Acetylcholine-Induced response of coronary resistance arterioles in cholesterol-fed rabbits

The extent to which reported abnormal responses of the human coronary circulation to acetylcholine in patients with hypercholesterolemia reflect endothelial injury is not clear. We used an in vitro rabbit model to determine whether these reactions involve endothelial or vascular smooth muscle dysfunction. Coronary resistance arterioles were isolated from hearts of rabbits fed 1% cholesterol to induce hypercholesterolemia or a control diet for 4 weeks. Arterioles were double cannulated with glass micropipettes and pressurized in a no-flow state. Acetylcholine contracted the arterioles in a concentration-dependent manner whether or not the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine was added. In control but not hypercholesterolemic preparations, contraction was significantly greater when endothelium was removed. In the hypercholesterolemic group, contraction significantly exceeded that in controls. In control but not high-cholesterol preparations, substance P dilated vessels with intact endothelium in a concentration-dependent manner. Addition of N(G)-monomethyl-L-arginine inhibited this response. With or without endothelium, norepinephrine contracted arterioles to a greater extent in the hypercholesterolemic group than in controls. We concluded that severe hypercholesterolemia decreased endothelially dependent factors by injuring endothelium and independently increased contractility of vascular smooth muscle.