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Investigation of Serotonin Receptors in the Isolated Penile Bulb of Rats

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Investigation of Serotonin Receptors in the Isolated Penile Bulb of Rats International Journal of Impotence Research (2006) 18, 510–516 & 2006 Nature Publishing Group All rights reserved 0955-9930/06 $30.00 www.nature.com/ijir ORIGINAL ARTICLE Investigation of serotonin receptors in the isolated penile bulb of rats G Soydan, E Tekes and M Tuncer Department of Pharmacology, Hacettepe University, Faculty of Medicine, Shhiye, Ankara, Turkey The aim of this study was to investigate serotonin (5-HT) receptors in the penile bulb, which have À7 À4 been suggested to play a role in penile erection. Serotonin (10 –3  10 M) contracted penile bulbs À9 À7 in a concentration-dependent manner. Ketanserin (5-HT2A antagonist, 10 –10 M) and prazosin À9 À7 (a1-adrenergic receptor blocker, 10 –10 M) suppressed the lower and upper parts of concentra- À5 tion–response curves to 5-HT, respectively. Guanethidine (adrenergic neuron blocker, 5  10 M) À4 À4 reduced the responses to 5-HT at only 10 and 3  10 M concentrations. NAN-190 (5-HT1A À8 À7 antagonist, 10 ,10 M) shifted the concentration–response curve to the right with a reduction À6 À5 in the maximum response to 5-HT. While ondansetron (5-HT3 antagonist, 10 –10 M)and À6 À5 GR55562 (5-HT1B/1D antagonist, 10 –10 M) had no effect on the concentration–response curve to À7 À4 5-HT. The 5-HT1A agonist 8-OH-DPAT (10 –3  10 M) contracted penile bulbs in a concentration- dependent manner with a lower pD2 value than that of 5-HT. Sumatriptan (5-HT1B/1D agonist, À8 À4 10 –10 M) did not produce any contractile response in the penile bulbs. Prucalopride, a selective À7 À4 5-HT4 agonist (R093877, 10 –3  10 M) produced concentration-dependent relaxation in penile À5 À7 À4 bulbs contracted by phenylephrine (10 M). 5-HT4 agonists cisapride (10 –10 M)and À7 À4 metoclopramide (10 –3  10 M) also relaxed the tissue, concentration-dependently. Selective À6 À5 À6 À5 5-HT4 antagonists GR125487 (10 –10 M) and GR113808 (10 –10 M)slightly,butnot significantly, decreased prucalopride- and cisapride-induced relaxation. Propranolol (b-adrenergic À6 À5 À4 receptor blocker, 10 –10 M)andL-NOARG (nitric oxide synthase inhibitor, 10 M) had no effect on prucalopride-induced relaxation. These results suggest the existence of a1-adrenergic, 5-HT1A and 5-HT2A serotonergic receptors in the penile bulb of rats, which are responsible for 5-HT-induced contraction. Additionally, a serotonergic receptor resembling a 5-HT4-type plays a role in the relaxation. The latter receptor is activated by 5-HT4 agonists, but is not antagonized by 5-HT4 antagonists. International Journal of Impotence Research (2006) 18, 510–516. doi:10.1038/sj.ijir.3901456; published online 9 March 2006 Keywords: penile bulb; serotonin receptors; ketanserin; prazosin; prucalopride Introduction stimulation of 5-HT1A or 5-HT2 receptors by admin- istration of 5-HT agonists inhibits penile erection in Serotonin (5-hydroxytryptamine, 5-HT) receptors rats.4 It is unknown whether peripheral administra- are classified into seven different subtypes, namely tion of 5-HT agonists in vivo produces penile 5-HT1,2,3,4,5,6,7, and 5-HT1 and 5-HT2 receptors are erection via central and/or peripheral mechanisms. subdivided into five subtypes (5-HT1A, 1B, 1D, 1E, 1F) Serotonin has been reported to induce contraction and into three subtypes (5-HT2A, 2B, 2C), respec- in the isolated corpus cavernosum penis (CCP) of tively1,2 (Table 1). Fenfluramin (5-HT-releasing rabbits.5 Therefore, it has been suggested that 5-HT agent) induced penile erection in rats through the agonists may peripherally inhibit penile erection central nervous system.3 On the other hand, the and contractile response to 5-HT in vitro, and may play an opposite role in the penile erectile response 5 to 5-HT via central 5-HT receptors in vivo. 5-HT4 agonists cause relaxation, which is not suppressed Correspondence: Dr M Tuncer, Department of Pharmacol- by selective 5-HT antagonists in human CCPs.6 The ogy, Hacettepe University, Faculty of Medicine, Shhiye, 4 Ankara, Turkey. existence of dual contractile and relaxing responses E-mail: [email protected] to 5-HT via 5-HT1, 5-HT2, and 5-HT4 receptors, Received 16 December 2005; revised 4 January 2006; respectively, in the CCP of rabbits has also been 7 accepted 8 January 2006; published online 9 March 2006 reported. Investigation of serotonin receptors in the isolated penile bulb of rats G Soydan et al 511 Table 1 Serotonin receptor subtypes2 Receptor type Principle transduction Selective agonists Selective antagonists a 5-HT1A Gi/0 8-OH-DPAT NAN-190 a 5-HT1B/D Gi/0 Sumatriptan GR55562 5-HT1E Gi/0 —— 5-HT1F Gi/0 LY334370 — a 5-HT2A Gq/11 a-Me-5-HT Ketanserin 5-HT2B Gq/11 a-Me-5-HT RS127445 5-HT2C/1C Gq/11 a-Me-5-HT SB242084 a þ 5-HT3 Ionotropic (Na channel) 2-Methyl-5-HT