Biochemical and pharmacological characterization of histamine-mediated up-regulation of human platelet serotonin uptake. Evidence for a subclass of histamine H₂ receptors (H_2h) highly sensitive to H₂ receptor antagonists

Abstract

The stimulatory effect of histamine: H (1.2 to 3-fold increase) on serotonin (5-HT) uptake by human platelets was observed after a 5 min incubation period in the presence of 2.5×10⁻⁷ M histamine, followed by subsequent 5 min incubation of the platelets with 10⁻⁷ M [³H] 5-HT. Methyl, ethyl and acetyl substituents in the side chain of H mimiked the stimulatory effect of H. In contrast, H analogs methylated at the position N-1 of the imidazole ring of H, as well as imidazole and histidine inhibited platelet 5-HT uptake. The cAMP-inducing agents forskolin and theophylline have no effect on 5-HT uptake when they are tested alone or in combinations with H. In contrast, the cGMP-inducing agent sodium nitroprusside (10⁻⁷ M–10⁻⁶ M) stimulated and potentiated H-mediated up-regulation of 5-HT uptake. Histamine H₂ receptor agonists and antagonists are more potent than drugs acting on H₁ receptors (H₂>H₁). However, the inhibition constants Ki are not consistent with those determined for typical H₁, H₂, H₃ receptors characterized in other tissues. This findings provide further evidence for the existence of multiple forms of H receptors and suggest the involvement of a subpopulation of H₂ receptors, highly sensitive to H₂ receptors antagonists (H_2h), mediating 5-HT uptake in human platelets.