Vasopeptidase inhibition improves insulin sensitivity and endothelial function in the JCR:LA-cp rat.
The insulin-resistant, hyperinsulinemic, normoglycemic, and obese JCR:LA-cp rat was used to study the effects of ramipril (an ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidases) on insulin sensitivity and vascular function. Both compounds reduced the surge of plasma insulin in a meal tolerance test by approximately 50%. Ramipril had no effect on acetylcholine-induced relaxation but increased the sensitivity to sodium nitroprus-side at low concentrations. AVE7688 significantly reduced the EC50 for acetylcholine to relax phenylephrine-contracted aortic rings. None of the compounds affected the baseline coronary flow and reactive hyperemia. Coronary flow response to bradykinin in AVE7688- and ramipril-treated rat hearts showed a significantly lower EC50 than in control rats. Maximum flow rate was not different between groups. In summary, both ramipril and AVE7688 had significant hypoinsulinemic and insulin-sensitizing effects. Whereas ramipril had limited vascular effects, AVE7688 had more marked beneficial vascular effects, probably of endothelial origin and possibly related to lowered insulin levels.
Russell
James C
JC
Department of Surgery, University of Alberta, Edmonton, Canada. Jim.Russell@ualberta.ca
Kelly
Sandra E
SE
Schäfer
Stefan
S
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology; D004032:Diet; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005215:Fasting / Q000097:blood; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D009765:Obesity / Q000235:genetics; D009929:Organ Size; D010656:Phenylephrine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D017257:Ramipril / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
C479877:AVE 7688; D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D006575:Heterocyclic Compounds, 3-Ring; D007328:Insulin; D009599:Nitroprusside; D010656:Phenylephrine; D015260:Neprilysin; D017257:Ramipril; D000109:Acetylcholine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester