Variation in the interaction of some phenylethylamine and imidazoline derivatives with alpha-1 adrenoceptors in rabbit arteries: further evidence for the variable receptor affinity hypothesis.

This study was undertaken to determine whether the variation in the affinity of the alpha-1 adrenoceptors previously found for norepinephrine and phenylephrine in different arteries is also seen with other alpha-1 adrenoceptor agonists, and if so, if one part of the structure is particularly responsible for the variation. The potency and dissociation constants of eight agonists, both phenylethylamines and imidazolines, were determined in five rabbit arteries. In each artery the rank order of phenylethylamine agonist potency was epinephrine greater than norepinephrine greater than phenylephrine greater than deoxyepinephrine greater than methoxamine greater than dopamine. The same rank order of dissociation constants was found. For the imidazolines, the potency order was oxymetazoline greater than clonidine. For each agonist, there was a linear correlation between artery sensitivity and receptor affinity. None of the regression line slopes differed from each other. For each artery there was a linear correlation between phenylethylamine sensitivity and affinity. With the exception of the ovarian, which was lower, slopes of the regression lines in each group do not differ from each other. There were differences in the spread of the dissociation constants of the phenylethylamine derivatives among the arteries. The range of affinities was most marked with norepinephrine (greater than 40-fold) and least with epinephrine (approximately 4-fold). They suggest that agonist affinity governs the biological activity of at least the phenylethylamines on rabbit arteries mediated by the alpha-1 adrenoceptor. Variation in agonist affinity can explain the extent of the biological response. Differences in range of amine affinities in different arteries suggest that the agonist recognition site, although similar in the different arteries, is not identical and may be related particularly to some variation of the amine attachment site of the molecule. The results provide further support for the variable receptor affinity hypothesis.