PHARMACOLOGICAL CHARACTERIZATION OF ALPHA-ADRENOCEPTORS THAT MEDIATE CONTRACTION IN SPLENIC ARTERY STRIPS FROM THE PIG

The alpha-adrenoceptors that mediate contractions in strips of splenic artery from the pig were characterized by the use of selective agonis ts and subtype-selective antagonists. Noradrenaline, the alpha(1)-sele ctive agonist phenylephrine and the alpha(1)-/alpha(2)-agonist oxymeta zoline caused the preparations to contract with potency (pD(2)) values of 6.94, 6.14 and 7.27, respectively. Compared to noradrenaline: phen ylephrine and oxymetazoline induced 93% and 78% of noradrenaline maxim um effect. Conversely, the two alpha(2)-selective agonists clonidine a nd B-HT 920 induced only 31% and 13% of noradrenaline maximum effect. B-HT 920 only marginally contracted the tissue even when it was precon tracted with phenylephrine. The alpha(2)-selective antagonist yohimbin e antagonized oxymetazoline- and phenyleprine-induced contractions wit h affinity (pA(2)) values (6.80 and 6.74, respectively) consistent wit h alpha(1)-adrenoceptor interaction. This suggests that the pig spleni c artery possesses only functional alpha(1)-adrenoceptors. The alpha(1 )-adrenoceptor antagonists of varying subtype selectivities like WB-41 01, 5-methylurapidil, benoxathian and BMY 7378 competitively antagoniz ed phenylephrine-induced contractions with affinity values of 9.46, 8. 26, 9.06 and 6.91, respectively. These values correlated highly with p ublished affinity values for functional alpha(1A)-adrenoceptors (r=0.9 2) and alpha(1a)-clones (r=0.94) and less well with affinity values fo r functional alpha(1B)-adrenoceptors (r=0.84) and alpha(1b)-clones (r= 0.87). Conversely, correlation with functional alpha(1D)-adrenoceplors (r=0.26) and alpha(1d)-clones (r=0.33) was poor. In addition the alph a(1D)-selective antagonist BMY 7378 had a low affinity value compared to that reported for alpha(1D)-adrenoceptors. Therefore, based on corr elation studies, the plot that resembled the line of equal values most closely was that for the alpha(1A)-subtype. The alpha(1A)-selective a ntagonist RS-17053 antagonized phenylephrine-induced contractions in a n apparently non-competitive manner and gave an apparent pA(2) value o f 7.06 which is similar to the ''low'' affinity values reported in oth er alpha(1A)-containing tissues. Exposure to the irreversible alpha(1B /D)-antagonist chloroethylclonidine slightly decreased maximum respons e to phenylephrine without significantly affecting its potency value, indicating that the phenylephrine response is substantially chloroethy lclonidine-insensitive. It is concluded that splenic artery ships from the pig contract in response to phenylephrine through activation of a lpha(1)-adrenoceptors which display the pharmacological profile of the alpha(1A)-subtype for which the recently reported alpha(1A)-selective antagonist RS-17053 shows low affinity. Evidence for contribution of the alpha(1B)-subtype in the overall contractile response is elusive w hile no evidence was obtained for the involvement of the alpha(1D)-sub type. The contribution of functional alpha(2)-adrenocepcors to the con tractile response was ruled out.