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- Title
T-1032, a cyclic GMP phosphodiesterase-5 inhibitor, acutely blocks physiologic insulin-mediated muscle haemodynamic effects and glucose uptake in vivo.
- Authors
Mahajan, Hema; Richards, Stephen M.; Rattigan, Stephen; Clark, Michael G.
- Abstract
1 Cyclic GMP phosphodiesterase-5 inhibitors have been shown in alter blood flow in specific tissues by potentiating local NO-dependent vasodilatory mechanisms. Since the haemodynamic effects of physiologic insulin, particularly capillary recruitment, may be critical for muscle glucose uptake in rim and are blocked by inhibitors of nitric oxide synhase. we have explored the acute effects of the specific cGMP phosphodiraterase-5 inhibitor T-1032 on physiologic insulin action in anaesthetized healthy rats in vivo. 2 Whole-body glucose infusion (GIR). femoral blood flow (FBF), hind leg vascular resistance (VR.). hind leg glucose uptake (HGU), 2-deoxyglucose uptake into muscles of the lower leg (R'g). hind leg metabolism of infused l-methylxanthine (l-MX), a measure of capillary recruitment, and muscle cGMP were determined. The experimental groups were T-1032 (10μg min[sup-1] kg[sup-1]) infused for 1h before and during a euglycaemic insulin clamp (3mU min¹ kg [sup-1]x2h). T-1032 infused for 3h with saline. T-1032 during a 2h clamp. T-1032 with saline for 2h. and a 2h saline control. 3 Insulin increased GIR from zero to 13 mg min[sup-1]kg[sup-1], HGU from 0.1± 0.01 to 0.43±0.05 μmol min[sup-1], R'g and 1-MX. marginally increased FBF. and had no effect on blood pressure or heart rate. T-1032 alone had no effect on blood pressure, heart rate. FBF. VR. HGU. R'g or 1-MX, but increased muscle cGMP. T-1032 1 h before and during insulin completely blocked GIR (1 h). HGU (2h). R'g(2h). and l-M\(2h). T-1032 commenced with insulin had only partial blocking activity against insulin. 4 We conclude that T-1032 is a potent acutely acting inhibitor of the muscle effects of physiologic insulin on capillary recruitment and glucose uptake in vivo. These, together with inhibition of whole-body glucose infusion during insulin, may caution against the use of isoenzyme-5-specific cyclic GMP phosphodiesterase inhibitors as therapeutic agents.
- Subjects
PHOSPHODIESTERASES; CYCLIC guanylic acid; BLOOD flow; NITRIC oxide; HEMODYNAMICS; INSULIN; GLUCOSE; ANIMAL experimentation; BLOOD-vessel physiology; METHYLXANTHINES; THERAPEUTICS
- Publication
British Journal of Pharmacology, 2003, Vol 140, Issue 7, p1283
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0705548