Ondansetron a 5-HT4 Gs Prucalopride GR113808 Cisapride (nonselective) GR125487 Metoclopramide (nonselective) 5-ht5A Gi/G0 —— 5-ht5B None identified — — 5-HT6 Gs — SB271046 5-HT7 Gs — SB656104 a Subtypes which were investigated in this study. Penile erection is caused by the relaxation of the Rats (male, 250–300 g) were killed by exsanguina- CCP. The penile bulb, which is the proximal part tion under general anesthesia with urethane (1.25 g/ of the corpus spongiosum, contains two layers of kg, i.p.). Penile bulbs were isolated and mounted smooth muscle, the parenchyma layer consisting of under a resting tension of 1 g in a 30 ml organ bath spongy cells, and the outer layer.8 These structures filled with Krebs-Henseleit solution at 371C and of the penile bulb have been suggested to play a role aerated with a 95% O2 and 5% CO2 gas mixture. The in erection. An important role for the penile bulb in composition of the Krebs-Henseleit solution was initiating the erection of the glans penis has been (in mM): NaCl, 118; KCl, 4.7; MgSO4, 1.2; CaCl2, 2.5; proposed because the onset of the hemodynamic KH2PO4, 1.2; NaHCO3, 25; glucose, 11.1. Isometric changes was found to be more rapid in the penile changes in tension were recorded with an isometric bulb than in the corpus cavernosum.9 force displacement transducer (FT03C) connected to It has not been shown whether or not 5-HT and its a polygraph (Grass Model 7B). agonists participate in contractile and/or relaxant responses in the penile bulb. The aim of this study was to determine the effects of 5-HT and which Experimental protocol subtypes of the 5-HT receptor participate in 5-HT- and The contractile responses to 5-HT, sumatriptan, and its agonists-induced responses in the penile bulb of 8-OH-DPAT, and the relaxation response to the 5-HT4 agonist prucalopride, in precontracted tissues rats. In this study, we used the selective 5-HT receptor À5 (10 M phenylephrine; 60–80% of maximum subtype antagonists NAN-190 (5-HT1A), GR55562 contraction) were evaluated. The concentration– (5-HT1B/D), ketanserin (5-HT2A), ondansetron (5-HT3), response curve to each agonist was made at the and GR125487 (5-HT4) in addition to the adrenergic end of the equilibration period of 1 h. All antago- antagonists prazosin (a1) and propranolol (b)to determine their antagonistic effects on 5-HT nists were present in the organ bath 20 min. before responses. Furthermore, we tested the serotonergic the agonist was administered. agonists sumatriptan (5-HT1B/1D) and 8-OH-DPAT (5-HT1A) for further clarification of contractile recep- tor subtypes and prucalopride- (R093877, 5-HT4) Data analysis and statistics induced relaxation response in the penile bulb of rats. Contractions and relaxations were expressed as Additionally, cisapride, a 5-HT4 agonist, and percentages of the 5-HT-induced maximum re- À5 metoclopramide, with both 5-HT3 antagonistic and sponse and phenylephrine (10 M)-induced sub- 5-HT4 agonistic effects, were used to further test maximal contraction, respectively. The maximum the existence of 5-HT4 receptors. response elicited by the agonist (Emax) and the concentration required to achieve half-maximum contraction and relaxation (EC50) were obtained Materials and methods from individual concentration–response curves. EC50 values were given as pD2 values, which are Tissue preparation defined as the negative logarithm of EC50 The procedures described were approved by the (pD2 ¼Àlog EC50). Animal Experimentation Ethics Committee of All values were expressed as the mean7standard Hacettepe University. error of the mean (s.e.m.). Statistical significance International Journal of Impotence Research Investigation of serotonin receptors in the isolated penile bulb of rats G Soydan et al 512 was determined by paired Student’s t-test for analysis of variance (ANOVA) with repeated mea- surements followed by Bonferroni’s test. P-values o0.05 were considered to be significant. Drugs used The study protocol included the following drugs: 8-OH-DPAT (Sigma, St Louis, MO, USA), Cisapride monohydrate (Mustafa Nevzat I˙lac Sanayi AS, I˙stanbul, Turkey), GR 113808 maleate (Glaxo Well- come, Stevenage, Herts, UK), GR 125487 sulphamate (Glaxo Wellcome), GR55562 di-p-toluenesulphonate À9 À7 (Glaxo Wellcome), guanethidine monosulphate Figure 1 Effect of ketanserin (5-HT2A antagonist, 10 –10 M) (Ciba-Geigy, Basel, Switzerland), ketanserin (Janssen on the concentration–response curves of 5-HT in the penile bulb of rats (n ¼ 6). *Po0.05 vs control. Pharmaceutica, Beerse, Belgium), metoclopramide hydrochloride (Sigma), NAN-190 (Sigma), NG-nitro- L-arginine (L-NOARG, Sigma), ondansetron (GR 38032, Glaxo Wellcome), phenylephrine hydro- chloride (Sigma), prazosin hydrochloride (Sigma), propranolol hydrochloride (Sigma), prucalopride (R093877, Janssen Pharmaceutica), serotonin creati- nine sulphate (Sigma), and sumatriptan succinate (GR 43175, Glaxo Wellcome).
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