Go Kito

Contractile activities of leukotrienes C4 and D4 on vascular strips from rabbits

Abstract Leukotrienes C4 (LTC4) and D4 (LTD4), major components of slow-reacting substances of anaphylaxis (SRS-A), caused dose-dependent contractions of rabbit coronary arteries in concentrations of 10−9 to 10−7 M and 10−10 to 10−7 M, respectively. The potency of LTC4 and LTD4, when compared with the concentration that elicits half of the contraction induced by 25 mM KCl, was 17 and 76 times, respectively, greater than that of histamine. In contrast, other blood vessels from rabbits were either unresponsive (renal artery and vein, mesenteric artery and thoracic aorta) or only weakly responsive (pulmonary artery and vein and portal vein) to both leukotrienes even at 10−7 M. The LTD4-induced coronary contraction was inhibited by FPL 55712 (10−7 and 10−6 M), a selective SRS-A inhibitor, in a dose-dependent manner, but not by diphenhydramine (10−7 M), a histamine H1-receptor blocker or by indomethacin (10−5 M), a prostaglandin synthetase inhibitor, suggesting that LTD4 has a direct effect on the coronary arteries. These results indicate that the leukotrienes may act as potent, selective coronary vasoconstrictors and that SRS-A responsive receptors exist in the rabbit coronary artery.

The antiobesity action of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124)

The antiobesity effects of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124) were examined in rats and dogs. AO-124 suppressed food intake dose dependently in normal, Zucker fatty and VMH-obese rats, and beagle dogs. Its anorectic activity was not altered by pretreatment with methysergide, a serotonin receptor blocker. AO-124 also reduced the hyperphagia induced by 2-deoxy-D-glucose but not that induced by insulin, noradrenaline or muscimol, suggesting that the anoretic mechanism of AO-124 may be implicated in a glucostatic regulatory system of feeding. In addition, AO-124 decreased insulin secretion in response to an oral, but not an intravenous, glucose load. Such a suppression in insulin secretion may be explained by slow absorption of glucose from the intestine: AO-124 delayed the gastric emptying time of glucose and inhibited the active transport of glucose as observed in the everted small intestine. Two week administration of AO-124 to Zucker fatty rats resulted in a significant reduction of plasma insulin levels, body weight gain, and body lipid without exerting any changes in body protein. These findings indicate that AO-124 may be useful as an antibesity agent on the basis of its unique mechanisms of action.