Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia

Coronary microvascular dysfunction (CMD) has been proposed as an important component of diabetes mellitus (DM)-and hypercholesterolemiaassociated coronary artery disease (CAD). Previously we observed that 2.5 mo of DM and high-fat diet (HFD) in swine blunted bradykinin (BK)-induced vasodilation and attenuated endothelin (ET)-1-mediated vasoconstriction. Here we studied the progression of CMD after 15 mo in the same animal model of CAD. Ten male swine were fed a HFD in the absence (HFD, n = 5) or presence of streptozotocininduced DM (DM + HFD, n = 5). Responses of small (similar to 300-mu m-diameter) coronary arteries to BK, ET-1, and the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine were examined in vitro and compared with those of healthy (Normal) swine (n = 12). Blood glucose was elevated in DM + HFD (17.6 +/- 4.5 mmol/l) compared with HFD (5.1 +/- 0.4 mmol/l) and Normal (5.8 +/- 0.6 mmol/l) swine, while cholesterol was markedly elevated in DM + HFD (16.8 +/- 1.7 mmol/l) and HFD (18.1 +/- 2.6 mmol/l) compared with Normal (2.1 +/- 0.2 mmol/l) swine (all P < 0.05). Small coronary arteries showed early atherosclerotic plaques in HFD and DM + HFD swine. Surprisingly, DM + HFD and HFD swine maintained BK responsiveness compared with Normal swine due to an increase in NO availability relative to endothelium-derived hyperpolarizing factors. However, ET-1 responsiveness was greater in HFD and DM + HFD than Normal swine (both P < 0.05), resulting mainly from ETB receptormediated vasoconstriction. Moreover, the calculated vascular stiffness coefficient was higher in DM + HFD and HFD than Normal swine (both P < 0.05). In conclusion, 15 mo of DM + HFD, as well as HFD alone, resulted in CMD. Although the overall vasodilation to BK was unperturbed, the relative contributions of NO and endothelium-derived hyperpolarizing factor pathways were altered. Moreover, the vasoconstrictor response to ET-1 was enhanced, involving the ETB receptors. In conjunction with our previous study, these findings highlight the time dependence of the phenotype of CMD.