A prostacyclin receptor antagonist inhibits the sensitized release of substance P from rat sensory neurons.
Prostacyclin, one of the cyclooxygenase metabolites, causes various biological effects, including vasodilation and antithrombogenicity, and is also involved in several pathophysiological effects, such as inflammatory pain and bladder disorders. The prostacyclin receptor (IP receptor) agonists iloprost, cicaprost, and carbacyclin have been useful for clarifying the role of the IP receptor signaling, since the endogenous ligand, prostacyclin, is very unstable. On the other hand, only a few IP receptor antagonists have been reported to date. Here, we characterized the biological activities of 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid (compound A) in various in vitro systems. Compound A inhibited the accumulation of the second messenger cyclic AMP in the UMR-108 rat osteosarcoma cell line and primary cultured rat dorsal root ganglion (DRG) neurons in a concentration-dependent manner up to 10 microM, without affecting other eicosanoid receptors. Functionally, the IP receptor plays an important role in DRG neuron sensitization, which is measured by release of the neurotransmitter substance P. Although the effects of iloprost or Lys-bradykinin, an inflammatory peptide, alone on substance P release were limited, stimulation of the neurons with both these ligands induced substantial amounts of substance P release. This synergistic effect was suppressed by compound A. Collectively, these results suggest that compound A is a highly selective IP receptor antagonist that inhibits iloprost-induced sensitization of sensory neurons. Furthermore, these findings suggest that IP receptor antagonist administration may be effective for abnormal neural activities of unmyelinated sensory afferents. Compound A should prove useful for further investigations of the IP receptor in various biological processes.
Nakae
Koichi
K
Urology, Research Center Kyoto, Bayer Yakuhin Ltd., Kyoto, Japan. nakaek@bikaken.or.jp
Saito
Kiyoko
K
Iino
Takashi
T
Yamamoto
Noriyuki
N
Wakabayashi
Mayo
M
Yoshikawa
Satoru
S
Matsushima
Satoshi
S
Miyashita
Hiroshi
H
Sugimoto
Hiromi
H
Kiba
Atushi
A
Gupta
Jung
J
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006224:Cricetinae; D000242:Cyclic AMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D007609:Kallidin / Q000494:pharmacology; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D015394:Molecular Structure; D009475:Neurons, Afferent / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D012516:Osteosarcoma / Q000473:pathology; D051381:Rats; D044006:Receptors, Epoprostenol / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D044006:Receptors, Epoprostenol; D013373:Substance P; D007609:Kallidin; D000242:Cyclic AMP; D016285:Iloprost; D002118:Calcium