thromboxane-a2 and triletide

There is accumulating evidence that the presence of the imidazole ring is essential for the inhibition of the thromboxane synthetase activity of several compounds synthetized so far. Inhibition of arachidonic acid (AA) induced platelet aggregation was observed by us with a series of tripeptides in which the imidazole ring belongs to histidine, included in a proper aminoacid sequence. Among these compounds the N-acetyl-L-phenylalanyl-L-phenylalanyl-L-histidine methylester (ZAMI-420) was the most effective. The bioassay of the supernatant of an AA-added platelet-rich plasma (PRP) preparation, preincubated with increasing concentrations of ZAMI-420, showed a dose-related reduction in thromboxane-A2 (TXA2)-like activity, an increase of PG-like response and disappearance of the TXB2 peak in the radiochromatogram; RIA experiments led to the same results. ZAMI-420 does not influence cyclooxygenase activity as the AA-induced increase in O2-consumption by the microsomal fraction of bovine seminal vesicles was unaltered by this compound. Administered orally to the rat, ZAMI-420 was able to prevent gastric damage provoked by a variety of pharmacological agents, including ASA, 5HT and alcohol. The protective effect on experimentally-induced gastric damage is not mediated through the antisecretory properties of this compound but is more likely to be due to a cytoprotective mechanism based on blockade of TXA2 synthesis.

Topics: Animals; Arachidonic Acids; Biological Assay; Carbenoxolone; Chromatography, Thin Layer; Cimetidine; Ethanol; Female; Guinea Pigs; Imidazoles; Oligopeptides; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Rabbits; Radioimmunoassay; Rats; Rats, Inbred Strains; Serotonin; Stomach; Stomach Ulcer; Thromboxane A2; Thromboxanes; Vasoconstriction

The tripeptide ZAMI-420 has been shown by Gervasi et al. (4) to be able to prevent experimentally-induced gastric damage, possibly by interfering with the synthesis and the action of thromboxane A2 (TXA2), a potent vasoconstrictor and platelet aggregator. Further studies on a canine stomach wedge preparation, supplied with a fixed flow of 10 ml/min-1 of arterial blood from the same dog have been designed to investigate this hypothesis. Bolus injection of arachidonic acid (AA) through a 30-sec incubation coil that allows the production of TXA2 resulted in a dose-related increase in resistance to flow in the stomach wedge vasculature and blanching of the gastric mucosa. This was progressively inhibited by ZAMI-420 perfused through the delay coil. Similar results were obtained with 1-benzylimidazole (BI). ZAMI-420, but not BI, produced a partial inhibition of TXA2-induced vasoconstriction when infused close to the stomach. Investigations of the antagonistic action of ZAMI-420 on the pharmacological effect of the formed TXA2 were carried out using strips of celiac and mesenteric artery from rabbits and gastric artery from dogs. Preincubation of these vascular preparations with ZAMI-420 led to progressive inhibition of the contraction induced either by the stable endoperoxide U-46619 or by CaCl2. Whittle et al. (3) reported that TXA2 may be involved in the pathogenesis of ulcerative disorders of the stomach; if so, both the inhibition of the synthesis and the antagonism of TXA2-induced effects could be of value in the prevention of experimentally-induced gastric disorders.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Celiac Artery; Dogs; Female; Gastric Mucosa; Ischemia; Male; Mesenteric Arteries; Oligopeptides; Prostaglandin Endoperoxides, Synthetic; Rabbits; Stomach; Thromboxane A2; Thromboxanes; Vasoconstriction