Sequential changes in autonomic regulation of cardiac myocytes after in vivo endotoxin injection in rat.
We report that in vivo injection of endotoxin (EDTX, 6 mg. kg(-)(1)) induces cardiovascular alterations in rats that closely mimic the clinical situation, as assessed by in vivo hemodynamic measurements in anesthetized and conscious, chronically instrumented animals. The patch-clamp technique was used to characterize the L-type calcium current (I(Ca)) and its autonomic regulation in isolated cardiac myocytes. The density of I(Ca) progressively decreased at 12 and 36 h after EDTX injection. However, the dihydropyridine (+/-)Bay K 8644 (100 nM) enhanced I(Ca) to levels similar to those in control and EDTX-treated myocytes. In addition, the net stimulatory effect of a beta-adrenergic agonist (isoproterenol) on I(Ca) was increased 12 h after EDTX injection. This change in the beta-adrenergic effect declined 24 h later. The potentiation in the beta-adrenergic stimulation of I(Ca) was mimicked by L858051 (10 microM), a direct activator of adenylyl cyclase, but not by IBMX (200 microM), a phosphodiesterase inhibitor. Besides, the antiadrenergic effect of acetylcholine on I(Ca) was unchanged 12 h after EDTX injection, but increased 36 h after EDTX injection. These results support the hypothesis that time-dependent changes in the adenylyl cyclase pathway in cardiac myocytes may contribute, via the autonomic regulation of I(Ca), to the severity of myocardial dysfunction during sepsis.
Abi-Gerges
N
N
INSERM U-446, Laboratoire de Cardiologie Cellulaire et Moléculaire, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, Cedex, France.
Tavernier
B
B
Mebazaa
A
A
Faivre
V
V
Paqueron
X
X
Payen
D
D
Fischmeister
R
R
Méry
P F
PF
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology / Q000502:physiology; D000262:Adenylyl Cyclases / Q000378:metabolism; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology; D004224:Diterpenes; D004594:Electrophysiology; D019446:Endotoxemia / Q000503:physiopathology; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D020536:Enzyme Activators / Q000494:pharmacology; D004926:Escherichia coli; D006321:Heart / Q000294:innervation* / Q000502:physiology; D006439:Hemodynamics; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D018805:Sepsis / Q000503:physiopathology
D018674:Adrenergic Antagonists; D000318:Adrenergic beta-Agonists; D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D004224:Diterpenes; D004731:Endotoxins; D020536:Enzyme Activators; D010726:Phosphodiesterase Inhibitors; C055627:L 858051; D005576:Colforsin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D000109:Acetylcholine; D015056:1-Methyl-3-isobutylxanthine