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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 Type:	Refereed Article
Keywords:	cyclic guanosine monophosphate; blood flow; insulin and glucose delivery to muscle; microvascular blood flow
Research Division:	Biomedical and Clinical Sciences
Research Group:	Clinical sciences
Research Field:	Endocrinology
Objective Division:	Health
Objective Group:	Clinical health
Objective Field:	Clinical health not elsewhere classified
UTAS Author:	Genders, AJ (Ms Amanda Genders)
UTAS Author:	Bradley, EA (Miss Eloise Bradley)
UTAS Author:	Rattigan, S (Professor Stephen Rattigan)
UTAS Author:	Richards, SM (Dr Stephen Richards)
ID Code:	71815
Year Published:	2011
Web of Science® Times Cited:	14
Deposited By:	Menzies Institute for Medical Research
Deposited On:	2011-08-09
Last Modified:	2017-11-06
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