Characterisation of the specific binding of the histamine H3 receptor antagonist radioligand [3H]GR168320.

We have examined the specific binding of the tritiated derivative of the potent histamine H3 receptor antagonist, [3,4-3H2]-cyclohex-yl-¿[4-(3H-imidazol-4-yl)-piperidin-l-yl] iminomethyl¿- amine ([3H]GR168320), to homogenates of rat cerebral cortex. Specific binding of [3H]GR168320 at 37 degrees C associated and dissociated rapidly. Binding was saturable (Bmax 412 +/- 89 fmol/mg protein) and of high affinity (Kd 0.12 +/- 0.11 nM). Saturation studies suggested the involvement of a single site. Histamine H3 receptor agonists and antagonists inhibited [3H]GR168320 binding with high affinity. Agonist and antagonist affinities correlated when compared with affinities obtained using the tritiated histamine H3 agonist radioligand N alpha-methylhistamine.

Gastric anti-secretory, mucosal protective, anti-pepsin and anti-Helicobacter properties of ranitidine bismuth citrate.

Ranitidine bismuth citrate is a novel compound formed from ranitidine and a bismuth citrate complex. In conscious dogs, ranitidine bismuth citrate had similar activity to ranitidine hydrochloride as an inhibitor of histamine-induced gastric acid secretion when oral doses containing equivalent amounts of ranitidine base (0.1 or 0.3 mg/kg) were compared. In the rat, ranitidine bismuth citrate (3-30 mg/kg p.o.) prevented gastric mucosal damage induced by ethanol (fundic damage) and indomethacin (antral damage). Ranitidine hydrochloride and tripotassium dicitrato bismuthate were also effective against indomethacin-induced damage, but were both significantly less potent than ranitidine bismuth citrate in this model. Ranitidine hydrochloride was inactive against ethanol-induced damage. In vitro, ranitidine bismuth citrate (1 mmol/L) inhibited human pepsin isoenzymes 1, 2, 3 and 5. Pepsin 1 was inhibited to a similar extent by ranitidine bismuth citrate, bismuth citrate and tripotassium dicitrato bismuthate at concentrations equivalent to 1 mmol/L bismuth, but ranitidine (1 mmol/L) was inactive. Ranitidine bismuth citrate was more potent than tripotassium dicitrato bismuthate as an inhibitor of pepsins 2, 3 and 5. Ranitidine bismuth citrate inhibited both Helicobacter pylori (effective concentration 4-32 micrograms bismuth/ml) and H. mustelae (1-4 micrograms bismuth/ml); similar results were obtained with tripotassium dicitrato bismuthate. Bismuth citrate was slightly less effective, and ranitidine hydrochloride was inactive (> 125 micrograms/ml). In ferrets naturally colonized with H. mustelae, oral treatment with ranitidine bismuth citrate, 12 or 24 mg/kg twice daily for 4 weeks, caused a dose related clearance of H. mustelae. Qualitatively similar results were obtained in a small study with tripotassium dicitrato bismuthate and bismuth citrate.