Alpha₂-adrenoceptor-mediated responses to so-called selective alpha₁-adrenoceptor agonists after partial blockade of alpha₁-adrenoceptors

Summary

In dog saphenous vein — a tissue possessing both postsynaptic α₁- and α₂-adrenoceptors — the effects of two selective α₁-adrenoceptor agonists (phenylephrine and methoxamine) were compared with that of the selective α₂-adrenoceptor agonist, UK-14,304, before and after phenoxybenzamine. Furthermore, the influence exerted by prazosin, yohimbine and verapamil on the effects of these agonists was also studied before and after phenoxybenzamine. In the absence of phenoxybenzamine, prazosin (56 nmol/l) caused a parallel shift of the concentration-response curves of both phenylephrine and methoxamine to the right (by 0.94 and 1.1 log units, respectively) and had no effect on the concentration-response curve of UK-14,304, while 20 nmol/l yohimbine caused a marked parallel shift of the concentration-response curve of UK-14,304 to the right (by 1.18 log units) and caused only minor displacements of those of phenylephrine and methoxamine (by 0.2 and 0.33 log units, respectively). After exposure of the strips to 30 nmol/l phenoxybenzamine, prazosin (56 nmol/l) caused small shifts of the concentration-response curves of both phenylephrine (by 0.36 log units) and methoxamine (by 0.31 log units) and did not change that of UK-14,304, while yohimbine (20 nmol/l) caused pronounced parallel shifts of the concentration-response curves (to the right) of all the agonists: phenylephrine (by 1.0 log units), methoxamine (by 0.93 log units) and UK-14,304 (by 1.28 tog units). When UK-14,304 was added to the bath during a sub-maximal contraction to phenylephrine it caused a further contraction almost up to the maximum; if this procedure was repeated after phenoxybenzamine (30 nmol/1), there was no further contraction to UK-14,304.

In the absence of phenoxybenzamine, verapamil (5 μmol/l) caused a parallel shift of the concentration-response curve of phenylephrine (or methoxamine) to the right and a non-parallel shift (with marked depression of the maximal effect) of that of UK-14,304. However, after phenoxybenzamine (30 nmol/l), the same concentration of verapamil caused non-parallel shifts of the concentration-response curves of the three agonists to the right with about equal depression of the maximal effects. We conclude that, after removal of α₁-adrenoceptor reserve by phenoxybenzamine, the responses to selective α₁-adrenoceptor agonists are predominantly α₂-adrenoceptor-mediated. This may explain why under these conditions, the selective α₁-and α₂-adrenoceptor agonists are equally antagonized by calcium entry blockers.