Effects of gamma-aminobutyrate B receptor modulation on normal micturition and oxyhemoglobin induced detrusor overactivity in female rats.
OBJECTIVE
Using baclofen (Sigma-Aldrich, Steinheim, Germany), a gamma-aminobutyrate B (GABA(B)) receptor agonist, and CGP62349 (AstraZeneca R & D Mölndal, Sweden), a GABA(B) receptor antagonist, in a rat model of conscious micturition we addressed certain questions, including whether there is a tonic GABA(B) receptor influence on normal bladder function, how baclofen affects normal and C-fiber activated micturition, and where the sites of GABA(B) receptor action are.


METHODS
Nonanesthetized female Sprague-Dawley rats were used. The bladder was catheterized and other catheters were placed intravenously, intrathecally or intracerebroventricularly. At 3 days the rats underwent cystometric investigation in a metabolic cage. Micturition was stimulated by infusing saline intravesically. Overactivity caused by C-fiber activation was induced by intravesical oxyhemoglobin. Drugs were given intravenously, intrathecally or intracerebroventricularly. Micturition parameters were recorded and compared before and after drug administration.


RESULTS
Baclofen at doses of 0.5 microg. intrathecally and 0.3 microg. intracerebroventricularly increased bladder capacity and threshold pressure. Overflow incontinence developed in 4 of 7 rats after 0.5 microg. baclofen intrathecally and in 5 of 7 after 1 microg. baclofen intracerebroventricularly. CGP62349 at a dose of 30 microg. intrathecally and intracerebroventricularly had a stimulatory effect on micturition, which was attenuated by baclofen. While intravenous baclofen at 1 mg. (-1)kg. was devoid of effects, intravenous baclofen at 4 mg. kg. (-1)tended to decrease micturition pressure, bladder capacity and micturition volume. Infusion volume decreased significantly, demonstrating a diuretic effect, which was abolished by pretreatment with subcutaneous desmopressin at 25 ng. kg. (-1). CGP62349 at 2 mg. kg. (-1) intravenously had a stimulatory effect on micturition, which was inhibited by baclofen. Intravesical oxyhemoglobin at 250 microM. induced bladder overactivity, which was attenuated by baclofen at 4 mg. kg. (-1) intravenously and abolished by baclofen 0.5 microg intrathecally.


CONCLUSIONS
In the normal rat stimulation of GABA(B) receptors, mainly in the central nervous system, inhibits micturition. Antagonism of GABA(B) receptors stimulates micturition, suggesting that the receptors are under tonic GABAergic influence. Baclofen intrathecally attenuated oxyhemoglobin induced detrusor overactivity, suggesting that the inhibitory actions of GABA(B) receptor agonists in the spinal cord may be useful for controlling micturition disorders caused by C-fiber activation in the urothelium and/or suburothelium.
Pehrson
Rikard
R
Department of Clinical Pharmaology, Lund University Hospital, Sweden.
Lehmann
Anders
A
Andersson
Karl-Erik
KE
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010108:Oxyhemoglobins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000502:physiology*; D001743:Urinary Bladder / Q000294:innervation / Q000502:physiology*; D014554:Urination / Q000502:physiology*
D001565:Benzoates; C114540:CGP 62349; D018755:GABA Agonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D010108:Oxyhemoglobins; D018080:Receptors, GABA-B; D001418:Baclofen