Introduction: Diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD) cause alterations in coronary microvascular NO-production and/or signaling, leading to impaired myocardial perfusion.
Hypothesis: Loss of NO due to DM, CKD and high fat diet (HFD) impairs myocardial blood flow regulation particularly during exercise.
Methods: In 6 female swine, DM (streptozotocin 3x50mg/kg iv) and CKD (renal embolization) were induced and HFD was given for 6 months (DM+HFD+CKD). 8 female healthy swine on normal pig chow served as controls (CON). Coronary flow regulation through the NO pathway was studied at rest and during treadmill exercise with/without eNOS inhibition (nitro-L-arginine), PDE5 inhibition (sildenafil) or the exogenous NO donor sodium nitroprusside (SNP).
Results: DM+HFD+CKD had hyperglycemia (18.7±1.9 vs 7.5±0.6mmol/L), renal dysfunction (glomerular filtration rate: 123±12 vs 202±8 ml/min) and hypercholesterolemia (7.3±0.7 vs 1.7±0.1mmol/l, all P<0.05). Myocardial oxygen delivery was impaired in DM+HFD+CKD swine at rest and during exercise, resulting in reduced coronary venous oxygen content (cvSO2) compared to CON (Fig. A, P<0.05). eNOS-inhibition resulted in coronary microvascular constriction in CON, reflected by reduced cvSO2 (Fig. B, P<0.05), but had no effect in DM+HFD+CKD (Fig. C). PDE5 inhibition increased cvSO2 similarly in DM+HFD+CKD (Fig. D) and CON (P=0.005, Fig. E), indicating maintained cGMP vasodilation. As the NO production was decreased, we investigated NO sensitivity to SNP. Coronary vascular conductance (CVC) increased more in response to SNP in DM+HFD+CKD vs CON, indicating an increased NO-sensitivity (P=0.043, Fig. F).
Conclusions: Altered myocardial flow regulation in swine with multiple co-morbidities is mediated by impaired coronary microvascular NO production, accompanied by increased sensitivity to NO, which likely contributed to the preserved cGMP-mediated vasodilator influence.