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(M-CPP) Induced Intracavernous Pressure Responses in Anaesthetized Rats

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(M-CPP) Induced Intracavernous Pressure Responses in Anaesthetized Rats International Journal of Impotence Research (2002) 14, 287–294 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir Metachlorophenylpiperazine (m-CPP) induced intracavernous pressure responses in anaesthetized rats ES Hayes1* and PG Adaikan1 1Department of Obstetrics and Gynaecology, the National University of Singapore, Singapore Here we have recorded the effects of metachlorophenylpiperazine (m-CPP) on intracavernous pressure (ICP) in anesthetized rats pretreated with various pharmacological agents in an attempt to determine the mechanism and relevance of the m-CPP induced ICP response to other models of erection. m-CPP elicited consistent and significantly greater increases in ICP (71.5 Æ 6.6 mmHg) compared with the mixed 5-HT2a=2c agonists trifluoromethylphenylpiperazine (3.4 Æ 1.3 mmHg) and quipazine (10.9 Æ 1.8 mmHg). Blockade of 5-HT2a receptors with ketanserin failed to unmask any stimulatory effect of quipazine (7.2 Æ 1.0 mmHg). m-CPP induced ICP responses (71 Æ 7.0 mmHg) were unaffected in the presence of mianserin (63 Æ 5 mmHg) and ketanserin (51 Æ 12 mmHg). Spiperone significantly reduced the m-CPP induced increase in ICP (8.0 Æ 1.0 mmHg). Naloxone, yohimbine and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) failed to elicit increases in ICP on their own. All three drugs significantly reduced the latency to the first m-CPP induced ICP response compared to saline. Yohimbine increased the duration of m- CPP induced ICP responses whereas 8-OHDPAT increased the mean number of m-CPP induced ICP responses compared to saline. The effects of m-CPP on ICP in anesthetized rats may not be mediated by 5-HT2c receptors and appears to be similar to erection in copula, but not erection elicited by other drugs or penile sheath retraction. International Journal of Impotence Research (2002) 14, 287–294. doi:10.1038=sj.ijir.3900888 Keywords: intracavernous pressure; cavernous nerve; erection; serotonin; agonist; antagonist Introduction actions at 5-HT1b receptors within the spinal cord. However, the receptor that mediates the effects of m- CPP on CN and ICP responses in rats remains Metachlorophenylpiperazine (m-CPP) is a non-se- undetermined. lective serotonin (5-HT) agonist that induces erec- Previously we demonstrated that the novel 5- tion in conscious rats in a manner that is dependent HT2c agonist, RSD992, also elicits erection in upon functional supraspinal 5-HT receptors.1,2 2c conscious rats in a manner dependent upon 5-HT2c Other non-selective 5-HT2a=2c agonists also induce receptors.6 However, unlike m-CPP RSD992 failed to erection in conscious rats when 5-HT2a receptors are induce CN and ICP responses in anesthetized rats.7 masked by pretreatment with selective 5-HT 2a Furthermore, the selective 5-HT1a and 5-HT1b 3,4 5 antagonists. Steers and de Groat found that m- agonists 8-OHDPAT and CGS12066B enhanced CPP also elicits firing of the cavernous nerve (CN) in and inhibited, respectively the m-CPP induced CN anesthetized rats with concomitant increases in and ICP responses.7 Others have demonstrated that intracavernous pressure (ICP). The same authors 8-OHDPAT and CGS12066B inhibit and have no showed that the effects of m-CPP on the CN and ICP effect on m-CPP induced erections, respectively, in in anesthetized rats were blocked by the non- conscious rats.3 Therefore contradictory evidence selective 5-HT antagonist metergoline, enhanced exists for the effects of m-CPP on erection in rather than inhibited by spinal transection and conscious rats versus its effects on CN and ICP abolished by pelvic nerve section. Based on the responses in anesthetized rats. results of those experiments the authors suggested ICP responses resulting from direct nerve stimu- that the m-CPP induced responses were due to lation and drug administration are often used as an index of penile erection.8,9 Therefore, the following studies were undertaken in an effort to determine if 5-HT receptors are responsible for the effects of m- *Correspondence: ES Hayes, University of Washington, 2c RPRC, 3000 Western Avenue, Seattle, WA 98121, USA. CPP on ICP responses in anesthetized rats, deter- E-mail: [email protected] mine the effects that drugs known to modulate Received 10 September 2001; accepted 25 April 2002 erection and=or sexual behavior in conscious rats m-CPP induced intracavernous pressure responses ES Hayes and PG Adaikan 288 have on m-CPP induced CN and ICP responses in ICP responses was determined by counting the anesthetized rats and, discuss the relevance of the number of obvious and rapid increases in ICP to m-CPP induced ICP response in relation to