CONCERNING THE MODE OF ACTION OF GUANETHIDINE AND SOME DERIVATIVES IN AUGMENTING THE VASOMOTOR ACTION OF ADRENERGIC AMINES IN VASCULAR TISSUES OF THE RABBIT

¹ Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont

At 10^-7 M and 5 x 10^-7 M guanethidine does not potentiate contractions induced in rabbit aortic strips by norepinephrine. At 10^-6 M and 5 x 10^-5 M guanethidine augments norepinephrine contractions while at 10^-6 M and 10^-3 M guanethidine antagonizes norepinephrine contractions. The potentiating action is not readily reversed by washing out the guanethidine but the antagonistic action is. Guanethidine produces a dose-dependent suppression of the uptake and binding of norepinephrine over the concentration range 10^-7 M to 5 x 10^-5 M. If strips are exposed to 5 x 10^-5 M guanethidine and then the guanethidine is repeatedly washed out of the bath, the capacity to potentiate norepinephrine is not diminished, but the uptake and binding are inhibited only to the same degree as during exposure to a nonpotentiating dose of guanethidine (5 x 10^-7 M).

The diffusible fraction of the total norepinephrine uptake is decreased by 10^-7 M and higher concentrations of guanethidine but the responses of the strips are similar to the response of untreated strips. At 10^-6 M and 5 x 10^x M guanethidine the responses are greater than in untreated strips. It would appear that by some unknown action guanethidine is causing muscle cells to hyperrespond to a diminished pool of active amine.

Structure-activity relationships for the capacity of a series of guanidines to potentiate a series of amines suggest that the guanidines act at the level of the adrenergic receptor to enhance the responses to amines. It is speculated that guanidines may change the configuration of the receptor "surface" in such a way as to improve hydrogen bonding or ion pair formation with selected amines and hence to enhance the affinity of the receptor-amine complex.