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Purinergic Signal. 2017 Sep;13(3):319-329. doi: 10.1007/s11302-017-9563-6. Epub 2017 May 24.

Altered purinergic signaling in uridine adenosine tetraphosphate-induced coronary relaxation in swine with metabolic derangement.

Author information

1
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
2
Unit of Cardiology, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
3
Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.
4
Department of Clinical Physiology and Nuclear Medicine, University of Turku, Turku, Finland.
5
Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
6
Division of Pharmacology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
7
Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. d.merkus@erasmusmc.nl.

Abstract

We previously demonstrated that uridine adenosine tetraphosphate (Up4A) induces potent and partially endothelium-dependent relaxation in the healthy porcine coronary microvasculature. We subsequently showed that Up4A-induced porcine coronary relaxation was impaired via downregulation of P1 receptors after myocardial infarction. In view of the deleterious effect of metabolic derangement on vascular function, we hypothesized that the coronary vasodilator response to Up4A is impaired in metabolic derangement, and that the involvement of purinergic receptor subtypes and endothelium-derived vasoactive factors (EDVFs) is altered. Coronary small arteries, dissected from the apex of healthy swine and swine 6 months after induction of diabetes with streptozotocin and fed a high-fat diet, were mounted on wire myographs. Up4A (10-9-10-5 M)-induced coronary relaxation was maintained in swine with metabolic derangement compared to normal swine, despite impaired endothelium-dependent relaxation to bradykinin and despite blunted P2X7 receptor and NO-mediated vasodilator influences of Up4A. Moreover, a thromboxane-mediated vasoconstrictor influence was unmasked. In contrast, an increased Up4A-mediated vasodilator influence via P2Y1 receptors was observed, while, in response to Up4A, cytochrome P450 2C9 switched from producing vasoconstrictor to vasodilator metabolites in swine with metabolic derangement. Coronary vascular expression of A2A and P2X7 receptors as well as eNOS, as assessed with real-time PCR, was reduced in swine with metabolic derangement. In conclusion, although the overall coronary vasodilator response to Up4A was maintained in swine with metabolic derangement, the involvement of purinergic receptor subtypes and EDVF was markedly altered, revealing compensatory mechanisms among signaling pathways in Up4A-mediated coronary vasomotor influence in the early phase of metabolic derangement. Future studies are warranted to investigate the effects of severe metabolic derangement on coronary responses to Up4A.

KEYWORDS:

Coronary relaxation; Cytochrome P450 2C9; Metabolic derangement; Purinergic receptor; Thromboxane; Up4A

PMID:
28540569
PMCID:
PMC5563292
DOI:
10.1007/s11302-017-9563-6
[Indexed for MEDLINE]
Free PMC Article

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