G-protein coupled receptor kinase 2 is altered during septic shock in rats.
BACKGROUND
One of the key mechanisms leading to beta-adrenergic receptor-specific desensitization is the phosphorylation of agonist-occupied receptors by the specific beta-adrenergic receptor kinase (GRK2). The present study examines whether GRK2 is altered during septic shock in rats.


METHODS
Male Wistar rats (7 weeks) weighing between 250 and 300 g were anesthetized with pentobarbital (10 mg/kg ip). Escherichia coli endotoxin (10 mg/kg in 0.3 mL of saline) or saline (0.3 ml) was injected intravenously via the dorsal vein. Hemodynamic parameters and humoral mediators were measured at 2 h after the administration of endotoxin. The hearts were immediately excised to examine beta-adrenergic receptor density and GRK2 level. We also studied the inotropic response to isoproterenol at the same time in other animals.


RESULTS
Myocardial beta-adrenergic receptor density in the membrane fraction was decreased after an intravenous administration of 10 mg/kg LPS (LPS group: baseline value; 82 +/- 11 fmol/mg protein; 120 min after LPS; 58 +/- 11 fmol/mg protein, P < 0.05). GRK2 levels in the membrane and cytosolic fraction of the control group did not change. In the LPS group, GRK2 levels in the membrane fraction were increased at 60 and 120 min after the treatment (60 min; control, 4.5 +/- 0.4; pithed control, 4.4 +/- 0.6; LPS group, 6.2 +/- 0.3; pithed LPS group, 5.5 +/- 0.4; 120 min: control, 4.4 +/- 0.3; pithed control, 4.9 +/- 0.7; LPS group, 7.1 +/- 0.3; pithed LPS group, 5.9 +/- 0.4; densitometric unit, respectively: P < 0.05).


CONCLUSIONS
GRK2 levels in the membrane fraction are increased during septic shock in rats. GRK2 might play a role in the impairment of the beta-adrenergic receptor signal transduction system.
Kadoi
Yuji
Y
Department of Anesthesiology and Reanimatology, Gunma University, School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. kadoi@med.gunma-u.ac.jp
Saito
Shigeru
S
Kawahara
Fuminori
F
Nishihara
Fumio
F
Goto
Fumio
F
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D054769:G-Protein-Coupled Receptor Kinase 2; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008070:Lipopolysaccharides; D008297:Male; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051552:beta-Adrenergic Receptor Kinases
D000318:Adrenergic beta-Agonists; D008070:Lipopolysaccharides; D011943:Receptors, Adrenergic, beta; D017868:Cyclic AMP-Dependent Protein Kinases; C496569:Grk2 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D019204:GTP-Binding Proteins; D007545:Isoproterenol