ETA and ETB Receptors Coexist on Rabbit Pulmonary Artery Vascular Smooth Muscle Mediating Contraction

Ladouceur, D. M.; Flynn, Margaret; Keiser, Joan A.; Reynolds, Elwood E.; Haleen, Stephen J.

doi:10.1006/bbrc.1993.2236

Cited by 80 publications

(45 citation statements)

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“…In humans, ET A receptors were found in both resistance and conduit arteries, and in the main pulmonary artery, ET A receptors predominated (90%) (5). Tracheal smooth muscle from rats and mice, however, exhibited approximately equal numbers of the two receptor subtypes (18), whereas ET B receptors were 50% more numerous than ET A in rat pulmonary artery smooth muscle cells (23). Thus the distribution and density of ET-1 receptors on various smooth muscle types may vary between species and location (5,31).…”

Section: Discussionmentioning

confidence: 92%

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

Balyakina

Chen²,

Lawrence³

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to exogenous ET-1 for 18 h revealed that only the L2 cells internalized ET-1, and internalization by hypertensive L2 cells was significantly reduced when compared with controls. Treatment with ET A (BQ-610) and ETB (BQ-788) receptor antagonists demonstrated that both receptors contributed to internalization of ET-1 in control L2 cells, whereas in hypertensive cells only when both receptor antagonists were used in combination was significant suppression of ET-1 internalization found. We conclude that in sheep receiving CAE, alterations in ET B receptors in cells of the L2 layer may contribute to the maintenance of CPH via alterations in their expression, distribution, and activity.ET A receptor; ETB receptor; smooth muscle cells; pulmonary hypertension; endothelin SINCE ITS DISCOVERY 12 YEARS AGO, endothelin (ET) has been shown to contribute to a wide variety of physiological and pathophysiological processes in various systems (22). The ET family of 21 amino acid peptides exists in three distinct isoforms: ET-1, ET-2, and ET-3. It is an extremely potent vasoconstrictor resulting in slowly developing and sustained contraction. Although the endothelial cell was originally described as the source of ET-1, it is now known that several other cell types, including pulmonary vascular smooth muscle cells, synthesize this peptide (33, 36).The biological effects of ET-1 are mediated by two distinct ET receptor subtypes, ET A and ET B (1, 35). The affinity of the ET A receptor for ET-1 has been shown to be ϳ100 times that for ET-3 (ET-1 Ͼ ET-2 Ͼ ET-3), whereas the affinity of the ET B receptor is equipotent for all three isoforms of ET (34). Early reports indicated that the ET A receptor on smooth muscle was responsible for the vasoconstrictor effect of ET-1, whereas the ET B receptor on endothelial cells modulated ET-1-induced vasodilation. However, recent pharmacological studies suggest that there are two classes of ET B with cell specific effects, ET B1 on endothelial cells mediating vasodilation and ET B2 on smooth muscle cells mediating vasoconstriction (9). The ET B receptor also functions as a "clearance receptor" and is particularly important in the lung, where 50% of ET-1 is retained (22,29).ET-1 has been linked to the development of chronic pulmonary hypertension (CPH). Increased expression of the peptide has been demonstrated in endothelial cells of pulmonary arteries from patients with idiopathic and secondary forms of pulmonary hypertension (15), and arterial-to-venous ratios of ET-1 protein were found to be elevated above the normal range in patients with pulmonary hypertension (40). Several studies have linked increased expression of ET-1 to the development of hypoxia-induced CPH in rats (5, 24), and use of ET-1 receptor antagonists has been shown both to inhibit progression of the disease and to promote recovery (4,10,43).Although these studies support a central role for ET-1 in the pathogenesis of CPH, the picture is likely more complicated than first suspected, in that prepro-ET-1 (ppET-1) mRNA is...

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Section: Discussionmentioning

confidence: 92%

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

Balyakina

Chen²,

Lawrence³

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…ETA and ETB receptors mediate contraction in the human bronchi and in rabbit pulmonary artery. In these tissues, dual blockade of both receptors is required to antagonize responses to ET-1 fully (LaDouceur et al, 1993;Fukuroda et al, 1994b;. Non-selective ET antagonists may, therefore, prove to be more effective antagonists in the human pulmonary arterial bed.…”

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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“…Previous workers (LaDouceur et al, 1993) reported that BQ123 was a weak antagonist of ET-l-induced contractions of rabbit pulmonary artery and demonstrated that this was a result of the tissue containing a mixed population of ETA and ETB receptors. Thus, an alternative hypothesis to account for the low potency of BQ123 in the present study could be that a small population of contractile ETB receptors are present in rat renal artery.…”

Section: Discussionmentioning

confidence: 99%

Characterization of endothelin receptors in rat renal artery in vitro

Clark

Pierre

1995

British J Pharmacology

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1 The aim of this study was to investigate the function and characteristics of endothelin receptors in rat main branch renal artery in vitro.2 Endothelin(ET)-l (mean ECjO = 9.8 nM) was approximately 12 fold more potent than ET-3 (mean EC50 = 120 nM) as a contractile agonist and produced a greater maximum response. In contrast, neither of the ETB receptor-selective agonists, alanine1l'3"1 "'ET-1 nor sarafotoxin S6c, (0.1 nM-I1tM), induced any contractile effect, or any relaxant effect in endothelium-intact preparations pre-contracted with the thromboxane A2 mimetic, U-46619. Sarafotoxin S6c (30 nM) also failed to induce any further contraction in tissues pre-contracted with an ECm concentration of ET-1.3 The ETA receptor-selective antagonist, BQ123, behaved as a weak and variable antagonist of the contractile effects of ET-1 (mean pA2 estimates in the range 5.8-6.3). In contrast, BQ123 antagonized ET-3 with a potency (mean pA2= 7.6) consistent with its affinity for ETA receptors. Co-incubation of BQ123 (3 IM) with the putative ETB receptor-selective antagonist, IRL1038 (10lM), produced no greater antagonism of ET-1 responses than was induced by BQ123 (3 JsM) alone. 4 In conclusion, ETB receptors do not appear to be present in rat main branch renal artery. The contractile effects of ET-3 in this tissue seem to be mediated by ETA receptors. While ETA receptors partly mediate the contractile effects of ET-1, these data raise the possibility that a population of novel BQ123-insensitive endothelin receptors may also contribute to this response.

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ETA and ETB Receptors Coexist on Rabbit Pulmonary Artery Vascular Smooth Muscle Mediating Contraction

Cited by 80 publications

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ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

Characterization of endothelin receptors in rat renal artery in vitro

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ETA and ETB Receptors Coexist on Rabbit Pulmonary Artery Vascular Smooth Muscle Mediating Contraction

Cited by 80 publications

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ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

EndothelinB receptor‐mediated contraction in human pulmonary resistance arteries

Characterization of endothelin receptors in rat renal artery in vitro

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Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries