The proinflammatory cytokines, including tumor necrosis factor-α (TNF- α) and interferon-γ (IFN-γ), are increased in heart failure and sepsis, clinical conditions for which the IV anesthetic ketamine is useful. The proinflammatory cytokines cause β-adrenergic receptor (βAR) hypofunction secondary to reduced function of the enzyme adenylylcyclase (AC). In this study, we evaluated the effect of ketamine alone, TNF-α and IFN-γ, and ketamine plus TNF-α and IFN-γ, on isoproterenol (ISO, aβAR agonist) and forskolin (FSK, an activator of AC)-induced intracellular accumulation of cAMP. An in vitro culture of a rat heart cell line (H9c2) was labeled with [3H]adenine to produce [3H]ATP, and we measured the intracellular accumulation of [3H]cAMP after stimulation with ISO or FSK to convert the [3H]ATP to [3H]cAMP. Pretreatment with either cytokine alone did not significantly affect ISO or FSK-induced intracellular cAMP accumulation, whereas the combination of TNF-α and IFN-γ caused a significant (P < 0.05 compared with untreated cells) reduction. Pretreatment with ketamine caused a significant (P < 0.05 compared with untreated cells) increase in ISO or FSK- induced cAMP accumulation. Pretreatment of the H9c2 cells with ketamine, plus the combination of TNF-α and FN-γ, inhibited the reduction of ISO or FSK- induced intracellular cAMP accumulation caused by the proinflammatory cytokines alone. These results demonstrate that the combination of the proinflammatory cytokines TNF-α and IFN-γ reduce poststimulation (ISO or FSK) intracellular cAMP accumulation. This action of the proinflammatory cytokines is consistent with the observation of βAR hyporesponsiveness to βAR agonist therapy in sepsis and heart failure. Ketamine augments the poststimulation cAMP accumulation in H9c2 cells while inhibiting the cytokine-induced reduction of cAMP accumulation. This may partly explain the improvement in cardiac function after ketamine use in clinical conditions known to have increased systemic levels of proinflammatory cytokines, such as sepsis and heart failure. Implications: Tumor necrosis factor-α and interferon-γ reduced poststimulation intracellular cAMP levels, whereas ketamine inhibits this action of the proinflammatory cytokines. Because cAMP is the second messenger for the β-adrenergic receptor, this may be a mechanism for improved blood pressure and cardiac output in sepsis and heart failure after ketamine use.
ASJC Scopus subject areas
- Anesthesiology and Pain Medicine