The histamine-like effects of tolazoline and clonidine:: evidence against direct activity at histamine receptors.

Both tolazoline and clonidine produce agonist effects sensitive to histamine H2-receptor antagonism in whole animals and a variety of isolated tissues. In guinea-pig right atria, tolazoline concentration-response curves were shifted to the right and progressively depressed by cimetidine. Clonidine produced a submaximal histamine-like tachycardia which was converted by cimetidine to a depression of sinus rate. Neither tolazoline nor clonidine stimulated histamine H2-receptors in rabbit right atria. Instead, these agents were very weak inhibitors of histamine with a pA2 for tolazoline of 3.3 and for clonidine of 3.7. No appreciable histamine H1-receptor activity was evident for either drug in experiments with guinea-pig ileum. The weak histamine H2-receptor affinity is inconsistent, from a quantitative point of view, with the hypothesis that the agonist activity results from direct stimulation of histamine receptors, but all data re compatible with previous evidence which suggests that these drugs release endogenous histamine.