Studies on the mode of action of somatostatin on insulin secretion.

The effect of somatostatin on insulin release by incubated slices of rat pancreas was studied. Somatostatin inhibited insulin release induced by arginine/glucose (A/G), glucagon, glibenclamide, pentoxifyllin, 3',5'-adenosine monophosphate (cAMP), phentolamine, and KCl. When A/G was used as a stimulus, the quantial inhibitory effect of somatostatin was not neutralized by progressively increasing glucose concentrations. The alpha adrenergic blocking agent phentolamine, the phosphodiesterase inhibitors theophylline (10 mM) or pentoxifyllin (10 mM), and KCl partially reversed the inhibitory effect of somatostatin on A/G stimulation. The maximal reversal of somatostatin inhibition was obtained when the slices of pancreas were stimulated with A/G in the presence of the calcium ioniphore A23187 plus ATP. These results suggest that the inhibitory effect of somatostatin on insulin secretion could result from calcium translocation in pancreatic beta cells.     

Studies on the mode of action of oxamniquine and related schistosomicidal drugs

Adult Schistosoma mansoni were incubated for 1 hour in vitro with various drugs and then returned into the mesenteric veins of permissive animal hosts. Survival of schistosomes was assessed 3-4 weeks later by portal perfusion. Under these conditions, oxamniquine and hycanthone proved effective in killing S. mansoni, whereas UK-3883, lucanthone and lucanthone-4-desmethyl had no lethal activity. The same drugs which were schistosomicidal in vitro also persistently inhibited DNA, RNA, and protein synthesis in S. mansoni, whereas they were only transiently inhibitory against Schistosoma japonicum, against hycanthone-resistant S. mansoni and against immature worms. When drugs were administered in vivo to infected mice and the synthesis of macromolecules was assayed in vitro on worms obtained 1 or 3 days after treatment, not only oxamniquine and hycanthone, but also UK-3883 and lucanthone, proved effective in inhibiting the synthesis of macromolecules in sensitive--but not in resistant--S. mansoni. It is suggested that oxamniquine, like hycanthone, may exert its schistosomicidal activity by inhibiting nucleic acid synthesis in the parasite.     

Studies of endothelium-derived relaxant factor (EDRF), its nature and mode of action

The effect of endothelium on constrictor responses to 5-hydroxytryptamine,histamine, phenylephrine and actylcholine was studied and shownto be much greater in isolated perfused coronary arteries thanaortic strips of the rabbit. Localised endothelial damage predisposednonspecifically to ‘coronary spasm’. Endothelium-dependentdilatation was shown by bioassay to be mediated by a humoralagent, endothelium-derived relaxant factor (EDRF), with half-lifeof 6 s. Experiments with inactivating agents indicate that EDRFis not a cyclo-oxygenase or lipoxygenase product and not a freeradical; they imply that it contains a carbonyl group at ornear its active site. Experiments in which guanylate cyclaseand cGMP phosophodiesterase were inhibited indicate that EDRFacts by elevating smooth muscle cGMP. Ergometrine was shownto stimulate EDRF activity which may be relevant to its clinicaluse in provoking coronary spasm. The physiological role andpathophysiological relevance of this novel, ubiquitous and potentendogenous vasodilator are not yet known; it may be of particularimportance in modulating coronary vasomotor responses.