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

Abstract

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...

Effects of Endothelin-1 on the Relaxation of Rat Coronary Arteries

“…In myocardial cells, endothelin-1 may antagonize b-adrenergic receptors, [17][18][19] but in vascular smooth muscle, the results are conflicting. [20][21][22] We hypothesize that endothelin-1 may modulate the b-adrenergic response of coronary arteries, as it has been described for the a-adrenergic vasoconstriction, thus participating in the regulation of coronary blood flow. Stimulation of b-adrenoceptors in the heart in vivo increases myocardial metabolism and oxygen consumption.…”

“…22 On the contrary, in the coronary circulation of dogs, endothelin-1 reduced the b-adrenergic vasodilatation through activation of ET A receptors and inhibition of adenosine triphosphate-dependent potassium channels. 21 This discrepancy may be due to differences in species (dog vs. rat) or in the experimental preparation (in vivo coronary blood flow measurement vs. isolated vascular segments). The potentiating effect of endothelin-1 in rat coronary arteries may be mediated by PKC, as it has been found in rat aorta, 22 because it was abolished by the blocker of this kinase chelerythrine.…”

Adenosine induced coronary vasospasm during Rubidium PET myocardial perfusion scan in a patient with Takayasu’s Arteritis

“…2,3 Endothelin-1 is a potent vasoconstrictor 2 and regulates arterial tone at rest. 4,5 However, during exercise, endothelin-1 levels decrease facilitating coronary vasodilatation. Work in animals has suggested that high circulating endothelin-1 reduces adenosine-induced coronary vasodilatation.…”

Endothelium-derived endothelin-1

“…NO strongly inhibits the release of ET-1 from the native endothelium [16,17], which makes ET-1 and NO functionally closely interdependent, with a strong inhibitory effect of ET-1 on NO-mediated dilation, including in human coronary and cerebral arteries, and vice versa [14,[18][19][20][21]. The inhibitory effects of ET-1 are not limited to the dilations induced by NO since ET-1, through activation of the protein kinase C pathway, also reduces β-adrenergic receptor-dependent relaxation both in vitro and in vivo [22,23]. This peptide is therefore a potent "anti-vasodilatory" factor released by the endothelium.…”