Modulatory role of a constitutively active population of α_1D-adrenoceptors in conductance arteries

Abstract

. Modulatory role of a constitutively active population of ␣1D-adrenoceptors in conductance arteries. Am J Physiol Heart Circ Physiol 282: H475-H481, 2002. First published October 18, 2001 10.1152/ajpheart.00411.2001.-A constitutively active population of ␣1D-adrenoceptors in iliac and proximal, distal, and small mesenteric rat arteries was studied. The increase in resting tone (IRT) that evidences it was observed only in iliac and proximal mesenteric and was inhibited by prazosin (pIC50 ϭ 9.57), 5-methylurapidil (pIC50 ϭ 7.61), and BMY 7378 (pIC50 ϭ 8.77). Chloroethylchlonidine (100 mol/l) did not affect IRT, but when added before the other antagonists it blocked their effect. The potency shown by BMY 7378 confirms the ␣1D-subtype as responsible for IRT. BMY 7378 displayed greater inhibition of adrenergic responses in iliac (pIC50 ϭ 7.57 Ϯ 0.11) and proximal mesenteric arteries (pIC50 ϭ 8.05 Ϯ 0.2) than in distal (pIC50 ϭ 6.94 Ϯ 0.13) or small mesenteric arteries (pIC50 ϭ 6.30 Ϯ 0.14), which confirms the functional role of the ␣1D-adrenoceptor in iliac and proximal mesenteric arteries. This subtype prevents abrupt changes in iliac and proximal mesenteric artery caliber when the agonist disappears, and this modulatory role is evidenced by the slower decay in the response to norepinephrine after removal. conductance vessels; resistance vessels; constitutive activity; ␣1D-adrenoceptors IT HAS BEEN CLEARLY SHOWN that activation of ␣ 1 -adrenoceptors mediates vasoconstriction, and considerable progress has been made toward elucidating the molecular structures and signal transduction mechanisms of these adrenoceptors. Molecular cloning studies have identified three ␣ 1 -adrenoceptor cDNAs (␣ 1a , ␣ 1b , and ␣ 1d ), and their primary structure corresponds to the model of the superfamily of G protein-coupled receptors. Moreover, three distinct ␣ 1 -adrenoceptor subtypes (␣ 1A , ␣ 1B , and ␣ 1D ) that correlate well with the cloned ␣ 1 -adrenoceptors have been identified pharmacologically in functional and binding experiments (8, 9). These three subtypes display high, subnanomolar affinities for prazosin. Furthermore, functional studies have provided evidence of the existence of an additional ␣ 1L -adrenoceptor subtype displaying low affinity for prazosin and some other ␣ 1 -adrenoceptor antagonists (3,4,23,33). This ␣ 1L -adrenoceptor has no molecular correlate. However, the physiological role of each ␣ 1 -adrenoceptor in the vascular smooth muscle is unclear, and the expression of an ␣ 1 -adrenoceptor subtype in a vessel is not always related to a functional role of this subtype in the contractile tone of the vessel (10,12,16,17,29,33).In addition to the complex functionality of the different subtypes of ␣ 1 -adrenoceptors, we have shown in previous studies (7,24,26) the existence of a population of constitutively active ␣ 1D -adrenoceptors in the rat aorta but not in the tail artery. The existence of this active conformation has been revealed mainly in artificial models such as receptor mutants or systems that show ...

The Impact of α1-Adrenoceptors Up-Regulation Accompanied by the Impairment of β-Adrenergic Vasodilatation in Hypertension

“…The higher potency, exhibited only by the ␣ 1D selective antagonist BMY 7378 and not by the selective ␣ 1A antagonist 5-methylurapidil, indicates an increased role of the ␣ 1D subtype in the sympathetic vasoconstriction of the aortas of SHRs. There were two hemodynamic consequences of the higher functionality of ␣ 1D -ARs: 1) a higher potency of phenylephrine in hypertensive aortas because of the higher affinity of this subtype for agonists (Minneman et al, 1994;Marti et al, 2005), then being the hypertensive vessels more sensitive to the contractile adrenergic stimulus; 2) a slower decay of the contractile response after removing the agonist because of the characteristic of the ␣ 1D -AR to remain active when the stimulus disappears, as the present results confirm and our previous studies describe in the aorta, main mesenteric artery, and small mesenteric arteries (Gisbert et al, , 2003bZiani et al, 2002). Therefore, the consequences of an increased functionality of ␣ 1D -ARs, a higher sensitivity to an ␣ 1 -adrenergic stimulus, together with a significantly slower decay in the contractile tone after stimulus removal, could all determine the pathological increase in the adrenergic vascular tone observed in hypertension.…”

“…An increased functional role of ␣ 1D -ARs has been proposed as one of the changes involved in the hypertensive increase of vascular resistance (VillalobosMolina et al, 1999;Gisbert et al, 2002;Tanoue et al, 2002a,b;Ziani et al, 2002;D'Ocon, 2003;Lyssand et al, 2008), but the mechanism responsible for this increase has not been elucidated previously.…”

Cytosolic Ca2+ and Phosphoinositide Hydrolysis Linked to Constitutively Active α1d-Adrenoceptors in Vascular Smooth Muscle

“…Two different groups have found constitutively active cloned ␣ 1D -adrenoceptors in stably transfected rat-1 fibroblasts (Garcia-Sainz and Torres-Padilla, 1999;McCune et al, 2000) and human embryonic kidney 293 cells (Chalothorn et al, 2002), which are mainly located in a perinuclear location (McCune et al, 2000;Chalothorn et al, 2002). In addition, we found a population of ␣ 1D -adrenoceptors in intact rat arterial vessels such as the aorta, the iliac, or the proximal mesenteric artery that exhibit several features resembling those of constitutively active receptors (Noguera and D'Ocon, 1993;Noguera et al, 1996;Gisbert et al, 2000Ziani et al, 2002) such as: 1) its activity occurs in the absence of an agonist; 2) it is inhibited by the ␣ 1 -adrenoceptor ligand prazosin and the selective ␣ 1D -adrenoceptor ligand BMY 7378, which behave as inverse agonists; 3) the irreversible ␣ 1 -adrenoceptor antagonist chloroethylclonidine, acting as a neutral antagonist, inhibited noradrenaline-induced contractions in this tissue and did not affect the constitutive response but prevented its inhibition by BMY 7378 and prazosin; and 4) it is only observed in vessels (e.g., aorta, iliac, or proximal mesenteric arteries) where ␣ 1D -adrenoceptors play a functional role. However, as opposed to constitutively active ␣ 1D -adrenoceptors in transfected cells, this type of response in native tissues requires prior stimulation with an ␣ 1 -adrenoceptor agonist.…”

Subtypes of functional α1-adrenoceptor

“…This phenomenon occurred in aorta [105] and iliac and proximal mesenteric arteries [106], but not tail artery (see [107]), and was blocked by benoxathian, WB 41001, prazosin, BMY 73778 and 5-methylurapidil [105,107]. Furthermore, increased potency of BMY 7378 in aorta from SHR suggested an increase in this phenomenon in hypertension (see [107]).…”