Coronary microvascular dysfunction (CMD) has been proposed as an important component of diabetes mellitus (DM) and hypercholesterolemia-associated coronary artery disease (CAD). Previously we observed that 2.5 months of DM and high fat diet (HFD) blunted bradykinin (BK)-induced vasodilation and attenuated endothelin-1 (ET-1)- mediated vasoconstriction. Here, we studied the progression of CMD after 15 months in a large animal model of CAD. Ten male pigs received HFD in the absence, (HFD, n=5) or presence of streptozotocin-induced DM (DM+HFD, n=5). Coronary small arteries (~300μm) responses to BK, ET-1 and nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) were examined in vitro, and compared to healthy pigs (Normal, n=12). DM+HFD had elevated blood glucose (17.6±4.5mM/l) versus HFD (5.1±0.4mM/l) and Normal (5.8±0.6mM/l), while both DM+HFD (16.8±1.7mM/l) and HFD (18.1±2.6mM/l), had elevated cholesterol compared to Normal (2.1±0.2mM/l, all P<0.05). Coronary small arteries showed early atherosclerotic plaques, in both HFD and DM+HFD groups. Surprisingly, both DM+HFD and HFD showed maintained BK-responsiveness compared to Normal (both P<0.05), due to an increase in NO availability relative to endothelium-derived hyperpolarizing factors (EDHF). However, ET-1 responsiveness was greater in HFD and DM+HFD versus Normal (both P<0.05), resulting from both ETA and ETB-mediated vasoconstriction. The calculated vascular stiffness coefficient was higher in DM+HFD and HFD versus Normal (both P<0.05). In conclusion, 15-months of DM+HFD but also HFD alone resulted in CMD. Although the overall vasodilation to BK was unperturbed, the relative contributions of the NO and EDHF pathways were altered. Moreover, the vasoconstrictor response to ET-1 was enhanced, involving both ETA- and ETB-receptors.
- coronary microvascular dysfunction
- Copyright © 2015, American Journal of Physiology-Heart and Circulatory Physiology