Agonist-specific impairment of coronary vascular function in genetically altered, hyperlipidemic mice

The objectives of the present study were to 1) examine mechanisms involved in endothelium-dependent responses of coronary arteries from normal mice an d 2) determine whether vascular responses of coronary arteries are altered in two genetic models of hypercholesterolemia [apolipoprotein E (apoE)-defi cient mice (apoE -/-) and combined apoE and low-density Lipoprotein recepto r (LDLR)-deficient mice (apoE + LDLR -/-)]. Plasma cholesterol levels were higher in both apoE -/- and apoE + LDLR -/- compared with normal mice on no rmal and high-cholesterol diets (normal chow: normal 110 +/- 5 mg/dl, apoE -/- 680 +/- 40 mg/dl, apoE + LDLR -/- 810 +/- 40 mg/dl; high-cholesterol ch ow: normal 280 +/- 60 mg/dl, apoE -/- 2,490 +/- 310 mg/dl, apoE + LDLR -/- 3,660 +/- 290 mg/dl). Coronary arteries from normal (C57BL/6J), apoE -/-, a nd apoE + LDLR -/- mice were isolated and cannulated, and diameters were me asured using videomicroscopy. In normal mice, vasodilation in response to A Ch and serotonin was markedly reduced by 10 mu M N-omega-nitro-L-arginine ( an inhibitor of nitric oxide synthase) or 20 mu M 1H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ; an inhibitor of soluble guanylate cyclase). Vasodi lation to nitroprusside, but not papaverine, was also inhibited by ODQ. Dil ation of arteries from apoE -/- and apoE + LDLR -/- mice on normal diet in response to ACh was similar to that observed in normal mice. In contrast, d ilation of arteries in response to serotonin from apoE -/- and apoE + LDLR -/- mice was impaired compared with normal. In arteries from both apoE -/- and apoE + LDLR -/- mice on high-cholesterol diet, dilation to ACh was decr eased. In apoE + LDLR -/- mice on high-cholesterol diet, dilation of corona ry arteries to nitroprusside was increased. These findings suggest that dil ation of coronary arteries from normal mice in response to ACh and serotoni n is dependent on production of nitric oxide and activation of soluble guan ylate cyclase. Hypercholesterolemia selectively impairs dilator responses o f mouse coronary arteries to serotonin. In the absence of both apoE and the LDL receptor, high levels of cholesterol result in a greater impairment in coronary endothelial function.