Altered cardiac bradykinin metabolism in experimental diabetes caused by the variations of angiotensin-converting enzyme and other peptidases.
The peptidases angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) mediate most of the kinin catabolism in normal cardiac tissue and are the molecular targets of inhibitory drugs that favorably influence diabetic complications. We studied the variations of those kininases in the myocardium of rats in experimental diabetes. ACE and NEP activities were significantly decreased in heart membranes 4-8weeks post-streptozotocin (STZ) injection. However, insulin-dependent diabetes did not modify significantly bradykinin (BK) half-life (t(1/2)) while the effect of both ACE (enalaprilat) and ACE and NEP (omapatrilat) inhibitors on BK degradation progressively decreased, which may be explained by the upregulation of other unidentified metallopeptidase(s). In vivo insulin treatment restored the activities of both ACE and NEP. ACE and NEP activities were significantly higher in hearts of young Zucker rats than in those of Sprague-Dawley rats. BK t(1/2) and the effects of peptidase inhibitors on t(1/2) varied accordingly. It is concluded that kininase activities are subjected to large and opposite variations in rat cardiac tissue in type I and II diabetes models. A number of tissue or molecular factors may determine these variations, such as remodeling of cardiac tissue, ectoenzyme shedding to the extracellular fluid and the pathologic regulation of peptidase gene expression.
Adam
Albert
A
Faculty of Pharmacy, Université de Montréal, Montréal, QC, Canada H3C 3J7.
Leclair
Patrick
P
Montpas
Nicolas
N
Koumbadinga
Gérémy Abdull
GA
Bachelard
Hélène
H
Marceau
François
F
D000704:Analysis of Variance; D000818:Animals; D001920:Bradykinin / Q000378:metabolism* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D007328:Insulin / Q000097:blood; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D015260:Neprilysin / Q000378:metabolism / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
D007328:Insulin; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D001920:Bradykinin