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Increased NO Sensitivity is Associated with Maintained Coronary Microvascular cGMP‐PDE5 Signaling in Exercising Swine with Multiple Co‐Morbidities
Author(s) -
Drie Ruben W.A.,
Sorop Oana,
Wouw Jens,
Merkus Daphne,
Duncker Dirk J.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.831.11
Subject(s) - medicine , diabetes mellitus , kidney disease , endocrinology , cardiology , vasodilation , coronary vasodilator
Background Multiple 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 results Five 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 NO 2 − +NO 3 − /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). Conclusion In 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 Information Funding: 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)].