Reduced nitric oxide bioavailability impairs myocardial oxygen balance during exercise in swine with multiple risk factors.

Autor: van de Wouw J; Department of Cardiology, Division of Experimental Cardiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, Netherlands., Sorop O; Department of Cardiology, Division of Experimental Cardiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, Netherlands., van Drie RWA; Department of Cardiology, Division of Experimental Cardiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, Netherlands., Joles JA; Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands., Danser AHJ; Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands., Verhaar MC; Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands., Merkus D; Department of Cardiology, Division of Experimental Cardiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, Netherlands.; Walter Brendel Center of Experimental Medicine (WBex), University Clinic Munich, 81377, LMU Munich, Germany.; German Center for Cardiovascular Research (DZHK), Munich Heart Alliance (MHA), Partner Site Munich, 81377, Munich, Germany., Duncker DJ; Department of Cardiology, Division of Experimental Cardiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, Netherlands. d.duncker@erasmusmc.nl.
Jazyk: angličtina
Zdroj: Basic research in cardiology [Basic Res Cardiol] 2021 Aug 26; Vol. 116 (1), pp. 50. Date of Electronic Publication: 2021 Aug 26.
DOI: 10.1007/s00395-021-00890-8
Abstrakt: In the present study, we tested the hypothesis that multiple risk factors, including diabetes mellitus (DM), dyslipidaemia and chronic kidney disease (CKD) result in a loss of nitric oxide (NO) signalling, thereby contributing to coronary microvascular dysfunction. Risk factors were induced in 12 female swine by intravenous streptozotocin injections (DM), a high fat diet (HFD) and renal artery embolization (CKD). Female healthy swine (n = 13) on normal diet served as controls (Normal). After 5 months, swine were chronically instrumented and studied at rest and during exercise. DM + HFD + CKD swine demonstrated significant hyperglycaemia, dyslipidaemia and impaired kidney function compared to Normal swine. These risk factors were accompanied by coronary microvascular endothelial dysfunction both in vivo and in isolated small arteries, due to a reduced NO bioavailability, associated with perturbations in myocardial oxygen balance at rest and during exercise. NO synthase inhibition caused coronary microvascular constriction in exercising Normal swine, but had no effect in DM + HFD + CKD animals, while inhibition of phosphodiesterase 5 produced similar vasodilator responses in both groups, indicating that loss of NO bioavailability was principally responsible for the observed coronary microvascular dysfunction. This was associated with an increase in myocardial 8-isoprostane levels and a decrease in antioxidant capacity, while antioxidants restored the vasodilation to bradykinin in isolated coronary small arteries, suggesting that oxidative stress was principally responsible for the reduced NO bioavailability. In conclusion, five months of combined exposure to DM + HFD + CKD produces coronary endothelial dysfunction due to impaired NO bioavailability, resulting in impaired myocardial perfusion at rest and during exercise.
(© 2021. The Author(s).)
Databáze: MEDLINE
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