Effects of selective endothelin ET(A) receptor antagonists on endothelin-1-induced potentiation of cancer pain.
In some diseases in which endothelin-1 production increases, e.g. prostate cancer, endothelin-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin ET(A) receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on the nociception potentiated by endothelin-1 in a cancer inoculation-induced pain model in mice, induced by inoculation of the androgen-independent human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency (SCID) mice. No pain responses were observed in the sham-operated mice, whereas monophasic pain responses were observed in the PPC-1-inoculated mice. Endothelin-1 (1 to 10 pmol/paw) but not sarafotoxin S6c potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3 to 3 mg/kg, p.o.) significantly inhibited the endothelin-1 (10 pmol/paw)-induced potentiation of nociception in a dose-dependent manner. These results suggest that selective endothelin ET(A) receptor antagonists might relieve pain in patients with various diseases in which endothelin-1 production is increased, e.g. prostate cancer.
Yuyama
Hironori
H
Applied Pharmacology Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Koakutsu
Akiko
A
Fujiyasu
Noriko
N
Tanahashi
Masayuki
M
Fujimori
Akira
A
Sato
Shuichi
S
Shibasaki
Kumiko
K
Tanaka
Shohei
S
Sudoh
Katsumi
K
Sasamata
Masao
M
Miyata
Keiji
K
D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000077868:Atrasentan; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D006614:Hindlimb; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D011471:Prostatic Neoplasms / Q000150:complications*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014757:Viper Venoms / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D011743:Pyrimidines; D011759:Pyrrolidines; D013449:Sulfonamides; D014757:Viper Venoms; C057354:sarafotoxins s6; D000077868:Atrasentan