Characterization of α₂‐adrenoceptors mediating contraction of dog saphenous vein: identity with the human α_2A subtype

Abstract

1 In the dog saphenous vein a 1 -and a 2 -adrenoceptors mediate noradrenaline-induced contractions in vitro. In order to study the a 2 -adrenoceptor in isolation, a 1 -adrenoceptors were inactivated by treatment of tissues with the alkylating agent phenoxybenzamine (3.0 mM for 30 min) in the presence of rauwolscine (1 mM) to protect a 2 -adrenoceptors. 2 Noradrenaline-induced contractions of tissues treated with phenoxybenzamine were antagonized competitively by the selective a 2 -adrenoceptor antagonist rauwolscine, pK B =8.63+0.07 (means+s.e.-mean; n=3), consistent with an interaction at a 2 -adrenoceptors. 3 Noradrenaline was a full agonist at a 2 -adrenoceptors in dog saphenous vein. By use of the method of partial receptor alkylation and analysis of concentration-e ect curve data by direct, operational model ®tting methods, the a nity (pK A ) and e cacy (t) were 5.74+0.07 and 7.50+1.05, respectively (n=6). Nine other agonists which were examined each had a nities higher than noradrenaline, but with the exception of the imidazoline, A-54741 (5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl-imidazoline) had relatively lower e cacies. 4 To compare the a 2 -adrenoceptor in dog saphenous vein to the human recombinant subtypes, the a nities of twenty-one compounds were estimated in functional studies in the dog saphenous vein and in radioligand binding studies for the human a 2A , a 2B and a 2C receptor subtypes expressed in Chinese hamster lung (CHL) cells. 5 Of twenty-one compounds examined in ligand binding studies, only nine had greater than ten fold selectivity for one human receptor subtype over either of the other two. These compounds were A-54741, oxymetazoline, guanfacine, guanabenz, prazosin, spiroxatrine, tolazoline, WB 4101 and idazoxan. In dog saphenous vein, their a nities (pK A and pK B for agonists and antagonists respectively) were: A-54741 (pK A =8.03+0.05), oxymetazoline (pK A =7.67+0.09), guanfacine (pK A =6.79+0.03); guanabenz (pK A =7.02+0.13); prazosin (pK B =5.19+0.08), spiroxatrine (pK B =6.59+0.04), tolazoline (pK B =6.21+0.07), WB 4101 (pK B =7.42+0.09) and idazoxan (pK B =7.11+0.08). 6 Comparisons of a nity estimates for these nine compounds at the receptor in dog saphenous vein and at the human recombinant subtypes suggest that the vascular receptor is most similar to the h a 2A subtype; correlation coe cients (r) were 0.82 (h a 2A ), 0.24 (h a 2B ) and 0.04 (h a 2C ).

Epididymal contraction and sperm parameters are affected by clonidine

“…This profile is quite similar to those previously reported for tissues presenting mixed populations of a 1 -and a 2 -adrenoceptors and could indicate that clonidine might induce contraction of distal cauda epididymis by activation of both adrenoceptors (MacLennan et al, 1997;Dantas da Silva Junior et al, 2014). The consecutive contractions of distal cauda epididymis induced by clonidine led to diminished responses (desensitization, as previously defined by Neubig et al, 2003) as reflected by the decreased values of pD 2 and E max with repeated exposures.…”

Actions of α2 adrenoceptor ligands at α2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for α2A adrenoceptors

“…α 2 receptors are divided into several subtypes: α 2A , α 2B , α 2C . Pharmacological, autoradiographical and gene knock-out studies have shown that the α 2A subtype (Trendelenburg et al 1993;Van Liefde et al 1993;O'Rourke et al 1994) is the key α 2 receptor involved in the modulation of nociception Tracey et al 1995;Hunter et al 1997;Millan 1997Millan , 1998, cardiovascular function (MacLennan et al 1997), lipid metabolism (Tarkovács et al 1994), the release of noradrenaline, dopamine and serotonin (5-HT; Trendelenburg et al 1994;Millan et al 1994;Gobert et al 1997aGobert et al , 1998, and, probably, in mood states (Dickinson 1991). In the central nervous system, α 2A adrenoceptors are more widely distributed than α 2B and α 2C adrenoceptors, being detected in cortex, septum, dorsal horn and the endopiriform nucleus (Uhlén and Wikberg 1997).…”

The Adrenergic System in Vascular Smooth Muscle

“…In the porcine palmer lateral vein and common digital artery, the low potency of prazosin suggests the presence of α 2A -adrenoceptors [12], and α 2A -adrenoceptors have also been reported in dog saphenous vein [86]. In the pig ciliary artery, the high potency of BRL44408 suggests the involvement of α 2A -adrenoceptors in contractions [143].…”