Sy. Sun et al., Activation of cardiac afferents by arachidonic acid: relative contributions of metabolic pathways, AM J P-HEAR, 281(1), 2001, pp. H93-H104
Citations number
38
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
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.