Relation of elevated plasma endothelin in congenital heart disease to increased pulmonary blood flow

Vincent, Julie A.; Ross, Robert D.; Kassab, Joseph; Hsu, Julie M.; Pinsky, William W.

doi:10.1016/0002-9149(93)90646-t

Cited by 76 publications

(40 citation statements)

References 8 publications

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“…However, all relevant studies are consistent in showing that the ET-1 levels are significantly increased in cases of pulmonary hypertension. The most dramatic increases in circulating ET-1 levels and ET-1 expression, appear to be associated with primary pulmonary hypertension (Stewart et al, 1991;Cacoub et al, 1993;Giaid et al, 1993;Nootens et al, 1995); although ET-1 levels are also significantly increased in pulmonary hypertension secondary to hypoxia (Stewart et al, 1991;Ferri et al, 1995), congenital heart defects (Yoshibayashi et al, 1991;Cacoub et al, 1993;Vincent et al, 1993), valvular heart disease (Stewart et al, 1991;Chang et al, 1993;Yamamoto et al, 1994;Zhu et al, 1994), chronic heart failure (Cody et al, 1992;Kiowski et al, 1995) and the adult respiratory distress syndrome (Langleben et al, 1993). Plasma ET-1 levels can be increased four fold in some of these studies.…”

Section: Resultsmentioning

confidence: 99%

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

McCulloch

Docherty

Morecroft

et al. 1996

British J Pharmacology

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Using wire myography, we have examined the endothelin (ET) receptor subtypes mediating vasoconstriction to ET peptides in human pulmonary resistance arteries (150–200 μm, i.d.). Cumulative concentration‐response curves to ET‐1, sarafotoxin 6c (SX6c) and ET‐3 were constructed in the presence and absence of the selective antagonists FR 139317 (ETA‐selective), BMS 182874 (ETA‐selective) and BQ‐788 (ETB‐selective). All agonists induced concentration‐dependent contractions. However, the response curves to ET‐1 were biphasic in nature. The first component demonstrated a shallow slope up to 1 nM ET‐1. Above 1 nM ET‐1 the response curve was markedly steeper. Maximum responses to ET‐3 and SX6c were the same as those to 1 nM ET‐1 and 30% of those to 0.1 μm ET‐1. The order of potency, taking 0.3 μm as a maximum concentration was SX6c > > ET‐3 > ET‐1 (pEC50 values of: 10.75 ± 0.27, 9.05 ± 0.19, 8.32 ± 0.08 respectively). Taking 1 nM ET‐1 as a maximum, the EC50 for ET‐1 was 10.08 ± 0.13 and therefore ET‐1 was equipotent to ET‐3 and SX6c over the first component of the response curve. Responses to ET‐1 up to 1 nM were resistant to the effects of the ETA receptor antagonists, FR 139317 and BMS 182874 but were inhibited by the ETB receptor antagonist, BQ‐788. Conversely, responses to ET‐1 over 1 nM were inhibited by the ETA receptor antagonists, FR 139317 and BMS 182874 but unaffected by the ETB receptor antagonist, BQ‐788. The results suggest that at concentrations up to 1 nM, responses to ET‐1 are mediated via the ETB receptor, whilst the responses to higher concentrations are mediated by ETA receptors.

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Section: Resultsmentioning

confidence: 99%

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

McCulloch

Docherty

Morecroft

et al. 1996

British J Pharmacology

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“…The mitogenic agonist(s) or Kv channel blocker(s) may be produced sporadically as a result of high blood flow and arterial pressure (e.g. shear stressmediated endothelium injury) (21)(22)(23). Another possibility is that the existing mitogenic agonists in serum are up-regulated in patients with PH secondary to congenital cardiopulmonary diseases.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of K+ Channel Activity in Human Pulmonary Artery Smooth Muscle Cells by Serum from Patients with Pulmonary Hypertension Secondary to Congenital Heart Disease

Limsuwan

Platoshyn

et al. 2001

Pediatr Res

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Activity of Kϩ channels regulates cytosolic free Ca 2ϩ concentration by controlling membrane potential. A rise in cytosolic free Ca 2ϩ concentration in pulmonary artery smooth muscle cells (PASMC) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. Whether serum from children with pulmonary hypertension (PH) secondary to congenital cardiopulmonary diseases contains a factor(s) that inhibits K ϩ channel function in PASMC was investigated using patch clamp techniques. PASMC isolated from normal subjects were cultured in media containing 5% serum from normotensive (NPH) or PH patients. Cell growth rate and the currents through voltage-gated K ϩ channels were determined and compared between the cells treated with serum from NPH and PH patients. In the absence of growth factors, incubation of PASMC in media containing NPH serum for 48 h increased cell numbers by 2.5-fold, whereas incubation of the cells in media containing PH serum increased cell numbers by 4.5-fold (p Ͻ 0.001). Amplitude of whole-cell voltage-gated K ϩ currents in NPH serum-treated cells (1119 Ϯ 222 pA at ϩ80 mV, n ϭ 43) was 3.5-fold greater than in PH serum-treated cells (323 Ϯ 34 pA, n ϭ 43, p Ͻ 0.001). Consistently, membrane potential was much more depolarized in PASMC treated with PH serum (Ϫ28 Ϯ 2 mV, n ϭ 29) than cells treated with NPH-serum (Ϫ47 Ϯ 2 mV, n ϭ 28; p Ͻ 0.001).These results suggest that a circulating mitogenic agonist, which induces membrane depolarization by inhibiting voltage-gated K ϩ channel activity in PASMC, may be produced or upregulated in pediatric patients with secondary PH. ] cyt , cytosolic free Ca 2ϩ concentration E m , membrane potential FBS, fetal bovine serum hEGF, human epidermal growth factor hFGF, human fibroblast growth factor I K(V) , whole-cell voltage-gated K ϩ currents Kv, voltage-gated K ϩ channels NPH, non-pulmonary hypertension cardiopulmonary disease PAP, pulmonary arterial pressure PASMC, pulmonary artery smooth muscle cells PH, pulmonary hypertension PPH, primary pulmonary hypertension PSS, physiologic salt solution SMBM, smooth muscle basal medium SMGM, smooth muscle growth medium VEGF, vascular endothelium growth factor PH contributes significantly to the morbidity and mortality of children with congenital heart defects (1). PH in congenital heart disease may be caused by increased pulmonary blood flow, left-side obstructive lesions, pulmonary vasoconstriction, vascular remodeling, and thrombosis in situ. These causes can be present in isolation or in combination (2). The most common cardiac defect associated with PH is a ventricular septal defect. If the defect is left open or remains large, many patients develop pulmonary vascular obstructive disease and irreversible PH (3); this phenomenon is called Eisenmenger syndrome. Patients with Eisenmenger syndrome have elevated pulmonary vascular resistance and systemic or suprasystemic PAP (which causes a right-to-left shunt).The pathophysiology of PH secondary to congenital heart lesions shares several characteristics with PPH; inclu...

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“…Elevated immunoreactive ET-1 levels have been found in primary pulmonary hypertension, the Eisenmenger syndrome (51), PPHN (52), children with pulmonary hypertension associated with congenital heart disease and bronchopulmonary dysplasia (53), and children with congenital heart disease and increased pulmonary blood flow (54,55). Increased expression of ET-1 in vascular endothelial cells has been reported in adult patients with primary pulmonary hypertension, suggesting that the local production of endothelin-1 may contribute to the altered vascular reactivity and structural changes seen in pulmonary hypertension (56).…”

Section: Discussionmentioning

confidence: 99%

Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus.

Ivy¹,

Parker²,

Ziegler³

et al. 1997

J. Clin. Invest.

116

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Relation of elevated plasma endothelin in congenital heart disease to increased pulmonary blood flow

Cited by 76 publications

References 8 publications

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

Inhibition of K+ Channel Activity in Human Pulmonary Artery Smooth Muscle Cells by Serum from Patients with Pulmonary Hypertension Secondary to Congenital Heart Disease

Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus.

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Relation of elevated plasma endothelin in congenital heart disease to increased pulmonary blood flow

Cited by 76 publications

References 8 publications

EndothelinB receptor‐mediated contraction in human pulmonary resistance arteries

EndothelinB receptor‐mediated contraction in human pulmonary resistance arteries

Inhibition of K+ Channel Activity in Human Pulmonary Artery Smooth Muscle Cells by Serum from Patients with Pulmonary Hypertension Secondary to Congenital Heart Disease

Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus.

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Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries