Pharmacological characterization of α-adrenoceptors that mediate contraction in splenic artery strips from the pig
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The α-adrenoceptors that mediate contractions in strips of splenic artery from the pig were characterized by the use of selective agonists and subtype-selective antagonists. Noradrenaline, the α1-selective agonist phenylephrine and the α1-/α2-agonist oxymetazoline caused the preparations to contract with potency (pD2) values of 6.94, 6.14 and 7.27, respectively. Compared to noradrenaline, phenylephrine and oxymetazoline induced 93% and 78% of noradrenaline maximum effect. Conversely, the two α2-selective agonists clonidine and B-HT 920 induced only 31% and 13% of noradrenaline maximum effect. B-HT 920 only marginally contracted the tissue even when it was precontracted with phenylephrine. The α2-selective antagonist yohimbine antagonized oxymetazoline- and phenyleprine-induced contractions with affinity (pA2) values (6.80 and 6.74, respectively) consistent with α1-adrenoceptor interaction. This suggests that the pig splenic artery possesses only functional α1-adrenoceptors. The α1-adrenoceptor antagonists of varying subtype selectivities like WB-4101, 5-methylurapidil, benoxathian and BMY 7378 competitively antagonized phenylephrine-induced contractions with affinity values of 9.46, 8.26, 9.06 and 6.91, respectively. These values correlated highly with published affinity values for functional α1A-adrenoceptors (r=0.92) and α1a-clones (r=0.94) and less well with affinity values for functional α1B-adrenoceptors (r=0.84) and α1b-clones (r=0.87). Conversely, correlation with functional α1D-adrenoceptors (r=0.26) and α1d-clones (r=0.33) was poor. In addition the α1D-selective antagonist BMY 7378 had a low affinity value compared to that reported for α1D-adrenoceptors. Therefore, based on correlation studies, the plot that resembled the line of equal values most closely was that for the α1A-subtype. The α1A-selective antagonist RS-17053 antagonized phenylephrine-induced contractions in an apparently non-competitive manner and gave an apparent pA2 value of 7.06 which is similar to the “low” affinity values reported in other α1A-containing tissues. Exposure to the irreversible α1B/D-antagonist chloroethylclonidine slightly decreased maximum response to phenylephrine without significantly affecting its potency value, indicating that the phenylephrine response is substantially chloroethylclonidine-insensitive.It is concluded that splenic artery strips from the pig contract in response to phenylephrine through activation of α1-adrenoceptors which display the pharmacological profile of the α1A-subtype for which the recently reported α1A-selective antagonist RS-17053 shows low affinity. Evidence for contribution of the α1B-subtype in the overall contractile response is elusive while no evidence was obtained for the involvement of the α1D-subtype. The contribution of functional α2-adrenoceptors to the contractile response was ruled out.
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