Stimulation of nitric oxide release from rat spinal cord by prostaglandin E₂

Abstract

1 We recently demonstrated that intrathecal administration of prostaglandin E 2 (PGE 2 ) and PGF 2a induced allodynia through a pathway that includes the glutamate receptor and nitric oxide (NO)-generating systems from pharmacological studies. In order to clarify the involvement of NO in prostaglandin-induced allodynia, we measured NO released from rat spinal cord slices by a chemiluminescence method. 2 PGE 2 stimulated NO release from both dorsal and ventral regions all along the spinal cord. PGE 2 stimulated the release within 10 min and increased it in a time-dependent manner. 3 The PGE 2 -induced NO release was observed at 100 nM ± 10 mM. PGF 2a stimulated the release at concentrations higher than 1 mM, but PGD 2 (up to 10 mM) did not enhance it. 4 17-Phenyl-o-trinor PGE 2 (EP 1 4EP 3 ) and sulprostone (EP 1 5EP 3 ) were as potent as PGE 2 , but PGE 1 was less potent, in stimulating NO release. While M&B 28767 (EP 3 ) did not enhance the release, butaprost (EP 2 ) stimulated it at 1 mM. The PGE 2 -evoked release was blocked by ONO-NT-012, a bifunctional EP 1 antagonist/EP 3 agonist. 5 The PGE 2 -evoked release was Ca 2+ -dependent and blocked by MK-801 (NMDA receptor antagonist) and L-NAME (NO synthase inhibitor). The release was also inhibited by PGD 2 and dibutyryl-cyclic AMP. 6 The present study demonstrated that PGE 2 stimulates NO release in the rat spinal cord by activation of NMDA receptors through the EP 1 receptor, and supports our previous ®ndings that the NOgenerating system is involved in the PGE 2 -induced allodynia.

mPGES-1-derived PGE2 mediates dehydration natriuresis

“…This finding is also in accordance with a series of our previous reports of defective NO and cGMP production in mPGES-1 null mice after highsalt loading or DOCA-salt treatment (22,24). Other investigations also suggest the potential of PGE 2 in stimulating NO and cGMP production in various renal or extrarenal systems (16,17,26,40). Overall, these results support the existence of PGE 2 /NO/cGMP pathway that appears to be important in renal salt handling.…”

Presynaptic Prostaglandin E 2 EP 1 -Receptor Facilitation of Cerebral Nitrergic Neurogenic Vasodilation

“…Moreover, EP 1 receptors have been implicated in neurotransmitter release from postganglionic sympathetic neurons, sensory nerves, and the spinal cord. [42][43][44] Lack of effects of EP 1 receptor antagonists on nicotineinduced relaxation, on the other hand, suggested that endogenous PGE 2 has an insignificant effect on the adrenergic transmission in the isolated cerebral arteries. This latter finding was further supported by the results that guanethidine, an adrenergic neuronal blocker, 6 did not affect SC-19220 inhibition of TNS-induced relaxation.…”

Prostaglandin E Inhibits Indomethacin-Induced Gastric Lesions through EP-1 Receptors

“…This effect was mimicked by other EP agonists having an affinity to EP 1 receptors, such as 17-phenyl PGE 2 (EP 1 agonist) and sulprostone (EP 1 /EP 3 agonist). Neither butaprost (EP 2 agonist), ONO-NT-012 (EP 3 agonist) [17, 23, 24]nor 11-deoxy PGE 1 (EP 3 /EP 4 agonist) was effective in reducing the severity of these lesions, indicating that the activation of the EP 2 , EP 3 , and EP 4 receptors does not lead to gastric protection against indomethacin. These results strongly suggest that the inhibition by PGE 2 of indomethacin-induced gastric lesions is brought about by activation of EP 1 receptor.…”

“…The following prostanoids were administered intravenously as a single injection from the tail vein 10 min before indomethacin; PGE 2 (EP 1 /EP 2 /EP 3 /EP 4 agonist: 0.01–0.3 mg/kg), sulprostone (EP 1 /EP 3 agonist: 0.01–0.3 mg/kg), butaprost (EP 2 agonist: 1–10 mg/kg), 17-phenyl-ω-trinor-PGE 2 (17-phenyl PGE 2 ; EP 1 agonist: 0.01–0.3 mg/kg), ONO-NT-012 (EP 3 agonist: 1–10 mg/kg) and 11-deoxy-PGE 1 (EP 3 /EP 4 agonist: 0.3–3 mg/kg). These prostanoids are considered to be the EP receptor subtype specific agonists [17, 21, 22, 23, 24], and the doses of these EP agonists were selected to show a gastroprotective action against HCl/ethanol or a stimulatory effect on HCO – 3 secretion, mucosal blood flow and/or mucus secretion in rats [17, 25]. In some animals, the effect of ONO-AE-829 (10–40 mg/kg), the EP 1 receptor antagonist [26], on the protective action of PGE 2 (0.3 mg/kg i.v.)…”