Endothelial function in coronary arterioles from pigs with early-stage coronary disease induced by high-fat, high-cholesterol diet: effect of exercise

Departments of 1 Biomedical Sciences, 2 Veterinary Pathobiology, 4 Medical Pharmacology and Physiology and 5 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211; and 3 Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1 Submitted 10 March 2004 ; accepted in final form 10 June 2004 Because hypercholesterolemia can attenuate endothelial function and exercise training can augment endothelial function, we hypothesized that exercise training would improve endothelial function of coronary arterioles from pigs in the early stages of cardiovascular disease induced by a high-fat, high-cholesterol (HF) diet. Yucatan miniature swine were fed a normal-fat (NF) diet or HF diet (2% cholesterol) for 20 wk in which 8 and 46% of their calories were derived from fat, respectively. Both groups were subdivided into sedentary (Sed) or exercise-trained (Ex) groups. This resulted in four experimental groups: NFSed, NFEx, HFSed, and HFEx. Endothelial function was assessed in coronary arterioles 75–100 µm in diameter dissected from the left ventricular apex. Responses to endothelial-dependent dilation induced by bradykinin (BK), ADP, and flow were similar in all four groups, whereas dilation to aggregating platelets in the presence of indomethacin and ketanserin was attenuated in HFSed arterioles ( P = 0.01). The attenuated response to aggregating platelets was prevented or reversed in HFEx arterioles ( P = 0.03). In HFSed arterioles, BK induced release of an indomethacin-sensitive prostanoid constrictor. In contrast, after exercise training, there was no evidence of this constrictor and BK-induced release of an indomethacin-sensitive prostanoid dilator in HFEx arterioles ( P = 0.04). Endothelial nitric oxide synthase protein in arterioles was significantly reduced in HF groups ( P < 0.05) and increased in Ex groups ( P < 0.05). Interestingly, the relative contribution of nitric oxide to BK-induced dilation, as assessed with nitro- L -arginine methyl ester, was similar in arterioles in the NF, HF, Sed, and Ex groups. These results suggest that, in the early stages of cardiovascular disease, a high-fat, high-cholesterol diet has modest effects on endothelial-dependent dilation in coronary arterioles; nonetheless, these effects are prevented or reversed with exercise training. porcine; nitric oxide; prostanoid; platelets Address for reprint requests and other correspondence: M. H. Laughlin, Dept. of Biomedical Scie