457P Granada Congress and Exhibitions Centre
6th European Congress of Pharmacology (EPHAR 2012)



α 1D -Adrenoceptors are responsible of the high sensitivity and the slow kinetic of adrenergic contraction in conductance arteries

MA Noguera1, N Flacco2, J Parés3, M Perez-Aso4, D Vicente5, MD Ivorra6, MP D´Ocon7. 1Universidad de Valencia, Farmacologia 46100, Spain, 2Universidad de Valencia, Farmacologia 46100, Spain, 3Universidad de Valencia, Farmacologia 46100, Spain, 4Universidad de Valencia, Farmacologia 46100, Spain, 5Universidad de Valencia, Farmacologia 46100, Spain, 6Universidad de Valencia, Farmacologia 46100, Spain, 7Universidad de Valencia, Farmacologia 46100, Spain


BACKGROUND: Vascular α1 adrenoceptor (α1-AR) subtypes may affect compliance of large and poorly innervated conductance vessels (α1D), as well as redistribution of blood flow through the well innervated distributing arteries (α1A). There are marked differences between subtypes in sensitivity to agonists and second messenger generation, being the α1D the most sensitive with the lower efficacy. Furthermore, α1D-AR acts as “constitutively active” receptor in conductance vessels maintaining an increased vascular tone after removing the adrenergic stimulus.

AIMS: To analyze the kinetic of the contractile response and the intracellular signals elicited by α1-subtypes in two different vessels, aorta (α1 D-subtype) and tail artery (α1 A-subtype).

METHODS: Tissues were obtained from male Wistar rats or genetically engineered mice (α1B-KO, α1D-KO and α1B/D-KO) and their controls (WT). Results of isometric contractility studies were compared with analysis of the [3H] inositol phosphates (IPs) accumulation and ERK1/2 phosphorylation after adrenergic stimulus in the same vessels.

RESULTS: Cumulative concentration-response curves to noradrenaline (NA, 1nM-100μM) elicited a concentration-dependent ERK1/2 phosphorylation, [3H]-IPs accumulation and contractile response in both rat aorta and tail artery. A higher potency (pD2) of NA together with a lower response was obtained in aorta vs. tail artery. In α1D-KO mice the pD2 value of NA was markedly reduced in aorta and only slightly diminished in tail artery. No significant change in the potency of NA was observed in aortic rings from α1B-KO mice but the magnitude of the response was lower. There is a great loss in the contractile response to NA in α1B/D-KO mice. The slow disappearance of the adrenergic contraction after removal of the agonist in rat aorta was not affected by preincubation (15min) with 100nM 5-methylurapidil (α1A selective ligand), but 10nM BMY7378 (α1D selective ligand) induced a faster recovery of the basal tone. In rat tail artery, no significant changes were observed, but NA-induced contraction returns faster than in aorta to basal levels after agonist removal. In aorta from α1D-KO mice, the recovery of basal tone after NA-removal was faster than in WT. By the contrary, the return to the baseline was markedly slower in aorta from α1B-KO mice. These results suggest an involvement of α1D-subtype in the slow recovery of basal tone observed in rat aorta, but not in tail artery, when the agonist was removed. This characteristic could be attributed to the constitutive activity exhibited by the α1D-AR in aorta, as we can evidence by IPs accumulation and increased contractile tone observed after removal of the agonist. The spontaneous increase in tone after removal of NA that evidences the constitutive activity of α1D-AR in rat aorta α1B-KO or WT mice, was not observed in tail from rat and aorta from α1D-KO and α1B/D-KO mice, confirming the peculiar behavior of the α1D-subtype.

CONCLUSION: α1D-AR, exhibit a higher sensitivity and lower efficacy to NA-activation and remains active after removal of the agonist, sustaining the adrenergic response and avoiding abrupt changes of vessel caliber in conductance arteries.

Acknowledgements: Study supported by a grant from Universitat de València