Avtor/Urednik		Štempelj, Mateja; Zorko, Matjaž; Peternel, Luka; Urleb, Uroš; Ferjan, Ilonka
Naslov		Histamine release, an undesired effect of thrombin inhibitors with basic character, is mediated through direct activation of Gi proteins
Tip		članek
Vir		Eur J Pharmacol
Vol. in št.		Letnik 538
Leto izdaje		2006
Obseg		str. 182-7
Jezik		eng
Abstrakt		The common structural feature of LK direct thrombin inhibitors is a strong basic group attached to the azaphenylatanine scaffold, which is important for the appropriate interaction at the thrombin active site. Our previous results have shown that this basic group could be responsible for a reduction of tracheal air flow and a fall of mean arterial pressure in anaesthetized rats, an undesired effect of direct thrombin inhibitors which correlated with their ability to release histamine from mast cells. In the present study, we investigated the mechanism of LK direct thrombin inhibitors-induce histamine release from rat peritoneal mast cells. We demonstrated that thrombin inhibitors with basic character (LK-732, LK-639 and LK-6063) provoked release of histamine from mast cells, while less basic analogs f LK-658, LK-633 and LK-6062) had no effect. Histamine released by LK-732 and LK-639 was suppressed by removal of sialic acid residues by neuraminidase and by pertussis toxin, an inhibitor of Gi protein activity. Additional demonstration that U proteins are the targets of LK-732 and LK-639 was provided by the increase of GTPomegaS binding rate to G proteins in rat brain cortical membranes. Our results indicate that basic direct thrombin inhibitors LK-732 and LK-639 provoke release of histamine from mast cells by direct activation of G; proteins through the similar biochemical pathway as basic secretagogues.
Deskriptorji		MAST CELLS HISTAMINE RELEASE THROMBIN GTP-BINDING PROTEINS NEURAMINIDASE PERTUSSIS TOXINS RATS, WISTAR