The role of hemodynamics in the action of diltiazem on hepatic fatty acid metabolism

The hemodynamic effects of diltiazem in the liver are strictly Ca2+-depende nt Consequently, Ca2+-free perfusion can be used for investigating the meta bolic effects of diltiazem without interference by hemodynamics. Livers wer e perfused with Krebs/Henseleit-bicarbonate buffer (pH 7.4). For performing Ca2+-free perfusion the cation was omitted from the perfusion fluid and th e cellular pools were exhausted by repeated phenylephrine infusions. Three conditions were investigated with and without Ca2+: (1) substrate-free perf usion fluid; (2) 0.3 mM [1-C-14]octanoate infusion; (3) 0.3 mM [1-C-14]palm itate infusion. The following results were obtained: 1. Oxygen uptake stimulation caused by octanoate and palmitate was abolishe d by 500 mu M diltiazem in the presence of Ca2+; in the absence of Ca2+ the re was no inhibition (octanoate) or it was much smaller (palmitate); 2. The (CO2)-C-14 production was inhibited in the presence of Ca2+; in the absence of Ca2+ there was no inhibition (palmitate) or even stimulation (oc tanoate). 3. Ketogenesis from endogenous sources, from palmitate and from octanoate w as inhibited by diltiazem in the presence as well as in the absence of Ca2. The beta-hidroxybutyrate/acetoacetate ratio was diminished in the presenc e and in the absence of Ca2It was concluded that inhibition of fatty acid oxidation by diltiazem depen ds partly on the Ca2+-dependent hemodynamic effects and partly on a Ca2+-in dependent action on some enzymatic system.