Endothelin has biological actions at pathophysiological concentrations.

Lerman, Amir; Hildebrand, Fredric L.; Aarhus, Lawrence L.; Burnett, John C.

doi:10.1161/01.cir.83.5.1808

Cited by 173 publications

(63 citation statements)

References 26 publications

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“…In the present study, our selection of doses of ET-1 for systemic delivery was guided by earlier studies showing that ET-1 at 2.5 ng⅐ kg Ϫ1 ⅐min Ϫ1 reaches the pathophysiological range (4,11). 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).…”

Section: Discussionsupporting

confidence: 80%

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: 80%

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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“…However, these studies lead to apparently opposite results: in vitro ET-1 The purpose of the present study was to determine the relationship between the renin-angioteninvariably suppresses renin secretion, 13,14 while injection of ET-1 into animals does not either effect sin-aldosterone system and plasma ET-1 levels in hypertensive patients with low, normal and highor increase PRA. 11,12,26 In healthy human volunteers, infusion of 0.4 pmol/kg/min ET-1, which elevated renin essential hypertension. The data that emerged from our study demonstrated that in patients with ir-ET-1 to levels similar to those found in several pathological conditions, increased diastolic BP, low-renin essential hypertension, the plasma ET-1 potentiates the angiotensin II-induced production of aldosterone.…”

Section: Discussionmentioning

confidence: 99%

High plasma endothelin-1 levels in hypertensive patients with low-renin essential hypertension

et al. 1997

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Endothelin-1 (ET-1) is a potent vasoconstrictor peptide plasma renin activity (PRA) and the ET-1 levels of hypertensives; instead there was a statistically significant derived from endothelial cells and may be important in the control of systemic blood pressure (BP) and local correlation between plasma ET-1 and plasma aldosterone (PA) (r = 0.393; P Ͻ 0.026). In particular mean blood flow. Immunoreactive ET-1 plasma levels may be normal or elevated in human arterial hypertension, plasma ET-1 values in patients with low-renin essential hypertension (12.6 ± 2.1 pg/ml) were significantly higher although the exact pathophysiological role of ET-1 remains to be established.(ANOVA = 0.000, P Ͻ 0.05) than those of normotensive subjects (7.7 ± 1.7 pg/ml), patients with normal-renin The aim of our study was to determine the relationship between the components of the renin-angiotensinessential hypertension (8.5 ± 2.8 pg/ml), and patients with high-renin essential hypertension (9.9 ± 3.8 pg/ml), aldosterone system and plasma ET-1 levels in patients with low, normal or high-renin essential hypertension.respectively. There was a statistical correlation between PA and ET-1 levels in patients with low-renin essential The study groups included 13 patients with low-renin essential hypertension (average age 43.5 ± 16.2 years), hypertension (r = 0.619, P Ͻ 0.024). Our study demonstrated that there was an increase of 16 patients with normal-renin essential hypertension (46.5 ± 13.4 years), 11 patients with high-renin essential circulating ET-1 levels in patients with low-renin essential hypertension and ET-1 plasma levels correlated with hypertension (40.7 ± 13.8 years) and 12 healthy subjects (43.1 ± 11.4 years).PA. The results suggest that ET-1 may play an important role in this particular form of human essential hypertenOur results demonstrated that the mean ET-1 values of all patients with essential hypertension were 10.4 ± sion. 3.4 pg/ml; there was not a statistical correlation between Keywords: endothelin-1; essential hypertension; renin-angiotensin-aldosterone system Direct evidence that ET-1 has a vasopressor effect

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“…Nitric oxide is involved in maintaining basal RBF in the late gestation ovine fetus (Bogaert, Kogan & Mevorach, 1993). Endothelin 1 (ET-1) is implicated in modulating peripheral vascular tone during normoxia and during acute hypoxia in the sheep fetus (Green, McGarrigle, Bennet & Hanson, 1995) and ET-1 constricts afferent arterioles in the adult rabbit kidney in vitro (Ito, Juncos, Nushiro, Johnson & Carretero, 1991) and increases RVR in the adult dog in vivo (Lerman, Hildebrand, Aarhus & Burnett, 1991). Endothelin-1 binding sites have been located in the human fetal renal blood vessels in greater quantities than in the adult (Grone, Laue & Fuchs, 1990) and ETA receptor subtypes have been implicated in the maintenance of baseline renal vascular tone in the adult rat (Pollock & Opgenorth, 1993).…”

Section: Blood Gases and Phmentioning

confidence: 99%

The role of carotid chemoreceptors in the effects of hypoxia on renal blood flow in the late gestation sheep fetus

Green

Robson²,

Hanson³

1997

Experimental Physiology

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SUMMARYPrevious studies of the effect of hypoxia on fetal renal haemodynamics have demonstrated a fall, a rise or no change in renal blood flow (RBF). The underlying mechanisms are not understood but involve a balance between neural vasoconstrictor and opposing vasodilator mechanisms. Since carotid chemoreflex mechanisms contribute to vasoconstriction in other fetal vascular beds and in the adult renal vasculature, we examined their effects on RBF during 1 h of acute hypoxia in late gestation fetal sheep (n = 12). Renal blood flow was measured continuously and urine collected at 15 min intervals. Seven fetuses underwent bilateral section of the carotid sinus nerves (CSD fetuses). During hypoxia CSD fetuses showed a transient initial rise in RBF (P < 0.05) and then a subsequent fall (P < 0.05) to levels comparable with that recorded in intact fetuses. There was no change in urine output in either intact or CSD fetuses during hypoxia. Thus the initial fall in RBF during hypoxia is a carotid chemoreflex but other mechanisms, e.g. vasoconstrictor hormones, contribute to the sustained response.

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Endothelin has biological actions at pathophysiological concentrations.

Cited by 173 publications

References 26 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

High plasma endothelin-1 levels in hypertensive patients with low-renin essential hypertension

The role of carotid chemoreceptors in the effects of hypoxia on renal blood flow in the late gestation sheep fetus

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