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Involvement of 5‐hydroxytryptamine (HT) 7 receptors in the 5‐HT excitatory effects on the rat urinary bladder
Author(s) -
Palea Stefano,
Lluel Philippe,
Barras Martine,
Duquenne Chantal,
Galzin AnneMarie,
Arbilla Sonia
Publication year - 2004
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2004.05114.x
Subject(s) - antagonist , 5 ht receptor , in vivo , urinary bladder , chemistry , stimulation , serotonin , endocrinology , receptor antagonist , pentobarbital , receptor , medicine , in vitro , detrusor muscle , pharmacology , biology , biochemistry , microbiology and biotechnology
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. MATERIALS AND 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 °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 µg/kg intravenous) dose‐dependently increased intravesical pressure (IVP). After administering 5‐HT at 30 µg/kg three times at 10 min intervals (controls), one dose of antagonist was perfused for 5 min and, after a further 5 min, 30 µg/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 µmol/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 µmol/L, R(+)lisuride at 0.3 µmol/L and the selective 5‐HT 7 receptor antagonist SB‐258741 at 0.3 µmol/L. In vivo , in anaesthetized rats, IVP increases induced by repeated doses of 30 µg/kg 5‐HT were reproducible. R(+)lisuride (3–100 µg/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 .