Activation of neuronal endothelin B receptors mediates pressor response through alpha-1 adrenergic receptors

Abstract

Abnormalities in activity of the endothelin (ET) system have been widely reported in a number of cardiovascular disease states such as hypertension and heart failure. Although the vascular responses to ET are well established, the interaction between ET and other important modulators of blood pressure, such as the sympathetic nervous system, are less understood. Previous reports implicate ET signaling through ET type B (ETB) receptors in increasing neuronal activity. Therefore, we hypothesized that activation of ETB receptors on sympathetic nerves would increase blood pressure through an adrenergic‐mediated mechanism. Thus, we used anesthetized ETB‐deficient rats, which only express functional ETB receptors on adrenergic neurons, and genetic controls, which express functional ETB receptors in vascular tissue and kidney epithelium. We determined the pressor response to the selective ETB receptor agonist sarafotoxin c (S6c). Separate groups of rats were treated with the α 1‐adrenergic receptor antagonist prazosin or the β‐adrenergic receptor antagonist propranolol to elucidate the role of adrenergic signaling in mediating the blood pressure response. We observed a dose‐dependent pressor response to S6c in ETB‐deficient rats that was reversed by prazosin treatment and augmented by propranolol. In genetic control rats, the effects of S6c on sympathetic neurons were mostly masked by the direct activity of ETB receptor activation on the vasculature. Heart rate was mostly unaffected by S6c across all groups and treatments. These results suggest that ETB activation on sympathetic neurons causes an increase in blood pressure mediated through α 1‐adrenergic receptor signaling.

Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers

“…Alpha-1 adrenergic receptors (α 1 ) and alpha-2 adrenergic receptors (α2) are chiefly expressed in vascular smooth muscle cells proximal and distal to sympathetic nerve terminals, respectively, and their activation elicits vasoconstriction of peripheral arteriolar and venous vessels while in the brain stem they modulate sympathetic outflow[ 97 ]. A recent study by Becker et al[ 98 ] showed that activation of neuronal endothelin B receptors can increase arterial blood pressure mediated through α 1 -adrenergic receptor signaling showing that abnormalities of endothelin system have a cross-talk with adrenergic systems in hypertension and HF[ 98 ].…”

“…Similarly, the addition of ACE inhibitor to ET A receptor antagonist significantly improved cardiac failure after extensive MI in a rat model of congestive HF, compared with ACE inhibition monotherapy[ 257 ]. A cross-talk between the endothelin system and the adrenergic system has been demonstrated as activation of ET B receptors on sympathetic neurons caused an increase in arterial blood pressure through vasoconstriction mediated by α 1 -adrenergic receptors[ 98 ]. Sympathoexcitatory effects are also promoted through the interaction of ET-1 with ET A receptors as this resulted in cardiomyocyte hypertrophy through adrenergic signaling pathways and massive NE release while it also contributed to impaired responsiveness of renal mechanosensory nerves in congestive HF[ 258 , 259 ].…”

Endothelin‐1 in the pathophysiology of obesity and insulin resistance

“…6,12 Furthermore, adipocytes take up glucose in an insulin-dependent process by increasing membrane bound GLUT4, an insulin sensitive glucose transporter. 22 This glucose is necessary for the formation of glycerol and the subsequent conversion of free fatty acids into its storage form of triacylglycerol. 13,56 In addition, ET-1 increases adipocyte hyperplasia after 4 weeks of infusion.…”

“…22 This constriction is thought to be due to activation of ET B receptors on adrenergic cells leading to release of norepinephrine, because the constriction, measured by changes in arterial pressure, can be abolished with an alpha adrenergic blocker and exacerbated by blockaded of beta adrenergic receptors. 22 Therefore, ET-1 promotes reductions in blood flow through activation of ET A receptors on vascular smooth muscle and ET B receptors on vascular nerve terminals. Furthermore, blockade of ET-1 receptors with Bosentan unmasked a vasodilatory property of insulin in rat aortas suggesting ET-1 inhibits insulin mediated vasorelaxtion.…”

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

“…The ET B receptor is expressed on sympathetic neurons, and recent studies in rats have demonstrated that exogenous activation of ET B receptors leads to an a 1 -adrenergic receptormediated pressor response. 52 Considering the importance of a 1 -adrenergic receptor activation to the CSS-induced pressor response and the herein identified role of endothelium-derived ET-1 in this response, we sought to determine if ET B receptor activation may contribute to the pressor response to CSS. ET B receptor antagonism alone results in hypertension that would confound pressor response results.…”