enalaprilat-anhydrous and zofenoprilate

Data from prospective studies suggest a significant reduction in the risk of new diabetes from drug therapies containing angiotensin-converting enzyme (ACE) inhibitors. Since the renin-angiotensin system (RAS) has been found locally in several tissues and cells, including pancreatic islets, we hypothesized that the positive metabolic effects of ACE inhibitors may be due to a beneficial action of these compounds on insulin-secreting beta-cells.. Isolated human pancreatic islets were studied after 24 h of incubation with 22.2 mmol/l glucose, with or without the presence in the incubation medium of 0.5-6.0 mmol/l zofenoprilat or enalaprilat, ACE inhibitor drugs which differ by the presence of a sulphydryl or a carboxyl group in their structural formula. Functional and molecular studies were then performed to assess insulin secretion, redox balance, mRNA and protein expression.. Angiotensinogen, ACE and angiotensin type 1 receptor mRNA expression increased in islets cultured in high glucose; this was similarly prevented by the presence of either ACE inhibitor. As expected, preculture of human islets in high glucose determined a marked reduction in insulin secretion which was associated with enhanced oxidative stress, as shown by increased nitrotyrosine concentrations, and enhanced expression of protein kinase C beta and NADPH oxidase. The presence of either of the ACE inhibitors counteracted several of the deleterious effects of high glucose exposure, including reduction of insulin secretion and increased oxidative stress; zofenoprilat showed significantly more marked effects.. These results showed that: (a) RAS molecules are present in human islets and their expression is sensitive to glucose concentration, (b) ACE inhibitors, and in particular zofenoprilat, protect human islets from glucotoxicity and (c) the effects of ACE inhibition are associated with decreased oxidative stress. Together, these findings provide evidence that the possible beneficial effects of ACE inhibitors in human diabetes are due, at least in part, to a protective action on pancreatic beta-cells.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Captopril; Enalaprilat; Female; Glucose; Humans; In Vitro Techniques; Insulin; Islets of Langerhans; Male; Middle Aged; Oxidative Stress; Peptidyl-Dipeptidase A; Proto-Oncogene Proteins c-akt; Receptor, Angiotensin, Type 1; Reverse Transcriptase Polymerase Chain Reaction; RNA; Tyrosine

The converting enzyme not only converts angiotensin I into angiotensin II but also metabolizes bradykinin. Furthermore, the effects of ischemia on myocardial tissue damage can be modulated by converting enzyme inhibitors. It is unknown whether these effects of ACE-inhibitors are due to increased bradykinin production. In this paper we describe the effects of captopril on bradykinin production in the ischemic isolated rat heart. The reduced deleterious effects of ischemia by captopril were associated with a stimulated bradykinin production. Beneficial effects of bradykinin could be due to an improved perfusion or to an effect on cellular metabolism. Therefore, we conclude that this effect on kinins by ACE-inhibitors is of importance in modulating tissue damage during ischemia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Captopril; Coronary Circulation; Coronary Disease; Coronary Vessels; Enalaprilat; Indomethacin; Myocardium; Rats; Vasodilation