title: cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle.
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.
authors.affiliation: Menzies Research Institute, University of Tasmania, Hobart 7001, Tasmania, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Genders
authors.forename: E A
authors.initials: EA
authors.lastname: Bradley
authors.forename: S
authors.initials: S
authors.lastname: Rattigan
authors.forename: S M
authors.initials: SM
authors.lastname: Richards
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C011145:zaprinast