Role of ET<sub>B</sub> receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Brünner, Friedrich; Doherty, Annette M.

doi:10.1016/0014-5793(96)01103-9

Cited by 48 publications

(27 citation statements)

References 26 publications

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“…Several studies have suggested that ET B receptors may act as clearance receptors for ET-1, 22 and the observation that ET-1 binding to ET B receptors is less stable than its binding to ET A receptors 19 supports the above hypothesis. Because the total density of ET B receptors is higher in ventricular membranes than in myocytes, it may be speculated that ET B receptors may contribute to preventing excessive ET-1 myocardial concentrations.…”

Section: Myocyte Et-1 Subtype Receptorssupporting

confidence: 62%

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy

Serneri

Cecioni²,

Vanni³

et al. 2000

Circulation Research

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Abstract-Only scarce information is available on the activity and modifications of the cardiac endothelin (ET)-1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quantifying cardiac mRNA for prepro-ET-1 (ppET-1), ET-converting enzyme-1, and ET A and ET B receptors both in myocardium and in isolated myocytes using Northern blot, reverse transcription-polymerase chain reaction, and in situ hybridization in 22 patients with DCM and 20 with ICM who underwent cardiac transplantation and in 7 potential heart transplant donors (nonfailing hearts). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, cardiac ET formation, mRNA levels for ppET-1, and ET A and ET B receptors were higher on both the myocardium and isolated myocytes from ICM than on those from DCM hearts (PϽ0.001 for all). ppET-1 and ET-converting enzyme-1 mRNAs were expressed on myocytes and endothelial and interstitial cells in ICM, whereas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ET A mRNA signal was expressed on both myocytes and nonmyocyte cells, whereas ET B mRNA was almost exclusively localized on nonmyocyte cells. ET A -and ET B -specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (rϭ0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenance of cardiac function. (Circ Res. 2000;86:377-385.)Key Words: endothelin Ⅲ heart failure Ⅲ myocytes Ⅲ receptors Ⅲ RNA E ndothelin (ET)-1 is a multifunctional peptide that exerts pleiotropic activities, including arterial and venous constriction, direct positive inotropic and chronotropic effects on isolated heart, and growth effects on vascular smooth muscle cells, fibroblasts, and isolated cardiomyocytes. 1 Prepro-ET-1 (ppET-1) mRNA is expressed by both rat and human cardiac myocytes and interstitial cells that synthesize and secrete mature ET-1. [2][3][4] The protease that catalyzes the conversion (ET-converting enzyme, ECE) from the 38-residue inactive intermediate big ET-1 to achieve ET-1 is expressed in the endocardium and myocardium. 5 The differing biological activities of ET-1 appear to be mediated through 2 receptor subtypes (ET A and ET B ), 6 which are both present in the human myocardium and that of other species. 7 Thus, a complete ET-1 system is represented in human myocardium.Cardiac ppET-1 mRNA expression and ET-1 synthesis have been found to be increased in experimental hypertrophy by pressure overload 8 -10 and in experimental models of congestive heart failure (CHF), [11][12][13] thus suggesting that the cardiac ET-1 system may be involved in cardiac diseases.There have been very f...

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Section: Myocyte Et-1 Subtype Receptorssupporting

confidence: 62%

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy

Serneri

Cecioni²,

Vanni³

et al. 2000

Circulation Research

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“…Additionally, ET B receptors have been suggested to play a role as endothelin clearance receptors. 33 Blockade of ET B receptors may, therefore, influence vascular reactivity and arterial pressure by increasing endogenous endothelin levels and activating ET A receptors. This proposition is supported by reports that the increased susceptibility to deoxycorticosterone acetate (DOCA) -salt-induced hypertension and vascular and renal injuries in ET B receptor-deficient rats was reduced during chronic treatment with an ET A receptor antagonist.…”

Section: Discussionmentioning

confidence: 99%

Role of Endothelin B Receptors in Enhancing Endothelium-Dependent Nitric Oxide–Mediated Vascular Relaxation During High Salt Diet

et al. 2001

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Abstract-High salt diet is often associated with increases in blood pressure, and the state of activation of endotheliumdependent vascular relaxation pathways is critical under these conditions. Basal activation of endothelial endothelin B (ET B ) receptors by endothelin has been suggested to stimulate the release of factors that promote vascular relaxation. However, whether ET B receptors play a role in enhancing endothelium-dependent vascular relaxation during high salt diet is unclear. In this study, we investigated whether chronic treatment with an ET B receptor antagonist is associated with impaired endothelium-dependent vascular relaxation and enhanced vascular reactivity particularly during high salt diet. Isometric contraction was measured in aortic strips isolated from male Sprague-Dawley rats on normal sodium (NS, 1%) and high sodium diet (HS, 8%) for 7 days and untreated or treated with the ET B receptor antagonist A-192621 (30 mg/kg per day) for 5 days.

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“…Brunner and Doherty 42 have demonstrated that BQ-788, an ET B receptor antagonist, increases ET-1 release and elevates coronary resistance in isolated rat hearts. They suggested that cardiac ET B receptors were involved in the local sequestration and clearance of ET-1, both in ischemic and nonischemic situations, and that ET-1 displaced by the ET B antagonist stimulated ET A receptors, which resulted in coronary constriction.…”

Section: Discussionmentioning

confidence: 99%

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

et al. 2005

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Background-Endothelin (ET)-1 and norepinephrine (NE) are involved in myocardial ischemia/reperfusion injury. We investigated the role of ET-1 in ischemia/reperfusion-induced NE overflow and cardiac dysfunction using a selective ET A receptor antagonist (ABT-627), a selective ET B receptor antagonist (A-192621), and the spotting lethal (sl) rat, which carries a naturally occurring deletion in the ET B receptor gene. Methods and Results-According to the Langendorff technique, isolated hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. In Sprague-Dawley rat hearts, ischemia/reperfusion-induced cardiac dysfunctions such as decreased left ventricular developed pressure and coronary flow and increased left ventricular end-diastolic pressure were worsened by treatment with A-192621. This agent enhanced excessive NE overflow in the coronary effluent from the postischemic heart. In contrast, treatment with ABT-627, in the absence or presence of A-192621, significantly improved postischemic cardiac dysfunction and markedly suppressed NE overflow to the same extent. Postischemic cardiac dysfunction and NE overflow in the heart of ET B receptor-deficient homozygous (sl/sl) rats were highly observed compared with cases in wild-type rats, and exaggerated responses to ischemia/reperfusion in sl/sl rats were abolished by ABT-627 treatment. Exogenously applied ET-1 produced severe cardiac dysfunction and a significant increase in NE overflow in a dose-dependent manner, but these responses were markedly suppressed in the presence of 5-N-ethyl-N-isopropyl-amiloride, an inhibitor of the Na ϩ /H ϩ exchanger (NHE). Conclusions-Pharmacological blockade or genetic deficiency of ET B receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ET A receptor activation. ET A /NHEmediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.

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Role of ET_B receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Cited by 48 publications

References 26 publications

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy

Role of Endothelin B Receptors in Enhancing Endothelium-Dependent Nitric Oxide–Mediated Vascular Relaxation During High Salt Diet

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

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Role of ETB receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788

Cited by 48 publications

References 26 publications

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy

Role of Endothelin B Receptors in Enhancing Endothelium-Dependent Nitric Oxide–Mediated Vascular Relaxation During High Salt Diet

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

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Role of ET_B receptors in local clearance of endothelin‐1 in rat heart: studies with the antagonists PD 155080 and BQ‐788