International Journal of Impotence Research (2003) 15, 287–289 & 2003 Nature Publishing Group All rights reserved 0955-9930/03 $25.00 www.nature.com/ijir Effects of moxonidine and metoprolol in penile circulation in hypertensive men with erectile dysfunction: results of a pilot study

J Piha1* and R Kaaja2

1Mehilainen Co, Erectile Dysfunction Clinic, Turku, Finland; and 2Helsinki University Hospital, Helsinki, Finland

Centrally acting (moxonidine) and peripherally acting (metoprolol) agents might have different actions upon penile circulation in hypertensive men with erectile dysfunction. A total of 11 nonsmoking, hypertensive but otherwise healthy men with erectile dysfunction were studied after 8 weeks on moxonidine monotherapy (0.4 mg per day, increased to 0.6 mg if needed) and then after 8 weeks of metoprolol monotherapy (100 mg per day, increased to 200 mg if needed) in a crossover design. At the end of each treatment phase, the subjects were asked about their subjective erectile capacity (nocturnal and coital erections), and resting and stimulated (after intracavernosal injection of a mixture of alprostadil and ) penile deep artery diameters and systolic peak velocities were measured by color Doppler ultrasonography. There were no significant differences in after either therapy. The change from earlier antihypertensive therapy, moxonidine produced significant subjective amelioration of sexual dysfunction in 9/11 of the men (Po0.001), whereas 9/11 returned to impaired dysfunction after crossover to metoprolol treatment. Resting and stimulated deep penile diameters and peak systolic velocities were higher after moxonidine treatment compared with metoprolol (diameters: Po0.004, Po0.0001; velocities: Po0.008, Po0.038). The centrally acting sympatholytic agent moxonidine seems to improve erectile function both subjectively and objectively and has a better effect on penile circulation compared with the peripherally acting sympatholytic agent metoprolol. International Journal of Impotence Research (2003) 15, 287–289. doi:10.1038/sj.ijir.3901007

Keywords: hypertension; sympathetic nervous system; sex; erectile dysfunction

Introduction Methods

Problems with erectile function have been a concern In all, 12 nonsmoking hypertensive men with in the treatment of hypertension and may influence erectile dysfunction, otherwise healthy, participated the choice of treatment regimens and decisions to in the study, which was approved by the Ethics discontinue drugs. Beta-blockers have been reported Committee of the University of Turku. All patients to be responsible for erectile dysfunction.1–3 There signed an informed consent document before enter- is no data on moxonidine in this respect. Centrally ing the study. One patient was dropped from the acting (moxonidine) and peripherally acting (meto- study during the first treatment phase because of prolol) sympatholytic agents might have different insufficient blood pressure (BP) control (BP4170/ actions upon penile circulation. We compared the 110 mmHg). effects of these two sympatholytic agents on erectile At the beginning of the study, the participants function and penile circulation at rest and after fulfilled International Index of Erectile Function stimulation in hypertensive men with erectile (IIEF-5) criteria. Serum testosterone was assayed in dysfunction order to disclose significant hypogonadism. At the end of the treatment phases, the subjects were asked about their subjective erectile capacity (nocturnal and coital erections). After a short washout period (1–3 days) all patients started moxonidine at 0.2+0.2 mg daily *Correspondence: J Piha, MD, PhD, Mehilainen Co, and after 3 weeks the dose was increased to Kauppiaskatu 8, FIN-20100 Turku, Finland. 0.4+0.2 mg if BP was 4160/100 mmHg. E-mail: [email protected] After 8 weeks of treatment, the patients were Accepted 2 February 2003 investigated according to the following schedule: Sympatholytic agents and erectile dysfunction J Piha and R Kaaja 288 penile deep artery diameter (at two sites, mean of statistically highly significant when compared with four measurements) and peak systolic velocity (PSV) moxonidine treatment (Po0.0002, w2 test) (Table 1). were measured with Acuson Sequoia color Doppler Resting and stimulated deep penile diameters equipment with an 8 MHz linear probe. Thereafter, were higher after moxonidine therapy compared to penile circulation was stimulated with an intraca- the diameters after metoprolol therapy (Po0.004 vernosal injection of a mixture of alprostadil (10 mg) and Po0.001, respectively). Resting and stimulated and phentolamine (0.1 mg) and the stimulated PSV deep penile artery velocities were also higher after was measured during the next 20 min. The stimu- moxonidine therapy compared to metoprolol (0.008 lated inner diameter of the deep penile arteries was and Po0.038, respectively) (Table 2). There was no measured 10–15 min after stimulation. correlation between BP and resting/stimulated deep After moxonidine therapy, the patients were penile artery diameters or velocities (data not crossed over to metoprolol (100 mg o.d.) for 3 weeks shown). and thereafter the dose of metoprolol was increased to 100 mg  2 if needed. After 5 weeks, the patients were investigated according to the same protocol as Discussion described above. The sitting BP was measured after 15 min rest, once a week during the study. Mean values of the Problems with erectile function can rise a concern in last three measurements are reported. the treatment of hypertension and may influence the Student’s paired t-test for parametric data and the choice of treatment regimens and decisions to w2 test for categorial data were used. Linear regres- discontinue drugs. We compared the effects of two sion analysis was used to investigate the relation sympatholytic agents in hypertensive men with between the BP taken just before penile circulation erectile dysfunction using color Doppler ultrasound assessment and deep penile artery diameters and method. Moxonidine seemed to produce significant velocities. Po0.05 was considered statistically sig- subjective improvement in sexual function in the nificant. majority of men (9/11), whereas metoprolol resulted in a return to reappraisal of erectile dysfunction. These subjective changes were accompanied by significantly higher resting and stimulated deep Results penile diameters and PSV values after moxonidine therapy compared to metoprolol. This pilot study was a open crossover study. For The mean (7s.d.) IIEF-5 score was 15.8 (78.5). Four safety and ethical reasons the washout period before of our patients had mild erectile dysfunction with either treatment were minimal. On the other hand, IIEF-5 score Z21 and the rest of our patients had the treatment phases (8 weeks) were long enough to moderate-to-severe erectile dysfunction (IIEF-5 show the pure effect of both the drugs on penile o21). The mean serum testosterone concentration circulation. was 13.1 (73.3) nmol/l and the mean age of the The use of color Doppler ultrasonography in patients was 50.5 years (range 41–58 years). assessing the penile circulatory parameters includes Out of 11 patients, seven were on ACE inhibitor some problems. The method is strongly dependent therapy when entering the study, but only two of them had monotherapy. The other five men took an ACE inhibitor in combination with a beta-blocker or Table 1 Subjective changes in nocturnal and/or coital erections a diuretic. One patient was on beta-blocker, after moxonidine and metoprolol treatment two on calcium-blocker and one was without any Patient no. IIEF Moxonidine* Metoprolol drug treatment. The dose antihypertensive was increased in nine 123+ F of the 11 subjects during moxonidine therapy and in 218+ F eight of the 11 subjects during metoprolol treatment. 322+ F Mean BP (7s.d.) during moxonidine therapy was 41+F F 163.8 (716.0)/96.2 (76.3) mmHg and during meto- 519+ 7 7 6400 prolol therapy, 157.8 ( 19.2)/93.6 ( 11.1) mmHg 78+F (P ¼ NS). 821+ F Nine of the 11 men reported subjective improve- 911+ F 10 27 0 0 ment in their erectile function during moxonidine F therapy, whereas two men reported no difference. 11 20 + The overall improvement was highly significant a+Improvement, Àimpairment and 0=no change in nocturnal and/ (Po0.001) compared with previous therapy. On the or coital erections. other hand, 9/11 reported impaired erectile function *Po0.001, w2 test IIEF, International Index of Erectile Function, after metoprolol treatment and this difference was erectile dysfunction is mild if IIEF Z21.

International Journal of Impotence Research Sympatholytic agents and erectile dysfunction J Piha and R Kaaja 289 Table 2 Penile circulation after moxonidine and metoprolol treatment

Moxonidine Metoprolol (N=11) (N=11) P-value

Deep cavernosal artery, peak systolic velocity, rest (cm/s) 19.8 (5.8) 15.6 (5.2) 0.008 Deep cavernosal artery, peak, systolic velocity, stimulated (cm/s) 64.0 (32.4) 53.9 (26.4) 0.038 Deep cavernosal artery, resting diameter (mm) 0.54 (0.13) 0.43 (0.16) 0.004 Deep cavernosal artery, stimulated diameter (mm) 0.89 (0.14) 0.66 (0.14) 0.0001

Values expressed as mean (7s.d.) on the investigators experience and in any case served difference between the drugs may also be particularly the measurement of inner diameters of more because of the known vasoconstrictive effect of arteries is quite nonrepeatable. In addition, the metoprolol than supportive effect of moxonidine. nonerect parameters are sensitive to the patients More studies, for example, comparison between situation during the investigation. In the present ACE inhibitor and moxonidine, are needed to study, we tried to minimize these problems by using confirm the potential positive role of centrally experienced investigator (Dr J Piha) and by making acting sympatholytic agents on erectile dysfunction. the measurements at the same time of the day and in the same room. However, ultrasonography is surely the best noninvasive method to get information on penile circulation after pharmacostimulation. Acknowledgements Beta-blockers have been reported to be responsi- ble for erectile dysfunction in many,1–3 but not all studies.4 It has been suggested that this may be This work was supported by the Finnish Hyperten- because of the change in balance between alpha and sion Society and Solvay Pharma /Algol. beta sympathetic influence, resulting in insufficient antagonism of alpha-1 .5 Many of these studies are biased by relatively heterogeneous groups of patients having organic or psychogenic (or References both) predisposing factors in addition to drug- related causes. We tried to minimize these con- 1 Lundberg PO, Biriell C. ImpotenceFthe drug risk factor. Int J founding factors and investigated relatively young Impot Res 1993; 5: 237 – 239. healthy men having mainly hypertension as a risk 2 Keene LC, Davies PH. Drug related erectile dysfunction. Adverse Drug React Toxicol Rev 1999; 18: 5 – 24. factor of vascular disease. 3 Fogari R et al. Sexual activity in hypertensive men treated Caverno-occlusive and autonomic dysfunction with valsartan or carvedilol: a crossover study. Am J has been proposed as a new concept in the etiology Hypertension 2001; 14: 27 – 31. of erectile dysfunction in young men.6 Moxonidine 4 Grimm RH et al. Long-term effects on sexual function of five is a centrally acting sympatholytic antihypertensive antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hyperten- agent, which binds selectively and with high affinity sion Study (TOMHS). Hypertension 1997; 29: 8 – 14. to imidazoline (I1) receptors in the rostral ventro- 5 Meinhardt WP et al. The influence of medication on erectile lateral medulla and .7 It could centrally function. Int J Impot Res 1997; 9: 17 – 26. stabilize autonomic dysfunction (sympathetic over- 6 Kifor I et al. Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects activity) and let the parasympathetic tone override in the corpus cavernosum. J Urol 1997; 157: 1920 – 1925. the sympathetic tone, as needed for initiation of 7 Kayigil O, Ergen A. Caverno-occlusive and autonomic dys- erection. Besides this direct effect on sympathetic function: a new concept in young patients. Eur Urol 1998; 34: tone, in contrast to beta-blockers, moxonidine 124 – 127. induces vasodilatation with no change in cardiac 8 Ernsberger PR, Westbrooks KL, Christen MO, Scha¨fer SG. A second generation of centrally acting antihypertensive agents output and little change in rate and it increases 8,9 act on putative imidazoline-II receptors. J Cardiovasc Phar- insulin sensitivity in insulin-resistant subjects. macol 1992; 20: 1 – 10. Our pilot study shows that centrally acting 9 Ziegler D et al. Pharmacology of moxonidine, an I1-imidazo- sympatholytic agent (moxonidine) may have a line . J Cardiovasc Pharmacol 1996; 27 (Suppl 3): S26 – S37. positive effect on erectile function. It also seemed 10 Haenni A, Lithell H. Moxonidine improves insulin sensitivity to increase penile circulation compared to the effect in insulin resistant hypertensives. J Hypertension 1999; 17 of a beta-blocker (metoprolol). However, the ob- (Suppl 3): S29 – S35.

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