Endothelin-A-receptor antagonist LU 302146 inhibits electrostimulation-induced bladder contractions in vivo.
OBJECTIVE
Endothelin (ET) is a strong constrictor of smooth muscle structures. The relevance of Endothelin-A receptors in the bladder was demonstrated in several in vitro studies. The aim of this functional study was to evaluate the acute effect of the selective ET-A-antagonist LU 302146 (LU) on neurostimulation-induced bladder contractions in vivo.


METHODS
Eight male mini pigs were anesthesized. The bladder was exposed and a double lumen catheter was inserted to perform intravesical pressure (pves) measurements. Laminectomy was performed for sacral anterior root stimulation (SARS) of S2. Four animals received the selective ET-A-antagonist LU, three atropine and one animal was treated with vehicle. Pves was recorded before and after drug administration as well as before and during neurostimulation. At the end of each LU trial, a supplementary application of 4 mg atropine was administered followed by a final SARS.


RESULTS
In all experiments reproducible pves values were elicited during electrostimulation before administration of the test substance. The selective ET-A-antagonist reduced stimulation-induced bladder contraction by a mean of 57%. Additional administration of atropine inhibited the detrusor contraction almost completely during SARS. The vehicle had no effect on bladder contraction.


CONCLUSIONS
In the presented animal model, ET-1 inhibition with the selective ET receptor-A-antagonist LU 302146 decreases stimulation-induced bladder contraction in vivo. The results suggest that the selective ET-A antagonist LU acts on the atropine-resistant component of efferent detrusor activation since additional administration of atropine almost completely abolish detrusor contraction. This observation in addition to the involvement of ET-1 in bladder smooth muscle proliferation, raises the possibility that ET-receptor antagonists might be beneficial in patients with neurogenic bladder dysfunction or in patients with functional or anatomical BOO.
Scheepe
J R
JR
Department of Urology and Pediatric Urology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. j.scheepe@erasmusmc.nl
van den Hoek
J
J
Jünemann
K P
KP
Alken
P
P
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D004558:Electric Stimulation; D065130:Endothelin A Receptor Antagonists; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000294:innervation / Q000502:physiology*; D010276:Parasympatholytics / Q000494:pharmacology; D011312:Pressure; D011743:Pyrimidines / Q000494:pharmacology*; D012445:Sacrococcygeal Region; D013126:Spinal Nerve Roots / Q000502:physiology; D013552:Swine; D013556:Swine, Miniature; D001743:Urinary Bladder / Q000294:innervation / Q000502:physiology*
C405519:BSF 302146; D001559:Benzhydryl Compounds; D065130:Endothelin A Receptor Antagonists; D010276:Parasympatholytics; D011743:Pyrimidines; D001285:Atropine