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cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle

Citation

Genders, AJ and Bradley, EA and Rattigan, S and Richards, SM, cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle, American Journal of Physiology: Endocrinology and Metabolism, 301, (2) pp. E342-E350. ISSN 0193-1849 (2011) [Refereed Article]


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Copyright Statement

Copyright © 2011 The American Physiological Society

DOI: doi:10.1152/ajpendo.00691.2010

Abstract

There is considerable support for the concept that insulin-mediated increases in microvascular blood flow to muscle impact significantly on muscle glucose uptake. Since the microvascular blood flow increases with insulin have been shown to be nitric oxide-dependent inhibition of cGMP-degrading phosphodiesterases (cGMP PDEs) is predicted to enhance insulin-mediated increases in microvascular perfusion and muscle glucose uptake. Therefore, we studied the effects of the pan-cGMP PDE inhibitor zaprinast on the metabolic and vascular actions of insulin in muscle. Hyperinsulinemic euglycemic clamps (3 mU·min(-1)·kg(-1)) were performed in anesthetized rats and changes in microvascular blood flow assessed from rates of 1-methylxanthine metabolism across the muscle bed by capillary xanthine oxidase in response to insulin and zaprinast. We also characterized cGMP PDE isoform expression in muscle by real-time PCR and immunostaining of frozen muscle sections. Zaprinast enhanced insulin-mediated microvascular perfusion by 29% and muscle glucose uptake by 89%, while whole body glucose infusion rate during insulin infusion was increased by 33% at 2 h. PDE2, -9, and -10 were the major isoforms expressed at the mRNA level in muscle, while PDE1B, -9A, -10A, and -11A proteins were expressed in blood vessels. Acute administration of the cGMP PDE inhibitor zaprinast enhances muscle microvascular blood flow and glucose uptake response to insulin. The expression of a number of cGMP PDE isoforms in skeletal muscle suggests that targeting specific cGMP PDE isoforms may provide a promising avenue for development of a novel class of therapeutics for enhancing muscle insulin sensitivity.

Item Details

Item Type:Refereed Article
Keywords:cyclic guanosine monophosphate; blood flow; insulin and glucose delivery to muscle; microvascular blood flow
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Endocrinology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Diabetes
Author:Genders, AJ (Ms Amanda Genders)
Author:Bradley, EA (Miss Eloise Bradley)
Author:Rattigan, S (Professor Stephen Rattigan)
Author:Richards, SM (Dr Stephen Richards)
ID Code:71815
Year Published:2011
Web of Science® Times Cited:9
Deposited By:Menzies Institute for Medical Research
Deposited On:2011-08-09
Last Modified:2017-11-06
Downloads:0

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