Premium
Loss of Nitric Oxide Contributes to Perturbations in Myocardial Oxygen Balance in Exercising Swine with Multiple Comorbidities
Author(s) -
Wouw Jens,
Sorop Oana,
Drie Ruben W.A.,
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.684.9
Subject(s) - medicine , endocrinology , cardiology , diabetes mellitus , endothelial dysfunction , kidney disease , enos , renal function , nitric oxide , nitric oxide synthase
Multiple comorbidities, including diabetes mellitus (DM), hypercholesterolemia, hypertension (HT) and chronic kidney disease (CKD) are thought to cause coronary microvascular dysfunction and reduce microvascular NO‐production, leading to impaired myocardial perfusion and contributing to the development of left ventricular diastolic dysfunction. In the present study, we aimed to investigate the detrimental effects of DM, CKD and high fat diet (HFD) on microvascular function and myocardial blood flow regulation and the role of NO bioavailability herein in swine. Methods DM and CKD were induced in 5 female swine that were subsequently fed HFD (DM+HFD+CKD), while 6 female healthy swine on normal pig chow served as controls (CON). At 6 months follow‐up coronary flow regulation was studied at rest and during treadmill exercise with/without eNOS inhibitor, nitro‐L‐arginine in 6 CON and 5 DM+HFD+CKD chronically instrumented animals. Results DM+HFD+CKD animals had hyperglycemia (glucose: 18.7±1.9 vs 7.5±0.6 mmol/L), renal dysfunction (reduced glomerular filtration rate: 123±12 vs 202±8 ml/min) and hypercholesterolemia (total cholesterol: 7.3±0.7 vs 1.7±0.1 mmol/l, all P<0.05). In vivo, myocardial oxygen delivery was impaired in DM+HFD+CKD swine, forcing the myocardium to increase its oxygen extraction (MO 2 ex) both at rest and during exercise ( Figure), and resulting in reduced coronary venous oxygen content compared to CON (all P<0.05). eNOS‐inhibition resulted in coronary microvascular constriction in CON, reflected in an increased MO 2 ex (P<0.05), while it had no effect in DM+HFD+CKD, suggesting that loss of NO was responsible for the increased oxygen extraction in DM+HFD+CKD. This was supported by lower myocardial levels of NO metabolites NO 2 − +NO 3 − in DM+HC+HT compared to CON (0.20±0.02 vs 0.34±0.06 μmol/mg protein, P<0.05). Conclusion Prolonged exposure to DM, HFD and CKD results in impaired coronary microvascular NO production, thereby hampering myocardial perfusion. 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)].