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Ketamine Increases Contractility Via an Increase in cAMP in Rat Ventricular Myocytes
Hiromi Kurokawa, M.D.; Paul A. Murray, Ph.D.; Derek S. Damron, Ph.D.
The Center for Anesthesiology Research, The Cleveland Clinic Foundation, Cleveland, Ohio, United States
BACKGROUND: Ketamine is a cardiovascular stimulant by virtue of its sympathomimetic effects, but may also have direct effects on myocardial function. It has been reported that clinically relevant concentrations of ketamine exert a direct positive inotropic effect in rat papillary muscle,1 whereas supraclinical concentrations exert a direct negative inotropic effect.2 Our objective was to examine the effects of clinically relevant concentrations of ketamine on cardiac contractility and intracellular Ca2+ concentration ([Ca2+]i), as well as to identify the cellular mechanism of action of ketamine in ventricular myocytes.

METHODS: Freshly isolated ventricular myocytes were obtained from adult rat hearts. [Ca2+]i and cell shortening were simultaneously measured using fura-2 (340/380 ratio) and video-edge detection in individual field-stimulated myocytes. Ketamine (1-100 μM) was administered in the presence or absence of isoproterenol or propranolol to identify potential interactions with the β-adrenergic pathway. cAMP accumulation was measured in suspensions of ventricular myocytes using an Enzyme Immunoassay Kit. Statistical analysis was performed using analysis of variance and Bonferroni t-test. Changes were considered statistically significant at p<0.05. Data are reported as means ± SEM.

RESULTS: Ketamine (1, 10, 30, 100 μM) increased [Ca2+]i by 5 ± 4, 7 ± 4, 13 ± 6 and 16 ± 8%, and shortening by 4 ± 2, 8 ± 5, 25 ± 12 and 48 ± 23%. Isoproterenol (10nM) increased [Ca2+]i and shortening by 47 ± 9% and 123 ± 25%. In the presence of isoproterenol, ketamine (100 μM) had no additional effect on [Ca2+]i or shortening. Propranolol (5 μM) alone decreased [Ca2+]i and shortening by 15 ± 5% and 33 ± 6%. Following pretreatment with propranolol, ketamine (100 μM) increased [Ca2+]i and shortening by 18 ± 10% and 40 ± 23% of the propranolol-stimulated control. Isoproterenol (100nM) increased cAMP levels by 836 ± 117%. Ketamine (100 μM) alone increased cAMP levels by 62 ± 26%. In the presence of isoproterenol, ketamine increased cAMP production by 68 ± 14% of the isoproterenol-stimulated control. Propranolol (5 μM) alone decreased baseline cAMP production by 32 ± 5%. In the presence of propranolol, ketamine (10, 100 μM) increased cAMP accumulation by 20 ± 3 and 45 ± 2% compared to the propranolol-stimulated control.

DISCUSSION: These results indicate that clinically relevant concentrations of ketamine directly increase [Ca2+]i and shortening in ventricular myocytes. The cellular mechanism appears to involve a ketamine-induced increase in cAMP production, suggesting activation of the β-adrenergic signal transduction pathway. Propranolol caused reductions in [Ca2+]i, shortening and cAMP, which indicates that there is constituitive activation of β-adrenergic receptors in rat ventricular myocytes. The cellular target of ketamine appears to be at a site downstream of the β-adrenergic receptor, suggesting an interaction with Gs, adenylyl cyclase and/or cAMP-dependent phosphodiesterase.

REFERENCES: 1. Riou et al., Anesthesiology 71:116-125, 1989. 2. Kanaya et al., Anesthesiology 88:781-791, 1998.

Anesthesiology 2001; 95:A621