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. 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 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.

Alfuzosin improves penile erection triggered by apomorphine in spontaneous hypertensive rats.

OBJECTIVES: Growing evidence suggest that BPH is a risk factor for ED. Since alfuzosin is a cornerstone in the treatment of BPH patients, we assessed the effect of alfuzosin on erectile function in rats when combined with a pro-erectile drug such as apomorphine. METHODS: Potencies of alfuzosin, apomorphine or the combination to relax norepinephrine (NE) precontracted corpus cavernosum tissue of spontaneous hypertensive rats (SHR) were determined. In anaesthetized rats, intracavernous and blood pressures were recorded after administration of apomorphine (10-250microg/kg s.c.) and alfuzosin (3-30microg/kg i.v.). RESULTS: Alfuzosin fully relaxed the NE-precontracted penile tissue (pIC(50)=6.62+/-0.7) while apomorphine, up to 10microM, did not produce any relaxation. The potency of alfuzosin to relax erectile tissue was not further enhanced with 10microM apomorphine. Apomorphine induced erections in rat while alfuzosin alone did not. However, alfuzosin (30microg/kg) significantly enhanced the potency of apomorphine, to induce erections (ED(50)=25microg/kg versus 57microg/kg). In addition, alfuzosin even at 3microg/kg, significantly increased the intracavernous pressure (ICP) during erectile events up to 52-55mmHg when compared to ICP values of 29mmHg with 50microg/kg apomorphine alone. CONCLUSION: These results show that alfuzosin enhances the number and amplitude of erections induced by apomorphine in SHR. Therefore, clinical evaluation of alfuzosin in association with apomorphine is warranted.