Nobuo Harada

Relationship between structure, positive inotropic potency and lethal dose of grayanotoxins in guinea pig

Relationship between chemical structure, positive inotropic potency and lethal dose of grayanotoxins and the related compounds was studied using guinea pigs. The positive inotropic effect (PIE) was examined in their papillary muscle isolated from the heart.The potency of these compounds was expressed by pD2 values, and was determined by depicting the concentration-PIE curve for each compound. The study has clarified the contribution of functional groups in the molecule; the presence of 3β-hydroxyl, 6β-hydroxyl and 10β-methyl groups attached to the grayanane skeleton is established to be essential for the development of PIE. The inotropic potency of compounds carrying these essential groups is increased by a 10α-hydroxyl group and the acylation of the 14β-hydroxyl group. LD50 value of 10 compounds with a high cardiotonic potency (pD2>4) was determined by up and down method using male guinea pigs. The relation of LD50 to pD2 bore a significant correlation (r = 0.68, p<0.05). The most cardiotropic and toxic compound found in this study was asebotoxin III.

EFFECT OF DOPAMINE-β-HYDROXYLASE INHIBITOR ON STRESS-INDUCED GASTRIC ULCER

Publisher Summary This chapter discusses the effect of dopamine-β-hydroxylase inhibitor on stress-induced gastric ulcer. 5-Dimethyldithiocarbamyl-picolinic acid—an inhibitor of dopamine-β-hydroxylase (DBH), which does not cross the blood-brain barrier—does not affect stress-induced gastric ulcer, which are thought to be mediated through the central nervous system. 5-butylpicolinic acid—which inhibits DBH passing the blood-brain barrier—exhibits the ability to prevent stress-induced gastric ulcer. These results might suggest the hypothesis but the inhibition of DBH in the central nervous system prevents the stress-induced gastric ulcer of the rat. The present study evaluates the role of DBH in the central nervous system in prevention of stress-induced gastric ulcers after different DBH inhibitors from the picolinic acids. These results suggest that the prevention of the stress-induced gastric ulcers by these three different groups of drugs is mediated through the in vivo inhibition of DBH in the central nervous system.