the first week of life [11,12]. These observations suggest that immediately after birth the interactions between the endothelium and the underlying smooth muscle may be different from those in adult porcine pulmonary vasculature.Vasodilators such as NO [13], prostacyclin [14], bradykinin [15], endothelium-derived hyperpolarizing factor (EDHF) [16], and vasoconstrictors such as endothelin (ET)-1 [17] and thromboxane [18] are important factors modulating pulmonary vascular tone. ET-1 plasma levels are higher at birth than at 3 days and in adults [19]. Although endothelium-dependent relaxation to acetylcholine (ACh) is absent, the amount of cyclic guanosine...

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“…The ET A receptor demonstrates higher affinity for ET-1 and ET-2 than ET-3, while the ET B receptor associates equally with all 3 isoforms. Both the ET A and ET B receptors are present on vascular smooth muscle cells and induce direct vasoconstriction and proliferation when stimulated [7,8]. On the other hand, endothelial ET B receptors have been demonstrated to play a dual role.…”

Section: Introductionmentioning

confidence: 99%

Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels

Sauvageau¹,

Thorin²,

Villeneuve³

et al. 2009

Pulmonary Pharmacology & Therapeutics

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Background and purpose-The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH). The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. However, we currently incompletely comprehend what local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists with various selectivities for the receptor subtypes. Therefore, the purposes of this study were to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline (MCT)-induced pulmonary arterial hypertension.Experimental approach-ET-1 levels were quantified by ELISA. PreproET-1, ET A and ET B receptor mRNA expressions were quantified in pulmonary resistance arteries using Q-PCR, while protein expression was evaluated by Western blots. Reactivity to ET-1 of isolated pulmonary resistance arteries was measured in the presence of ET A (A-147627), ET B (A-192621) and dual ET A/B (bosentan) receptor antagonists.Key results-In rats with PAH, plasma ET-1 increased (p < 0.001) while pulmonary levels were reduced (p < 0.05). In PAH arteries, preproET-1 (p < 0.05) and ET B receptor (p < 0.001) gene expressions were reduced, as were ET B receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ET A or the ET B receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ET A receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01).

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Endothelin ETA- and ETB-Receptor-Mediated Vasoconstriction in Rat Pulmonary Arteries and Arterioles

Cited by 110 publications

References 0 publications

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells

Maturational changes of endothelial vasoactive factors and pulmonary vascular tone at birth

Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels

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