INCREASE OF HUMAN PLATELET SEROTONIN UPTAKE BY ATYPICAL HISTAMINE-RECEPTORS

Histamine and the guanosine 3',5'-cyclic monophosphate (cGMP)-inducing agent sodium nitroprusside both increased serotonin (5-HT) uptake and cGMP levels in isolated human platelets in vitro. Histaminergic stimu lation was observed at concentrations ranging from 10 nM to 0.25 mu M [mean effective concentration (EC(50)) = 0.1 mu M histamine]. The inhi bition produced by the H-2-receptor antagonists tiotidine, metiamide, and cimetidine was 10-10(5) times more potent on histamine receptors r egulating 5-HT uptake and cGMP generation in human platelets than on t he histaminergic receptors H-1, H-IC, H-2, and H-3 in other tissues. T he in vitro histamine-induced 5-HT uptake was prevented by preincubati on of isolated human platelets in the presence of the nitric oxide syn thase inhibitor NG-monomethyl-L-arginine or the cGMP-lowering agent LY -83583. Histamine was ineffective in stimulating cAMP generation in hu man platelets and did not interact with effector sites known to downre gulate 5-HT uptake, including imipramine, gamma-aminobutyric acid A, p eripheral type benzodiazepine-binding sites, and V-1a vasopressin rece ptors inducing human platelet shape change and aggregation. These atyp ical human platelet histaminergic receptors differ from the previously classified histamine receptors by their apparent high affinity to his tamine H-2-receptor antagonists and their apparent link with the solub le, nitric oxide-dependent guanylate cyclase. These findings suggest t hat human platelets express a new subtype H-2h of histamine receptors.