Insulin-sensitizing and cardiovascular effects of the sodium-hydrogen exchange inhibitor, cariporide, in the JCR: LA-cp rat and db/db mouse.
The effects of the sodium-hydrogen (Na/H) exchange inhibitor cariporide (HOE642), on insulin sensitivity and vascular function were studied in the JCR:LA-cp rat and the db/db mouse. In the insulin-resistant rat, cariporide reduced fasting insulin levels (42%, P < 0.02) and insulin response in a meal tolerance test (50%, P < 0.01), indicating increased insulin sensitivity. The ACE inhibitor, ramipril, used as a reference agent, reduced the insulin response to the meal, but not fasting levels. The EC50 for acetylcholine-mediated relaxation of phenylephrine-precontracted aortic rings was significantly lower in cariporide-treated rats (P < 0.002), but not in ramipril-treated rats. Flow response of the coronary circulation to bradykinin was significantly greater in both cariporide- and ramipril-treated rats, (3-fold decrease in the EC50, P < 0.05). Cariporide-treated hearts were smaller, slower beating, with greater developed LVP. In the obese db/db mouse, chronic treatment with cariporide obviated vascular hypercontractility and improved endothelial function. Thus, cariporide had beneficial effects on the abnormal insulin metabolism and associated vascular dysfunction in the JCR:LA-cp insulin-resistant rat, which develops advanced cardiovascular disease and ischemic myocardial lesions. It also improved vascular function in a similar mouse model of insulin resistance. These effects were markedly greater than those of ramipril.
Russell
J C
JC
Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, Agriculture Forestry Centre, University of Alberta, Edmonton, Alberta, Canada. Jim.Russell@ualberta.ca
Proctor
S D
SD
Kelly
S E
SE
Löhn
M
M
Busch
A E
AE
Schäfer
S
S
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009599:Nitroprusside / Q000494:pharmacology; D009765:Obesity / Q000503:physiopathology*; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D006146:Guanidines; D007328:Insulin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D009599:Nitroprusside; C093373:cariporide; D017257:Ramipril; D000109:Acetylcholine