Potentiation by cyclooxygenase inhibitors of the release of catecholamines from the rabbit carotid body and its reversal by prostaglandin E2

Abstract

Key wor&v Carotid body: Arterial chemoreceptor; Prostaglandin E.; Acetylsalicylic acid: lndomethacin Salicylates, at the high therapeutic doses used in the treatment of rheumatoid arthritis, produce an increase in ventilation and augment the carotid body reactivity to hypoxic stimulus, leading to an exaggerated hyperventilation during hypoxia. These effects had been related to the action of salicylates as uncouplers of oxidative phosphorylation. In the present study, carried out in an in vitro preparation of the rabbit carotid body, we show that acetylsalicylic acid and indomethacin, two anti-inflammatory drugs that are also powerful inhibitors of cyclooxygenase, the prostaglandinsynthetizing enzyme, produce an increase in the [3H]catecholamine release evoked by low oxygen stimulation. The drugs did not affect basal normoxic release, a finding that suggests that at the concentration used these anti-inflammatory agents do not have uncoupling actions, and that their effects on hypoxic-induced release of [3H]catecholamines is mediated by their specific action as cyclooxygenase inhibitors. In agreement with this suggestion we found that prostaglandin E~ completely prevented the effects of both anti-inflammatory agents. In addition, our data indicate that endogenously synt hetized prostaglandins are powerful modulators of chemoreceptor cell function.Salicylates at high doses stimulate ventilation, the effect being mediated by peripheral and central chemoreceptors [6], It has been reported also that salicylates potentiate the carotid body-mediated hyperventilation produced by hypoxia in man [10]. The mechanism of action of salicylates at the carotid body (CB) level has been related to their well known respiratory uncoupling effect [3, 61. On the other hand, it is well known also that salicylates are potent and irreversible inhibitors of cyclooxygenase, an enzyme involved in the synthesis of prostaglandins [4]. Since it has been reported [5] that prostaglandin E2 in vivo inhibits ongoing chemoreceptor discharges in the carotid sinus nerve, we have tested the possibility that at least part of the CB-mediated effects of salicylate on ventilation could be produced by a specific effect of the antiinflammatory drugs by inhibiting prostaglandin synthesis. Taking into consideration that all chemostimulant agents tested increase in parallel the action potential frequency in the carotid sinus nerve and the release of catecholamines (CAs) from chemoreceptor cells [1, 7 9], we (34) (83) 42 30 85. have measured the release of catecholamines as an index of the CB chemoreceptors activation.The experiments were performed in CBs isolated from adult New Zealand rabbits anesthetized with sodium pentobarbital (30-40 mg/kg, Sigma) administered via the lateral vein of the ear. After tracheostomy, the bifurcation of the carotid artery was dissected, removed as a block and placed in a Lucite chamber filled with ice-cold saline. The CBs were identified and cleaned of surrounding connective tissues under a dissecting scope. Thereafter the ...

Influence of indomethacin on ventilatory and cerebrovascular responsiveness to CO2and breathing stability: the influence of Pco2gradients

“…An important consideration when assessing the effect of INDO on ventilatory CO 2 sensitivity is its effects of peripheral chemoreceptor activation. In animal studies, it has been demonstrated that INDO enhances carotid body chemosensitivity to hypoxia and hypercapnia, while no change was observed under normoxic, eucapnic conditions (22,23). In contrast, carotid denervation studies have demonstrated that the effect of prostaglandin inhibition on V E is unlikely to be mediated by the carotid bodies (31,37).…”

Influence of indomethacin on the ventilatory and cerebrovascular responsiveness to hypoxia

“…Animal studies have reported an enhanced carotid body chemosensitivity to hypoxia and hypercapnia with INDO, whilst no changes were observed under normoxic and eucapnic conditions (Gomez-Nino et al 1992. In contrast, other studies have found that, since bilateral carotid section failed to abolish INDO-induced increases in respiratory movement or _ V E ;, the effect of INDO on _ V E is unlikely to be mediated by the carotid bodies (Jansen et al 1984;McQueen and Belmonte 1974).…”

Potential Link Between Dietary Intake of Fatty Acids and Behavior: Pilot Exploration of Serum Lipids in Attention-Deficit Hyperactivity Disorder

“…Prostaglandins (PGs) and thromboxanes (TXs) are formed by cyclooxygenase, which is inhibited by anti-inflammatory agents, including aspirin (Gomez-Nino et al 1992). They are distinguished by their ring structure ("cyclo") from other eicosanoids formed by other enzymes.…”

“…For example, dopamine (D2) receptor stimulation potentiates release of arachidonic acid for PGE2 synthesis; high levels of D2 receptors and PGE2 in such CNS areas as hypothalamus and amygdala suggest a modulatory role for PGE2 in dopamine transmission (Di Marzo and Piomelli 1992). Prostaglandins and norepinephrine act antagonistically on Purkinje cell firing; PGE2 reduces neostriatal and cortical release of dopamine and norepinephrine; dopamine stimulates phospholipase-A mobilization of prostaglandin precursors from ester bonds; the binding of biogenic amines to postsynaptic receptors releases prostaglandins into the synaptic cleft, which inhibit neurotransmitter release through calcium-mediated negative feedback to the presynaptic neuron (Gross et al 1977, Molderings et al 1992, Gomez-Nino et al 1992). Sympathetic (and parasympathetic) stimulation releases prostaglandins, probably synthesized in the postsynaptic effector cell de novo (Sherbourne et al 1992); PGE2 may inhibit the presynaptic release of norepinephrine (Wolfe andHorrocks 1993, Racke et al 1992).…”