other pressures equivalent to or above those attained models of erection. during pre-drug nerve stimulation. Latency to the onset of the first m-CPP induced ICP response was calculated from the start of drug administration to Materials and methods the first rapid rise in ICP. The duration of m-CPP induced ICP responses were calculated as the time from the onset of the first response to the time at The National University of Singapore animal use which the ICP returned to pre-drug levels. and care committee approved all experimental The first experiment examined the effects of the procedures. Drugs were obtained from Sigma non-selective 5-HT agonists m-CPP, trifluoromethyl- Chemical Co (m-CPP, naloxone, quipazine, yohim- phenylpiperazine (TFMPP) and quipazine on CN bine) or Research Biochemicals Inc. (8-OHDPAT, and ICP responses in anesthetized rats. The second ketanserin, mianserin, spiperone, trifluoromethyl- experiment examined the effects of a series of 5- phenylpiperazine) and prepared according to HT2a=2c antagonists on the m-CPP induced CN and manufacturers instructions. ICP responses in anesthetized rats. The third Male Sprague-Dawley (SD) rats were anesthetized experiment examined the effects of drugs known to with sodium pentobarbitone (65 mg=kg; i.p.) and modulate erection and sexual behavior in conscious prepared for drug administration and blood pressure rats on the m-CPP induced CN and ICP responses in recording through cannulation of the external anesthetized rats. Table 1 provides a description of jugular vein and internal carotid artery, respec- the pharmacological and binding profiles of the test tively. The trachea was cannulated for assisted drugs at selected receptors. respiration at a volume of 10 ml=kg and a rate of Data are expressed as the mean Æ standard error of 60 breaths=min. the mean (s.e.m.) for n ¼ 5 animals per test group. A median incision was made in the lower pelvic Differences between drug and saline treated groups region and the cavernous nerve was isolated from for m-CPP induced ICP variables were determined the prostatic pelvic plexus by blunt dissection and using ANOVA followed by Dunnett’s test for multi- suspended on platinum hook electrodes. The pelvic ple comparisons and P < 0.05 was taken as a cavity was filled with warm mineral oil to prevent significant result in all cases. dehydration. Blunt dissection of the ischiocaver- nous musculature was used to isolate the right penile crus. ICP responses elicited by direct stimu- Results lation of the cavernous nerve and drug administra- tion were recorded on computer using polyethylene Agonist induced intracavernous pressure responses tubing connected to a 27-gauge needle that was ICP responses resulting from direct stimulation of placed into the crus. the CN (20 Hz, 2.5 V, 1 ms pulse width) were similar Experiments were initiated by stimulation of the cavernous nerve and recording of ICP to determine viability of nerve responses. Fifteen minutes after Table 1 Selected pharmacological and binding profiles of the initial nerve stimulation saline or test drugs were drugs used in the present study injected and CN and ICP responses were recorded Drug Receptor Agonist (pEC50) Antagonist (pKB or pA2) for a further 15 min. After administration of saline or test compounds m-CPP was injected and CN and m-CPP 5-HT1b 6.5 — ICP responses were monitored for an additional 5-HT2c 6.9 — TFMPP 5-HT1b 6.9 — 15 min. To end the experiments the CN was again 5-HT2c 6.8 — stimulated and ICP recorded to confirm responsive- Quipazine 5-HT1b — 6.2 ness to direct stimulation. All drugs were prepared 5-HT2c 6.2 — fresh in saline and injected intravenously in a Ketanserin 5-HT2a — 9.3 5-HT — 6.5 volume of 1.0 ml=kg. 2c Mianserin 5-HT2a — 8.0 Arterial blood pressure (BP) and ICP were 5-HT2c — 8.7 1 recorded on a MacIntosh computer using Ma- Spiperone 5-HT2a — 9.1 1 1 cLab analog to digital conversion and Chart 5-HT2c — 6.1 software. The CN was stimulated with square-wave 8-OHDPAT 5-HT1a 8.2 — 1 5-HT1b 4.9 — pulses delivered from the MacLab output at 20 Hz, Yohimbine a2 — 8.5 2.5 V and 1 ms pulse width until a plateau in ICP 5-HT2b — 7.3 was observed (30 – 60 s). Changes in ICP were Naloxone OP3 — 9.1 calculated as the difference between the maximal Data are expressed as pEC50 values (agonists) or, pKB or pA2 response and the mean ICP over 2 min prior to direct values (antagonists) as adopted from Hoyer et al,10 Bonhaus stimulation or drug administration. The number of et al,14 Bigoni et al41 and Paiva et al.42 International Journal of Impotence Research m-CPP induced intracavernous pressure responses ES Hayes and PG Adaikan 289 amongst treatment groups and ranged from number, latency and duration of ICP responses 27 Æ 4 mmHg to 41 Æ 10 mmHg (P > 0.30). Prelimin- between treatment groups.
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