title: Impaired endothelium-mediated relaxation in coronary arteries from insulin-resistant rats.
abstract: OBJECTIVE
  The insulin resistance syndrome is associated with atherosclerosis and cardiovascular events; however, the underlying mechanism of vascular dysfunction is unknown. The purpose of the current study was to assess endothelium- and smooth-muscle-mediated vasodilation in isolated coronary arteries from insulin-resistant rats and to determine whether insulin resistance alters the activity of the specific endothelium-derived relaxing factors.
  
  
  METHODS
  Male Sprague-Dawley rats were randomized to insulin resistance or control. Insulin resistance was induced by a fructose-rich diet. After 4 weeks of diet, coronary arteries were removed and vascular function was assessed in vitro using videomicroscopy. Acetylcholine (10(-9)-3 x 10(-5) M)- or sodium-nitroprusside (10(-9)-3 x 10(-4) M)-induced relaxations were determined. To evaluate the role of the specific endothelium-derived relaxing factors, several inhibitors were used, including N-nitro-L-arginine (LNNA), charybdotoxin/apamin (CTX/apamin), and indomethacin.
  
  
  RESULTS
  Studies with nitroprusside showed that smooth-muscle-dependent relaxation did not differ between insulin resistance and control groups. In contrast, maximal relaxation (E(max)) to acetylcholine was decreased in the insulin resistance group (56 +/- 7%) versus control (93 +/- 3%). LNNA pretreatment further impaired E(max) in the IR group from 56 +/- 7 to 17 +/- 2% (p < 0.01). In control, E(max) was only slightly impaired by LNNA (93 +/- 3 to 63 +/- 6%; p < 0.05). The addition of CTX/apamin also decreased relaxation in the control group (93 +/- 3 to 47 +/- 7%; p < 0.05), whereas relaxation in insulin-resistant rats was not affected (45 +/- 5% with CTX/apamin vs. 56 +/- 7% with acetylcholine alone, NS). Pretreatment with indomethacin did not affect relaxation in either group, while pretreatment with the combination of LNNA and CTX/ apamin completely abolished relaxation in both groups.
  
  
  CONCLUSIONS
  Endothelium-dependent relaxation is impaired in small coronary arteries from insulin-resistant rats. The mechanism of this defect is related to a decrease in an endothelium-dependent, nitric oxide/prostanoid-independent relaxing factor or endothelium-derived hyperpolarizing factor.
authors.affiliation: University of Georgia College of Pharmacy, Augusta, GA, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Miller
authors.forename: P V
authors.initials: PV
authors.lastname: Katakam
authors.forename: M R
authors.initials: MR
authors.lastname: Ujhelyi
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007333:Insulin Resistance; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D018999:Charybdotoxin; D019335:Nitroarginine; D001030:Apamin; D000109:Acetylcholine