The Pharmacology of Some Angiotensin Antagonists

Abstract

Interactions between tetraethylthiuram disulphide (disulfiram), its metabolite diethyldithiocarbamate (DDC) and the vasoactive polypeptide angiotensin have been studied. In the pithed rat preparation, both disulfiram and DDC were shown to specifically reduce pressor responses to injected angiotensin. The possible involvement of the sympathetic nervous system in this activity was investigated and the results discussed. It was not possible to reproduce these effects of disulfiram and DDC in the chloralosed, conscious or pithed cat preparations, thus suggesting some form of species specificity. Possible reasons for this are discussed. Using a variety of test procedures, the effects of disulfiram and DDC on two isolated smooth muscle preparations were determined. In the case of the rat isolated colon preparation, pretreatment with disulfiram was shown to inhibit the spasmogenic activity of 5-hydroxvtryptamine and acetylcholine in addition to that of angiotensin. The effect of disulfiram, on the contractile responses of the Guinea pig isolated ileum was to reduce the fast, cholinergically mediated component of the response to angiotensin without reducing the direct component. In preparations treated with hyoscine, the direct component of the angiotensin response was selectively reduced by DDC. The effects of prolonged treatment with disulfiram on the development of renal and DOCA/saline hypertension in rats were studied. With the exception of the early stages of renal hypertension, disulfiram did not retard the onset or extent of the hypertension. The reasons for these effects are discussed in the light of published reports concerning renin levels during experimental hypertension. The mechanism of action of these effects of disulfiram is largely unknown. Results presented in the latter part of this thesis derived from attempts to mimic these antiangiotensin effects using a number of unrelated compounds possessing some activity shared with disulfiram or DDC. Dimercaprol, an inhibitor of enzyme -SH groups, produced a non-specific reduction in reactivity to vasoactive agents in the pithed rat. Chelating agents were shown not to inhibit pressor responses to angiotensin in the rat. The results of these experiments are discussed in the light of current knowledge on the metabolism and actions of disulfiram and DDC.