Activation of cardiac afferents by arachidonic acid: Relative contributions of the different metabolic pathways

Arachidonic acid (AA) is metabolized by cyclooxygenase (COX), 5-lipoxygenase (5-LOX) and cytochrome P450 (P450) to produce a variety of bioactive products. The role of AA and its metabolites in the activation of cardiac afferents have not been investigated. This study aimed to examine the effects of exogenous AA on the activity of cardiac afferents and to evaluate the relative contributions of its three metabolic pathways in these effects. Single-unit activity of cardiac chemosensitive afferents was recorded from the cervical vagi in anesthetized rats, and their response to epicardial application of AA was measured with and without blockade of COX, 5-LOX and P450 respectively. The effects of some AA metabolites from the different pathways on the activity of cardiac afferents were also examined. AA (0.3-30 nmol) activated cardiac vagal afferents dose-dependently. Blockade of either COX (indomethacin, 5 mg/kg, iv) or P450 (17-octadecynoicacid, 1 mg/kg, iv), but not of 5-LOX (nordihydroguaiaretic acid, 5 mg/kg, iv), attenuated AA-induced activation of the cardiac afferents. Simultaneous blockade of COX and P450 totally blocked the activation evoked by AA. Among the tested metabolites from COX, PGE₂, PGI_Z and TXA₂ activated cardiac afferents, while TXB₂ and PGF_2α, did not. 20-HETE and 14, 15-EET, the metabolites from P450 which were tested, also activated cardiac afferents. These data suggest that the AA-induced activation of cardiac vagal afferents is mediated by the metabolites from COX and P450, but not 5-LOX pathways in normal rats.