Differential roles of peripheral and spinal endothelin receptors in the micturition reflex in rats.
OBJECTIVE
We investigated the effects of endothelin (ET) receptor activation in the bladder and the spinal cord on the micturition reflex in urethane anesthetized rats.


METHODS
The effects of ET receptor activation on bladder activity were examined during continuous infusion cystometrograms. ET-1 was administered intrathecally or intravesically in normal rats or rats pretreated with capsaicin. The effects of intravenous injection of the selective ETA receptor antagonist ABT-627, or selective ETB receptor antagonist A-192621 (Abbott Laboratories, Abbott Park, Illinois) intrathecal injection of the opioid receptor antagonist naloxone hydrochloride on changes in bladder activity induced by intravesical or intrathecal ET-1 administration were investigated.


RESULTS
Intravesical injection of ET-1 (0.1 to 10 microM) induced detrusor overactivity, as evidenced by a decrease in intercontraction intervals, in a dose dependent manner. ET-1 induced detrusor overactivity was suppressed by intravenous application of ABT-627 (0.1 mg/kg) as well as capsaicin pretreatment but not by A-192621. In contrast, intrathecal injection of ET-1 (0.5 to 50 fmol) increased intercontraction intervals dose dependently and ET-1 at a higher dose (50 fmol) induced urinary retention. These inhibitory effects were antagonized by ABT-627 (10 mg/kg) and also by intrathecal application of naloxone but not by A-192621.


CONCLUSIONS
These results indicate that the activation of ETA receptors in capsaicin sensitive C-fiber afferents in the bladder can induce detrusor overactivity, while ETA receptor activation in the spinal cord can inhibit the micturition reflex via activation of a spinal opioid mechanism. Thus, targeting peripheral ETA receptors could be an effective treatment for bladder overactivity and/or painful conditions.
Ogawa
Teruyuki
T
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Kamo
Izumi
I
Pflug
Beth R
BR
Nelson
Joel B
JB
Seki
Satoshi
S
Igawa
Yasuhiko
Y
Nishizawa
Osamu
O
de Groat
William C
WC
Chancellor
Michael B
MB
Yoshimura
Naoki
N
D000344:Afferent Pathways / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D000077868:Atrasentan; D002211:Capsaicin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D007278:Injections, Spinal; D009122:Muscle Hypertonia / Q000139:chemically induced / Q000503:physiopathology; D009270:Naloxone / Q000494:pharmacology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D010525:Peripheral Nerves / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000502:physiology*; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology; D012018:Reflex / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology*; D001743:Urinary Bladder / Q000294:innervation*; D014554:Urination / Q000502:physiology*; D014563:Urodynamics / Q000187:drug effects / Q000502:physiology
C120508:A 192621; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D017466:Receptors, Endothelin; D011957:Receptors, Opioid; D009270:Naloxone; D002211:Capsaicin; D000077868:Atrasentan