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A series of 1-[3-(acylthio)-3-aroylpropionyl]-L-proline derivatives was synthesized. A number of these compounds are potent angiotensin converting enzyme (ACE) inhibitors that lowered blood pressure in aorta-coarcted renal hypertensive rats. The most active derivatives are 1-[3(R)-(acetylthio) -3-substituted-benzoyl)-2(S)-methyl-propionyl]-L-prolines with an in vivo activity equivalent to SQ 14,225 (captopril). Structure-activity relationships are discussed. Changes in the configuration of the alpha-methyl group and the S-acetyl group affect the ACE activity. Coupling of 3-(substituted-benzoyl)-2-methylpropionic acids to L-proline via enol lactones is described.

The relationship of Ireland to the Commonwealth during the period of its membership was a tortuous one. Forced to accept dominion status under threat of the renewal of Anglo-Irish hostilities, Ireland was not an enthusiastic member of the club as were the older dominions. The Constitutional Amendment (No. 27) Bill, enacted on 11 December 1936, removed all references to the crown and governor general from the constitution while the Executive Authority (External Relations) Bill, enacted the next day, recognised the crown only for purposes of diplomatic representation and international agreements. These two measures, commonly referred to as the External Relations Act, left Ireland a more or less undeclared republic with ambiguous links to the Commonwealth. Wartime neutrality differentiated Ireland even further from the other dominions, aroused British anger and brought the question of Ireland's constitutional status into even greater prominence. Ireland was, the Canadian high commissioner in Dublin considered in 1944, a more or less unknown quantity' The Canadian government, though it would have preferred a different choice, respected Ireland's neutrality and resented British actions, taken without prior consultation, that might have contrived to drive Ireland from the Commonwealth. The end of the war removed a major cause of grievance but left Ireland's nosition unresolved.

Prostacyclin, being a potent vasodilator and platelet aggregation inhibitor, is of interest because of its possible relationship to microangiopathy associated with diabetes and other vascular diseases. Using a radioimmunoassay for the stable product of prostacyclin breakdown (6-keto PGF1 alpha) we have examined the ability of serum from diabetic patients to stimulate prostacyclin production in human endothelial cells. Results in the study of the effects of human serum on prostacyclin production by endothelial cells showed that there was a highly significant difference between diabetics and controls, with diabetic serum causing much lower prostacyclin production from cultured cells. The effect of serum in this study was not dependent on the age or sex of the donor.

A series of 1-[3-(acylthio)-3-aroylpropionyl]-L-proline derivatives was synthesized. A number of these compounds are potent angiotensin converting enzyme (ACE) inhibitors that lowered blood pressure in aorta-coarcted renal hypertensive rats. The most active derivatives are 1-[3(R)-(acetylthio) -3-substituted-benzoyl)-2(S)-methyl-propionyl]-L-prolines with an in vivo activity equivalent to SQ 14,225 (captopril). Structure-activity relationships are discussed. Changes in the configuration of the alpha-methyl group and the S-acetyl group affect the ACE activity. Coupling of 3-(substituted-benzoyl)-2-methylpropionic acids to L-proline via enol lactones is described.

Polyamine concentrations have been measured in blood samples from a series of cystic fibrosis (CF) patients and control subjects. Analyses were made by a fluorometric method, in which the amines were reacted with dansyl chloride and separated by thin layer chromatography on Kieselguhr. There was no significant difference between the polyamine concentrations of blood samples from CF patients and control subjects. Also, the spermidine-spermine ratio was similar in both groups. Polyamines were also analyzed in exocrine fluids, and although none could be detected in either CF or control sweat or saliva, significant amounts of spermine and spermidine were present in all samples of bile and duodenal fluids. It thus seems likely that the biliary route is a significant pathway in the human for excretion of polyamines. The observation that polyamines are excreted in considerable concentrations via the bile in children may be of interest in view of the reports of elevated urinary polyamine concentrations in neoplastic states. Since measurable amounts of spermine and spermidine were detected in all six bile preparations available for this study, analysis of these substances in bile may be of benefit in particular cases.

1. An enzyme (EC 2.8.2.1) that catalyses the transfer of sulphate from adenosine 3′-phosphate 5′-sulphatophosphate to phenols was purified approx. 2000-fold from male rat livers. 2. The purified preparation did not catalyse the sulphurylation of dehydroepiandrosterone, butan-1-ol, l-tyrosine methyl ester, 1-naphthylamine or serotonin. 3. At pH8.0 and 37°C the K m values of the enzyme for p -nitrophenol and adenosine 3′-phosphate 5′-sulphatophosphate are 51 and 14μm respectively. The K m value for either substrate is independent of the concentration of the other. 4. The sulphurylation of phenol is inhibited by thiol compounds and glutathione at a concentration of 3mm caused an approx. 50% decrease in enzyme activity. 5. The K m of the enzyme for adenosine 3′-phosphate 5′-sulphatophosphate is unaffected by the presence of added glutathione but at a concentration of 5mm-glutathione the K m of the enzyme for its phenolic substrate is decreased.