Effects of antimuscarinics on voiding function after cerebral infarction in a rat model of overactive bladder.
Muscarinic receptor antagonists are used clinically for their therapeutic peripheral effects on bladder function. However, these agents may also act on central muscarinic receptors, especially in individuals with compromised blood-brain barrier function. We compared the effects of atropine and tolterodine, agents that do and do not readily cross the blood-brain barrier, respectively, administered peripherally (intravenous [i.v.]) and centrally (intracerebroventricular [i.c.v.]) on cystometrography in conscious rats after cerebral infarction induced by middle cerebral artery occlusion or sham surgery. We hypothesized that tolterodine would produce greater improvement in bladder capacity and less impairment in bladder contractility and that the effects of both agents would be greater in rats with cerebral infarction and sham-operated rats after peripheral administration, but that tolterodine and atropine would exert similar effects after central administration. Bladder capacity was markedly reduced following cerebral infarction. Low-dose i.v. tolterodine (<or=20 nmol/kg) significantly reversed this effect without altering residual volume or bladder contraction pressure. Low-dose i.v. atropine (2 nmol/kg) had no effect on bladder capacity but significantly decreased bladder contraction pressure. Higher doses of i.v. atropine (>or=20 nmol/kg) significantly increased bladder capacity but also significantly increased residual volume and decreased bladder contraction pressure. Tolterodine was significantly more efficacious than atropine in increasing bladder capacity, whereas atropine produced significantly greater increases in residual volume and reductions in bladder contraction pressure; these treatment group differences were also observed in sham-operated animals. Tolterodine and atropine administered i.c.v. significantly increased bladder capacity following cerebral infarction or sham surgery; however, this was accompanied by significantly increased residual volume and decreased bladder contraction time. The decrease in bladder contraction time was significantly smaller after tolterodine vs atropine. Peripherally acting muscarinic receptor antagonists may be preferable to centrally acting agents for minimizing adverse events, such as incomplete bladder emptying, even in individuals with compromised blood-brain barrier function.
Yusup
Anwar
A
Department of Urology, Faculty of Medical Science, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Fukui 910-1193, Japan.
Akino
Hironobu
H
Miwa
Yoshiji
Y
Oyama
Nobuyuki
N
Aoki
Yoshitaka
Y
Ito
Hideaki
H
Tanase
Kazuya
K
Matsuta
Yosuke
Y
Nakai
Masaharu
M
Yokoyama
Osamu
O
D000818:Animals; D001285:Atropine / Q000008:administration & dosage / Q000627:therapeutic use*; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D003408:Cresols / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000503:physiopathology; D007276:Injections, Intraventricular; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010665:Phenylpropanolamine / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D014546:Urinary Catheterization; D014554:Urination / Q000187:drug effects*
D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D001285:Atropine