BackgroundMultiple comorbidities, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD) are thought to cause coronary microvascular dysfunction through a reduction in microvascular NO signaling, leading to impaired myocardial perfusion. Here we investigated whether NO‐cGMP‐PDE5 coronary microvascular signaling is modified in swine with DM+HC+CKD, by studying the vasodilator responses to PDE5 inhibition and to exogenous NO in chronically instrumented swine.Methods and resultsFive female swine (DM+HC+CKD) with Diabetes Mellitus (streptozotocin 3×50mg/kg), chronic kidney disease (renal embolization) were fed high fat diet for 6 months, while six healthy female swine served as controls (CON). Hyperglycemia (21±1.4 vs 8.9±1.5mmol/l in in DM+HC+CKD vs CON, P=0.0002), hypercholesterolemia (7.8±1.0 vs 2.8±1.2mmol/l, P=0.013) and chronic kidney disease (GFR: 123±12 vs 191±9ml/min, P=0.001) were present. Myocardial oxygen delivery was impaired in DM+HC+CKD swine, forcing the myocardium to increase its oxygen extraction both at rest and during exercise (Figure), and resulting in reduced coronary venous oxygen content compared to CON (both P<0.05). PDE5 inhibition with sildenafil (8mg i.v.) decreased myocardial oxygen extraction in both DM+HC+CKD (P=0.016) and CON (P=0.005, Figure), to a similar extent (P=0.34), indicating maintained NO‐cGMP vasodilator influence. As myocardial NO production was decreased (0.19±0.03 vs 0.34±0.13μM NO2−+NO3−/mg protein, P=0.02), we investigated whether an increase in NO sensitivity contributed to maintain NO‐cGMP vasodilator influence, by infusion of the NO donor sodium nitroprusside (SNP). Coronary vascular conductance (CVC) decreased more in DM+HC+CKD compared to CON, indicating an increased NO‐sensitivity (P=0.043, Figure).ConclusionIn swine with multiple co‐morbidities reduced bioavailability of NO appears to be compensated by increased sensitivity to NO, which is associated with maintained cGMP‐mediated vasodilator influence.Support or Funding InformationFunding: This study was supported by grants from the European Commission FP7‐Health‐2010 grant MEDIA‐261409, the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2014‐11 (RECONNECT)].