Amrinone

[Eagle]

Horm Metab Res 1998 Nov;30(11):684-8

Importance of phosphodiesterase 3 for the lipolytic response in adipose tissue during insulin-induced hypoglycemia in normal man.

Moberg E, Enoksson S, Hagstrom-Toft E.
Department of Medicine, Huddinge Hospital, Sweden.

The present investigation aimed to clarify the role of phosphodiesterase (PDE) type 3 for in vivo lipolysis in human adipose tissue during simultaneous insulin and catecholamine stimulation. Therefore, ten healthy subjects were investigated during insulin-induced hypoglycemia. Microdialysis probes were implanted in the subcutaneous adipose tissue and perfused by solvents with or without addition of the specific PDE 3 antagonist amrinone. Furthermore, changes in the local blood flow surrounding the dialysis probes were assessed by the ethanol escape technique.

During the 60 min period before the start of the insulin infusion, adipose tissue glycerol levels (lipolysis index) increased significantly when amrinone was added to the perfusate (p = 0.0006, one-factor ANOVA).
The antilipolytic response to the early phase of insulin infusion decreased (delta glycerol 9.0+/-3.5 vs. 29.9+/-6.0 micromol/l, p = 0.04) and the lipolytic response after hypoglycemia increased (AUC 122.4+/-18.0 vs. 13.4+/-16.3 micromol x l(-1) x h, p = 0.0001) comparing the experiments with or without amrinone, respectively.
When amrinone was excluded from the perfusate, there was an increase in the nutritive blood flow during hypoglycemia, whereas there were no significant changes in the local blood flow surrounding the probe when amrinone was added to the perfusate.
In conclusion, during insulin-induced hypoglycemia, PDE 3 activation clearly counteracts the lipolytic effect of catecholamines. When PDE 3 is specifically blocked, lipolysis increases greatly. Thus, PDE 3 is important for the in vivo regulation of the antilipolytic and lipolytic responses to hormones in human adipose tissue.




2: Diabetologia 1998 May;41(5):560-8
Various phosphodiesterase subtypes mediate the in vivo antilipolytic effect of insulin on adipose tissue and skeletal muscle in man.

Enoksson S, Degerman E, Hagstrom-Toft E, Large V, Arner P.
Department of Vascular Surgery, Huddinge University Hospital, Karolinska Institute, Sweden.

The antilipolytic effect of insulin on human abdominal subcutaneous adipose tissue and skeletal muscle during local inhibition of cAMP-phosphodiesterases (PDEs) was investigated in vivo, by combining microdialysis with a euglycaemic, hyperinsulinaemic clamp. During hyperinsulinaemia, the glycerol concentration decreased by 40% in fat and by 33% in muscle.
Addition of the selective PDE3-inhibitor amrinone abolished the insulin-induced decrease in adipose glycerol concentration, but did not influence the glycerol concentration in skeletal muscle.
Nor did the PDE4-selective inhibitor rolipram or the PDE5-selective inhibitor dipyridamole influence the insulin-induced decrease in muscle tissue glycerol.
However, the non-selective PDE-inhibitor theophylline counteracted the antilipolytic action of insulin at both sites.
The specific activity of PDEs was also determined in both tissues. PDE3-activity was 36.8+/-6.4 pmol x min(-1) x mg(-1) in adipose tissue and 3.9+/-0.5 pmol x min(-1) x mg(-1) in muscle. PDE4-activity in skeletal muscle was high, i.e., 60.7+/-10.2 pmol x min(-1) x mg(-1) but 8.5 pmol x min(-1) x mg(-1) or less in adipose tissue.
In conclusion, insulin inhibits lipolysis in adipose tissue and skeletal muscle by activation of different PDEs, suggesting a unique metabolic role of muscle lipolysis.



3: Biochem Biophys Res Commun 1997 Jul 30;236(3):665-9

Modulation of insulin secretion and glycemia by selective inhibition of cyclic AMP phosphodiesterase III.

Parker JC, VanVolkenburg MA, Nardone NA, Hargrove DM, Andrews KM.
Pfizer Inc., Central Research Division, Groton, Connecticut 06340, USA.

The effects of selective inhibition of cyclic AMP phosphodiesterase type III on insulin and glucose levels during an oral glucose challenge were evaluated in obese, diabetic ob/ob mice and in lean, non-diabetic littermates using the selective inhibitor, milrinone.
Oral administration of milrinone increased plasma insulin levels both in ob/ob and in lean mice.
Glucose tolerance was improved in lean, but not in ob/ob mice, where glucose levels were increased by milrinone treatment.
In isolated hepatocytes from normal rats incubation with 200 microM milrinone caused a 30% increase in glucose release with a corresponding depletion of glycogen stores. Stimulation of isolated rat adipocytes with 200 microM milrinone increased glycerol release 7-fold.
We conclude that selective inhibitors of cyclic AMP phosphodiesterase III are effective insulin secretagogues, but their therapeutic utility may be limited by their concurrent stimulation of lipolysis and hepatic glucose output.


4: Diabetes 1995 Oct;44(10):1170-5

Role of phosphodiesterase III in the antilipolytic effect of insulin in vivo.

