Evidence for a functional α1A- (α1C-) adrenoceptor mediating contraction of the rat epididymal vas deferens and an α1B-adrenoceptor mediating contraction of the rat spleen

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Abstract
1 The α1-adrenoceptor subtype mediating contraction of the rat epididymal vas deferens and rat spleen has been investigated by use of α1-adrenoceptor antagonists that have shown selectivity between the different cloned receptor subtypes. 2 In the rat epididymal vas deferens the potency of noradrenaline and phenylephrine was increased in the presence of neuronal and extra-neuronal uptake blockers, cocaine and β-oestradiol, but these did not alter that of methoxamine. The order of potency of the agonists in the presence or absence of uptake blockade was noradrenaline > phenylephrine > methoxamine. In the rat spleen the potency of these agonists was not altered in the presence of cocaine and β-oestradiol, and their order of potency was the same as in the vas deferens. 3 The non subtype selective α1-adrenoceptor antagonist prazosin (up to 1 × 10−7M) was found to antagonize contractions to noradrenaline in the vas deferens competitively (pA2 9.2), but only in a non competitive manner in the spleen. Contractions to phenylephrine in the spleen however were competitively antagonized by prazosin (up to 1 × 10−7 M) with a pA2 of 9.2. This suggests that there is an α1- and a non α1-adrenoceptor response to noradrenaline in the rat spleen. 4 Pretreatment with chlorethylclonidine (10−4 M for 30 min) did not alter the noradrenaline contractions in the vas deferens, but contractions to noradrenaline and phenylephrine in the spleen were shifted 30 and 300 fold to the right of the control curve, respectively. This suggests that only the contractions in the spleen were mediated by α1B-adrenoceptors. 5 The noradrenaline contractions in the vas deferens were competitively antagonized by WB 4101 (pA2 9.6), 5-methyl-urapidil (pA2 8.7), phentolamine (pA2 8.3), benoxathian (pA2 9.4), spiperone (pA2 7.5), indoramin (pA2 8.4) and BMY 7378 (pA2 6.7), consistent with the affinities of these antagonists in binding studies on tissue α1A-adrenoceptors. These values correlated best with their published affinities on the expressed α1c-adrenoceptor clone and poorly with those at either the expressed α1b- or α1d-adrenoceptor clones. Therefore the classical α1A-adrenoceptor appears to be the same as the expressed α1c-adrenoceptor clone. 6 The phenylephrine contractions in the spleen were competitively antagonized by WB 4101 (pA2 8.1), 5-methyl-urapidil (pA2 7.1), phentolamine (pA2 7.3), benoxathian (pA2 7.4), spiperone (pA2 7.9), indoramin (pA2 7.5) and BMY 7378 (pA2 7.4), consistent with the affinities of these antagonists in binding studies on tissue α1B-adrenoceptors. The pA2 values correlated best with the published affinities of these compounds on the expressed α1b-adrenoceptor clone and poorly with those at either the expressed α1d- or α1c-adrenoceptor clones. Therefore the α1B-adrenoceptor appears to be the same as the expressed α1b-adrenoceptor clone. 7 The results provide pharmacological evidence that the α1-adrenoceptor mediating noradrenaline contractions in the epididymal portion of the rat vas deferens is the α1A-(α1C) subtype and that contractions to phenylephrine in the rat spleen are mediated by the α1B-subtype.