Effects of ketamine and fentanyl on lung metabolism in perfused rat lungs

The effects of ketamine and fentanyl on serotonin (5-hydroxytryptamine; 5-HT) metabolism, angiotensin-converting enzyme (ACE), and protein synthesis (PS) were investigated in an isolated lung model. Rat lungs were perfused in situ with a blood-free physiological salt solution. The pulmonary vasculature was exposed to ketamine (0.005-2.1 mM) or fentanyl (1.8-4.5 microM) for up to 2 h. After 1 h, accumulation of 5-[14C]hydroxyindoleacetic acid (5-HIAA) by the lung was monitored as an index of 5-HT metabolism. ACE activity was estimated from hydrolysis of [3H]benzoylphenylalanyl-alanyl-proline, a synthetic substrate for the enzyme. [3H]phenylalanine was added to the perfusate after 1 h, and its incorporation into acid-precipitable lung protein was measured over the subsequent hour. Ketamine inhibited 5-HT uptake in a concentration-related manner. The inhibition was characterized as competitive and reversible. Fentanyl had no effect on lung 5-HIAA accumulation. Neither drug altered ACE activity or protein synthesis over the concentration ranges tested. The results indicate an action by ketamine that inhibits the 5-HT membrane-transport process. The different effects observed by ketamine and fentanyl on this process could contribute to the diverse pharmacological properties of these two drugs.