In vitro and in vivo effects of endothelin-1 and YM598, a selective endothelin ET A receptor antagonist, on the lower urinary tract.
We investigated the contractile response of the lower urinary tract to endothelin-1 in vitro (rabbits) and in vivo (dogs). We also assessed 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 endothelin-1-induced contractile responses. In the in vitro study, endothelin-1 induced contractile responses in isolated rabbit bladder base, urethra, and prostate tissues. YM598 (10(-7)-10(-5) M) antagonized these endothelin-1-induced contractile responses without affecting the maximal responses. In the in vivo study, endothelin-1 induced the elevation of non-prostatic urethral pressure as well as prostatic urethral pressure even in the presence of tamsulosin (10 microg/kg, i.v.) in anesthetized male dogs. YM598 (0.1-3 mg/kg, i.v.) inhibited these endothelin-1-induced contractile responses in a dose-dependent fashion. These results suggest that endothelin ET A receptors play an important role in the lower urinary tract contraction, and that the selective endothelin ET A receptor antagonist YM598 has ameliorating effects on various urinary dysfunctions, including benign prostatic hyperplasia.
Ukai
Masashi
M
Applied Pharmacology II, Pharmacology Research Labs., Institute for Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. masashi.ukai@jp.astellas.com
Yuyama
Hironori
H
Fujimori
Akira
A
Koakutsu
Akiko
A
Sanagi
Masanao
M
Ohtake
Akiyoshi
A
Sato
Shuichi
S
Sudoh
Katsumi
K
Sasamata
Masao
M
Miyata
Keiji
K
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D044023:Receptor, Endothelin B / Q000819:agonists; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000077409:Tamsulosin; D014521:Urethra / Q000187:drug effects* / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology; D014757:Viper Venoms / Q000494:pharmacology
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; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D014757:Viper Venoms; C057354:sarafotoxins s6; D010656:Phenylephrine; D000077409:Tamsulosin; D000109:Acetylcholine