α_1D‐Adrenoceptors are responsible for the high sensitivity and the slow time‐course of noradrenaline‐mediated contraction in conductance arteries

Abstract

The objective of this study was to determine whether the different time-course characteristics of α1-adrenoceptor-mediated contraction in arteries can be related to the subtypes involved. Contractile responses to noradrenaline (NA) were compared with inositol phosphate accumulation and extracellular signal-regulated kinase (ERK)1/2 phosphorylation after α1-agonist stimuli in the same vessels in the presence or absence of α1-antagonists in rat or in α1-subtype knockout (KO) mice. Aorta, where α1D-AR is the main functional subtype, had higher sensitivity to NA (in respect of inositol phosphate [IP], pERK1/2, and contractile response) than tail artery, where the α1A-adrenoceptor subtype is predominant. Furthermore, the contraction in aorta exhibited a slower decay after agonist removal and this was consistent in all strains harboring α1D-adrenoceptors (from rat, α1B-KO, and wild-type [WT] mice) but was not observed in the absence of the α1D-adrenoceptor signal (α1D-adrenoceptor blocked rat aorta or aorta from α1D-KO). IP formation paralleled α1-adrenoceptor-mediated contraction (agonist present or postagonist) in aorta and tail artery. High sensitivity to agonist and persistence of response after agonist removal is a property of α1D-adrenoceptors. Therefore, the preponderance of this subtype in noninnervated conductance arteries such as aorta allows responsiveness to circulating catecholamines and prevents abrupt changes in vessel caliber when the stimulus fluctuates. Conversely, in innervated distributing arteries, high local concentrations of NA are required to activate α1A-adrenoceptors for a response that is rapid but short lived allowing fine adjustment of the contractile tone by perivascular sympathetic nerves.

Activation of α1A‐adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing

“…The present results provide evidence of the importance of the modulatory α 1A ‐adrenoceptor/nNOS pathway in aorta where the α 1D ‐adrenoceptor subtype, sensitive to low levels of circulating catecholamines (Flacco et al , ), is primarily responsible for α 1 ‐adrenoceptor‐mediated vasoconstriction. In this vessel, the α 1A ‐adrenoceptor subtype, located in endothelial cells (Ciccarelli et al , ), regulates an nNOS‐dependent desensitization pathway that potentially attenuates vasoconstriction during excessive (intense or sustained) stimulation by circulating catecholamines.…”

“…It is well known that among the three α 1 ‐adrenoceptor subtypes present in the aorta, α 1D is the main subtype involved in contractile responses, the α 1A subtype participates but has a minor role, whereas the α 1B ‐adrenoceptor has not been implicated in the control of vascular tone so far (Flacco et al , ). A selective α 1D ‐adrenoceptor antagonist (BMY 7378) did not affect, while a selective α 1A ‐adrenoceptor antagonist (5‐methylurapidil) prevented the desensitization process, suggesting that it is mediated by activation of α 1A ‐adrenoceptors.…”

“…The α 1A subtype needs higher concentrations of the agonist than the α 1D subtype to be activated (Flacco et al , ). Therefore, differences in sensitivity to agonists between subtypes reaffirm the hypothesis that the α 1A ‐adrenoceptor is the subtype responsible for desensitization, which only appears when high concentrations of the agonist are employed.…”

Updates in the function and regulation of α1‐adrenoceptors

“…The α 1Aadrenoceptors predominate in resistance arteries such as the small mesenteric artery (Marti et al, 2005;Methven, McBride, Wallace, & McGrath, 2009;Nourian et al, 2008;Philipp & Hein, 2004) and distributing arteries such as the renal (Hrometz et al, 1999) Gisbert et al, 2000;Hussain & Marshall, 1997;Marti et al, 2005;Methven, Simpson, & McGrath, 2009;Nourian et al, 2008;Piascik et al, 1995;Rudner et al, 1999). This differential distribution of α 1A -adrenoceptors indicates physiological relevance; the dominant α 1Dadrenoceptors in conductance arteries result in high sensitivity to catecholamines, and the activation of this subtype leads to persistent vasoconstriction that tends to continue even after agonist removal, preventing sudden changes in the vessel calibre during variations in the circulating levels of catecholamines (Flacco et al, 2013;Gisbert et al, 2000;Noguera et al, 1996;Ziani et al, 2002).…”

Localization of α‐adrenoceptors: JR Vane Medal Lecture

“…We could not contribute to the argument about whether the subtypes were differently involved in agonist-induced internalisation because our antagonist ligand, at any concentration that is useful for receptor localisation, blocks responses to even high concentrations of phenylephrine . However, by labeling the surface receptors with an antibody that only fluoresces once internalised, colleagues were able to show that both α 1A-and α1B-subtypes could be internalised after activation by high concentrations of phenylephrine with only a small difference in time course (Flacco et al, 2013;Perez-Aso et al, 2013;Segura et al, 2013).…”