Involvement of 5-hydroxytryptamine (HT)7 receptors in the 5-HT excitatory effects on the rat urinary bladder.
OBJECTIVE
To investigate the in vitro and in vivo effects of 5-hydroxytryptamine (5-HT) on the rat urinary bladder and to characterize the receptors involved in mediating these pharmacological effects by using selective antagonists.


METHODS
Female Wistar rats (250-350 g) were used for all studies. In vitro, detrusor muscle strips were mounted between two platinum electrodes in organ baths filled with a modified Krebs' solution bubbled with 95% O(2) and 5% CO(2) at 37 degrees C. After equilibration and a contraction to 80 mmol/L KCl, strips were exposed to electrical field stimulation for 30 min and incubated with the antagonist or vehicle for a further 30 min, then a 5-HT concentration-response curve (CRC) was obtained. In vivo, rats were anaesthetized with pentobarbital, and the ureters and urethra ligated, the bladder catheterized and infused with saline. 5-HT (3-100 microg/kg intravenous) dose-dependently increased intravesical pressure (IVP). After administering 5-HT at 30 microg/kg three times at 10 min intervals (controls), one dose of antagonist was perfused for 5 min and, after a further 5 min, 30 microg/kg 5-HT was tested again. This cycle was repeated four times using increasing doses of the antagonist to be tested.


RESULTS
In vitro, 5-HT (0.01-100 micromol/L) induced a concentration-dependent enhancement of the neurogenic response, with a mean (sd) pEC(50) of 6.36 (0.15) and E(max) of 41.1 (4.6)% KCl (eight rats). In unstimulated tissues, 5-HT induced no contractile effect. Selective 5-HT(4), 5-HT(3) and 5-HT(1A) receptor antagonists had no effect on the 5-HT potentiating effects. The potentiating effect of 5-HT was antagonized by mesulergine at 0.3 micromol/L, R(+)lisuride at 0.3 micromol/L and the selective 5-HT(7) receptor antagonist SB-258741 at 0.3 micromol/L. In vivo, in anaesthetized rats, IVP increases induced by repeated doses of 30 microg/kg 5-HT were reproducible. R(+)lisuride (3-100 microg/kg) dose-dependently inhibited the 5-HT-induced increase of IVP. At the maximum dose tested, R(+)lisuride almost totally inhibited the 5-HT effect.


CONCLUSIONS
In rat isolated detrusor muscle the 5-HT(7) receptor antagonists SB-258741, R(+)lisuride and mesulergine blocked the 5-HT potentiating effect with the expected potency. Moreover, in anaesthetized rats, R(+)lisuride abolished 5-HT effects on IVP at doses that antagonize physiological effects known to be mediated by 5-HT(7) receptor activation in several animal species. These results suggest the involvement of 5-HT(7) receptors in the modulation of rat bladder contraction both in vitro and in vivo.
Palea
Stefano
S
Sanofi-Synthélabo Recherche, Rueil-Malmaison, France. stefano.palea@noos.fr
Lluel
Philippe
P
Barras
Martine
M
Duquenne
Chantal
C
Galzin
Anne-Marie
AM
Arbilla
Sonia
S
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D009119:Muscle Contraction; D009415:Nerve Net / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D001743:Urinary Bladder / Q000378:metabolism*
D011985:Receptors, Serotonin; C078730:serotonin 5 receptor; D012701:Serotonin; D001285:Atropine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat