Effect of phosphodiesterase inhibition with amrinone or theophylline on lipolysis and blood flow in human adipose tissue in vivo as measured with microdialysis

• Published in: Journal of lipid research 1993-10, Vol.34 (10), p.1737-1743
• Main Authors: Arner, P, Hellmer, J, Hagstrom-Toft, E, Bolinder, J
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; ACTIVIDAD ENZIMATICA; ACTIVITE ENZYMATIQUE; Adipose Tissue - blood supply; Adipose Tissue - metabolism; Adolescent; Adult; Amrinone - pharmacology; Biological and medical sciences; Blood Flow Velocity; CIRCULACION SANGUINEA; CIRCULATION SANGUINE; COMPOSICION DE LA SANGRE; COMPOSITION DU SANG; DEBIT; Dialysis; ESTERASAS; ESTERASE; Ethanol - metabolism; Female; Fundamental and applied biological sciences. Psychology; GASTO; GENERO HUMANO; GENRE HUMAIN; GLICEROL; GLYCEROL; Glycerol - metabolism; Humans; INHIBICION; INHIBIDORES DE ENZIMAS; INHIBITEUR D'ENZYME; INHIBITION; Isoenzymes - antagonists & inhibitors; Kinetics; Lipids. Glycolipids; LIPOLISIS; LIPOLYSE; Lipolysis - drug effects; Male; Metabolisms and neurohumoral controls; Middle Aged; TEJIDO ADIPOSO; TEOFILINA; THEOPHYLLINE; Theophylline - pharmacology; TISSU ADIPEUX; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1016/S0022-2275(20)35736-9

Phosphodiesterase III (cyclic GMP-inhibited, particulate, low Km) is believed to play a dominant role in the cyclic AMP breakdown and lipolysis regulation in fat cells. Its importance for lipolysis activity was investigated in situ in humans by comparing the effects of a selective (amrinone) and a nonselective (theophylline) inhibitor of the enzyme. Abdominal subcutaneous adipose tissue of healthy nonobese humans was microdialyzed with solvents containing one or both of these agents, and glycerol (lipolysis index) or the escape of ethanol from the dialysis solvent (blood flow index) was continuously monitored in the perfusate. Both agents caused a dose-dependent and sustained increase in the glycerol level in the perfusate for at least 2.5 h. Although amrinone was 5000 times more potent than theophylline on a molar basis, its maximum activity was only 35% as compared to the maximum activity of theophylline. Half-maximum lipolytic effect of the two drugs occurred at about 0.1 micromoles/l and 1 mmol/l, respectively (P 0.001). At maximum effective concentrations, amrinone stimulated lipolysis by about 63% and theophylline by about 200% (P 0.01). At these concentrations amrinone increased the rate of disappearance of ethanol from the perfusate by about 20% and theophylline increased the rate by about 75%, the difference being statistically significant (P 0.01). When the two drugs were added together, the level of lipolysis stimulation was not different from that with theophylline alone both at maximal and submaximal effective concentrations of drug combinations. In conclusion, amrinone stimulates lipolysis and blood flow in situ at much lower concentrations than theophylline does, but its maximal effect is only a fraction of that of theophylline. This suggests that PDE III is not the only phosphodiesterase that is involved in the regulation of lipolysis and blood flow in human adipose tissue in vivo