Effects of LY117018 and the estrogen analogue, 17alpha-ethinylestradiol, on vascular reactivity, platelet aggregation, and lipid metabolism in the insulin-resistant JCR:LA-cp male rat: role of nitric oxide.
The JCR:LA-cp rat is obese and insulin resistant and develops a major vasculopathy, with associated ischemic damage to the heart. Male rats were treated with 17alpha-ethinylestradiol (EE), LY117018, and/or the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). LY117018 decreased plasma cholesterol esters, with a 40% reduction in total cholesterol. EE increased triglyceride levels and modestly decreased cholesterol esters. L-NAME increased blood pressure and aortic contractile sensitivity to phenylephrine and inhibited acetylcholine-induced relaxation. LY117018 decreased the force of contraction. The L-NAME-mediated increase in force of contraction and decrease in response to acetylcholine was inhibited by LY117018. L-NAME-induced hypertension was prevented by LY117018. Platelet aggregation was not different between obese and lean rats and was unaffected by L-NAME. LY117018, both in the absence and presence of L-NAME, inhibited platelet aggregation. The effects of LY117018 are apparently mediated through both NO-dependent and -independent mechanisms. The changes induced by EE and LY117018 may reflect the activation of multiple mechanisms, both estrogen receptor-dependent and -independent. The changes induced by LY117018 are significant and may prove to be cardioprotective in the presence of the insulin resistance syndrome.
Russell
J C
JC
Department of Surgery, University of Alberta, Edmonton, Canada. Jim.Russell@ualberta.ca
McKendrick
J D
JD
Dubé
P J
PJ
Dolphin
P J
PJ
Radomski
M W
MW
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002788:Cholesterol Esters / Q000097:blood; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045166:Estradiol Congeners / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D013876:Thiophenes / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; D045166:Estradiol Congeners; D004965:Estrogen Antagonists; D011759:Pyrrolidines; D013876:Thiophenes; D014280:Triglycerides; D009569:Nitric Oxide; D004997:Ethinyl Estradiol; C025430:LY 117018; D019331:NG-Nitroarginine Methyl Ester