Hagstrom-Toft E, Bolinder J, Eriksson S, Arner P.
Department of Medicine, Huddinge Hospital, Karolinska Institute, Sweden.

The effect of three types of phosphodiesterase (PDE) inhibitors on in vivo antilipolysis was investigated in healthy subjects using a 2-h euglycemic, hyperinsulinemic (40 mU.m-2.min) clamp together with microdialysis of abdominal subcutaneous adipose tissue.
During hyperinsulinemia (approximately 330 pmol/l), the circulating glycerol concentration was reduced to approximately 50% of the basal level of 53.2 +/- 3.6 mumol/l, indicating an antilipolytic effect.
The decrease in adipose tissue dialysate glycerol, which mirrors the change in interstitial glycerol concentration, was about 40% during hyperinsulinemia when Ringer's solution alone was perfused.
Local perfusion with a selective PDE IV inhibitor, rolipram (10(-4) mol/l), did not influence the insulin-induced decrease in dialysate glycerol (F = 0.8 vs. perfusion with Ringer's solution by two-factor analysis of variance [ANOVA]), although rolipram increased the dialysate glycerol level by 144 +/- 7% of the baseline value.
However, local perfusion with a selective PDE III inhibitor, amrinone (10(-3) mol/l), or a nonselective PDE inhibitor, theophylline (10(-2) mol/l), abolished the ability of insulin to lower dialysate glycerol (F = 16.5, P < 0.01 and F = 8.5, P < 0.01, respectively, as compared with perfusion with Ringer's solution).
The findings could not be explained by changes in the local blood flow (as measured by a microdialysis--ethanol escape technique), which was not affected by hyperinsulinemia in the presence or the absence of PDE inhibitors in the dialysis solvent.
We conclude that PDEs play an important role in mediating the antilipolytic effect of insulin in vivo and that PDE III is the dominant isoenzyme modulating this effect.

[Eagle]

5: Am J Physiol 1995 Mar;268(3 Pt 1):E491-500

Amrinone prevents muscle protein wasting during chronic sepsis.

Jurasinski CV, Kilpatrick L, Vary TC.
Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey 17033.

The time course for the effects of sepsis on rates of protein synthesis, RNA contents, and translational efficiencies was measured in mixed muscles of rat hindlimb perfused in vitro 3, 5, and 10 days after induction of sepsis. Furthermore, the effect of daily injections of amrinone (5 mg.kg-1.day-1) on muscle protein synthesis was investigated.
On day 3 of sepsis, decreased rates of protein synthesis in muscle from untreated septic animals or septic rats treated with amrinone resulted from a reduced food intake.
When food intake became normalized to control after 5 days, rates of protein synthesis in untreated septic rats remained depressed. Treatment of septic animals with amrinone for 5 days prevented the sepsis-induced inhibition of protein synthesis by abolishing the inhibition of peptide-chain initiation and restoring translational efficiency to control values.
In contrast, amrinone treatment of control rats for 5 days did not cause an accretion of muscle protein or augment protein synthesis.
Ten days after induction of sepsis, there were no differences in rates of protein synthesis, RNA content, or translational efficiency in septic animals compared with control or amrinone-treated septic rats.
Thus, amrinone prevented the sepsis-induced abnormalities in skeletal muscle protein synthesis.



6: Crit Care Med 1994 Aug;22(8):1235-40

Thermogenic effect of amrinone in healthy men.

Ruttimann Y, Chiolero R, Revelly JP, Jeanpretre N, Schutz Y.
Department of Anesthesiology, University Hospital, Lausanne, Switzerland.

OBJECTIVES: The thermogenic effect of amrinone is unknown and its utilization in patients with severe cardiac failure could potentially increase oxygen requirements and therefore aggravate oxygen debt. Consequently, the present study was undertaken to assess the thermogenic response to amrinone at three different plasma concentrations under controlled conditions and to analyze amrinone's effects on various biochemical variables. DESIGN: A prospective, unblinded, controlled study. The initial control period was followed by three sequential, experimental treatments.
SUBJECTS: Ten young, healthy, male volunteers with normal body weight. INTERVENTIONS: Three experimental periods. Amrinone was administered intravenously in progressive doses: a) 0.5 mg/kg followed by 5 micrograms/kg/min; b) 0.5 mg/kg followed by 10 micrograms/kg/min; and c) 1.0 mg/kg followed by 10 micrograms/kg/min. MEASUREMENTS AND MAIN RESULTS: Oxygen consumption (VO2) and CO2 production were continuously measured by means of a computerized indirect calorimeter. At the highest dose, amrinone produced a slight and significant (p < .01) increase in VO2 and in resting metabolic rate (+4.5% and +3.7%, respectively), while no change in CO2 production or in respiratory quotient occurred throughout the study. At the medium and high doses, amrinone increased plasma free fatty acid concentrations by 38% and 53%, respectively (p < .05). No variation in plasma glucose, lactate, insulin, norepinephrine, or epinephrine concentrations was observed during the study.
CONCLUSIONS: Amrinone administered intravenously at therapeutic doses has minimal thermogenic and metabolic effects in humans without cardiac failure.