Chronic Oral Endothelin Type A Receptor Antagonism in Experimental Heart Failure

Borgeson, Daniel D.; Grantham, J.Aaron; Williamson, EE; Luchner, Andreas; Redfield, MM; Opgenorth, T J; Burnett, Jr Jc

doi:10.1161/01.hyp.31.3.766

Cited by 58 publications

(38 citation statements)

References 40 publications

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“…Our measurements of plasma ET-1 are consistent with values reported in human (1,6,13,20,24) and animal heart failure (3,22,25). Our larger dose of ET-1 (4.0 ng⅐ kg Ϫ1 ⅐min Ϫ1 ) is close to the upper limit of the pathophysiological range of ET-1 plasma levels reported earlier.…”

Section: Discussionsupporting

confidence: 90%

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Okajima

Parent

Thorin

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Lavallée. Pathophysiological plasma ET-1 levels antagonize ␤-adrenergic dilation of coronary resistance vessels in conscious dogs. Am J Physiol Heart Circ Physiol 287: H1476 -H1483, 2004. First published June 17, 2004 10.1152/ajpheart.00297.2004.-On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K ϩ (KATP) channel opening, which is pivotal in ␤-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair ␤-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O2 consumption (MV O2) increased, the disproportionate rise in coronary sinus (CS) PO2 indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with ␤-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the PO 2-MV O2 and CBF-MV O2 relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ET A receptor blocker, prevented reduction of the slope of PO2-MV O2 and CBF-MV O2 relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of PO 2-MV O2 and CBF-MV O2 relations. To assess effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, intracoronary ACh and nitroglycerin were given to directly target coronary vessels. CBF responses to ACh and nitroglycerin were maintained during ET-1 delivery. In contrast, responses to intracoronary K ATP channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired ␤-adrenergic dilation of resistance coronary vessels through an ET A receptor-dependent process. In contrast, left ventricular inotropic responses to dobutamine were not impaired during ET-1 delivery. Our data suggest that ET-1 may interfere with smooth muscle K ATP channels to impair ␤-adrenergic coronary dilation. endothelin-1; coronary blood flow; dobutamine; ATP-dependent potassium channels; myocardial oxygen consumption PLASMA ENDOTHELIN (ET)-1 levels are elevated in human heart failure (1,6,13,20,24) and pulmonary hypertension (33). The pulmonary circulation acts as the primary source of circulating ET-1 (5, 24). Even if local ET-1 activity is increased in failing hearts (2), circulating ET-1 is still being extracted by the heart, which acts as a consumer, rather than a producer, of circulating ET-1 (5, 24). In humans, increases in circulating ET-1 levels within the pathophysiological range led to decreases in coronary sinus (CS) blood flow and venous blood O 2 saturation, consistent with coronary constriction (19). In normal conscious pigs (14, 15) and dogs (26), blockade of ET-1 receptors led to increases in coronary venous blood O 2 saturation. Thus ET-1 activity may reach the threshold for altering myocard...

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Section: Discussionsupporting

confidence: 90%

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Okajima

Parent

Thorin

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…19 The recovery of the extraction procedure was 81% and 80%, as determined by the addition of synthetic ET-1 and big ET-1, respectively, to plasma. Interassay and intra-assay variations for ET-1 were 9% and 5%, respectively.…”

Section: Radioimmunoassaymentioning

confidence: 95%

Modulation of Functionally Active Endothelin-Converting Enzyme by Chronic Neutral Endopeptidase Inhibition in Experimental Atherosclerosis

Grantham¹,

Schirger²,

Wennberg³

et al. 2000

Circulation

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Background-Endothelin-converting enzyme-1 (ECE-1) processes big endothelin-1 (ET-1) to ET-1, a peptide implicated in atheroma formation. ECE-1 exists in 2 isoforms (ECE-1␣ and ECE-1␤), the result of alternative splicing of a common gene. Neutral endopeptidase (NEP) is a genetically distinct metallopeptidase that degrades the natriuretic peptides. These peptides mediate antiproliferative and vasodilating actions. We sought to demonstrate the distribution of the 2 ECE-1 isoforms in experimental atherosclerosis, to determine the effects of chronic NEP-I on plasma cGMP concentrations, vascular wall ECE-1 activity, and ET-1 concentration, and to correlate these actions with atheroma formation. Our hypothesis was that chronic NEP-I, in association with augmented cGMP, would inhibit ECE-1 conversion of big ET-1 to active ET-1, thus reducing tissue ET-1 concentrations and associated atheroma formation. Methods and Results-Cholesterol-fed New Zealand White rabbits (nϭ8, 1% cholesterol diet) and NEP-I-treated cholesterol-fed New Zealand White rabbits (nϭ8; candoxatril, 30 mg/kg per day, Pfizer) were euthanized after 8 weeks of feeding. ECE-1␣ and ECE-1␤ immunoreactivity was present in the aortas of both groups. Compared with control values, plasma cGMP concentrations were increased (2.8Ϯ0.6 versus 8.4Ϯ1.2 pmol/mL, PϽ0.05), ECE-1 activity was attenuated (68Ϯ3% versus 32Ϯ8%, PϽ0.05), aortic tissue ET-1 concentrations were reduced (4.6Ϯ0.5 versus 3.2Ϯ0.3 pg/mg protein, PϽ0.05), and atheroma formation was attenuated (62Ϯ6% versus 34Ϯ5%, PϽ0.01) by NEP-I. Conclusions-These studies suggest that ECE-1 is present and functionally active in the vascular wall in atherosclerosis.Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the endothelin system in this cardiovascular disease state.

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“…21 Plasma ET-1 was determined by radioimmunoassay using an endothelin-1,2[I 1,25 ]assay system (Amersham) as previously described. 22,23 …”

Section: Plasma Assaysmentioning

confidence: 99%

Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

et al. 1999

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Background-Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. Methods and Results-Acetylcholine (10 Ϫ6 to 10 Ϫ4 mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: Ϫ41.6%Ϯ10.7%, group 2: Ϫ4.7%Ϯ11.9%, group 3: 11.4%Ϯ7.4%). Conclusions-Chronic

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Chronic Oral Endothelin Type A Receptor Antagonism in Experimental Heart Failure

Cited by 58 publications

References 40 publications

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Modulation of Functionally Active Endothelin-Converting Enzyme by Chronic Neutral Endopeptidase Inhibition in Experimental Atherosclerosis

Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

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