Activation of cardiac afferents by arachidonic acid: relative contributions of metabolic pathways

Arachidonic acid (AA) is metabolized via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 (CP450) pathways to a variety of bioactive pro ducts. The sensitivity of cardiac afferent endings to AA and its metabolite s, especially those derived from LOX and CP450 pathways, is currently uncle ar. We examined AA-induced activation of cardiac vagal chemosensitive affer ents in non- and postischemic hearts in rats and evaluated the relative con tributions of the three metabolic pathways to the effects. Epicardial appli cation of AA activated the cardiac afferents dose dependently in both nonis chemic and postischemic hearts, with afferent responses greater in the latt er condition. In nonischemic hearts, the afferent response to AA was abolis hed only after simultaneous administration of indomethacin and 17-octadecyn oic acid (COX and CP450 inhibitors, respectively). Nordihydroguaiaretic aci d (a LOX inhibitor) had no effect on the afferent response to AA. In postis chemic hearts, abolition of the afferent response to AA required simultaneo us blockade of all three pathways. None of the AA metabolic inhibitors affe cted resting activity of cardiac afferents in nonischemic hearts, but each suppressed afferent activity during ischemia-reperfusion. Most COX metaboli tes, CP450 metabolites, and 5-LOX metabolites tested were capable of activa ting cardiac afferents. The 12-LOX metabolites and 15-LOX metabolites had n o effect on afferent activity. These data indicate that in the nonischemic heart, basal AA metabolism does not contribute to resting afferent activity , but AA is capable of activating cardiac afferents via COX and CP450 but n ot LOX pathways. During ischemia-reperfusion, all three metabolic pathways contribute to activation of cardiac vagal afferents with an enhanced respon siveness to AA. Our results suggest that induction of the 5-LOX pathway con tributes to the enhanced sensitivity of cardiac vagal afferents to AA in th e ischemic condition.