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From the Departments of * Urology and
Biochemistry, Boston University School of
Medicine, Boston, Massachusetts; and the
Institute of Cardiovascular Research II, Bayer
AG Pharmaceutical Business Group, Wuppertal, Germany.
| Correspondence to: Abdulmaged M. Traish, PhD, Department of Urology, Boston University School of Medicine, 700 Albany St W607, Boston, MA 02118 (e-mail: atraish{at}bu.edu ). |
| Received for publication August 8, 2001; accepted for publication November 13, 2001. |
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Abstract |
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Key words: Pelvic nerve-mediated erection, intracavernosal pressure
Intracellular cGMP concentrations are regulated by the action of guanylyl cyclases and cGMP-specific phosphodiesterases (PDEs) (Boolell et al, 1996). Soluble guanylyl cyclase, when activated by NO, catalyzes the formation of cGMP from guanosine triphosphate (GTP), whereas cGMP-specific phosphodiesterases catalyze the hydrolysis of cGMP to GMP. Termination of signal transduction by hydrolysis of cGMP depends on the specificity of PDE isozymes and the expression of the specific enzyme in the target tissues (Boolell et al, 1996). To date, 11 PDE isozymes have been characterized, each with different cAMP or cGMP specificities (Fawcett et al, 2000). Several PDE isoforms have been identified in extracts of whole penile human tissue (Kuthe et al, 2001). Activity profiles obtained from whole penile tissue extracts, after ion exchange chromatography, demonstrated that PDE type 5 (PDE 5) is the predominant PDE isoform, hydrolyzing cGMP at low substrate concentrations (Km = 0.75-2 µM) (Boolell et al, 1996; Taher et al, 1997; Moreland et al, 1999).
Vardenafil hydrochloride is a new purinone-type PDE 5 inhibitor. Oral administration of vardenafil in conscious rabbits caused dose-dependent penile erection (Bischoff et al, 2001). Recent clinical studies have demonstrated that use of vardenafil increased penile rigidity and tumescence in patients with erectile dysfunction (Klotz et al, 2001; Stark et al, 2001). Vardenafil is currently undergoing safety and efficacy clinical trials for the treatment of male erectile dysfunction (Klotz et al, 2001; Porst et al, 2001; Stark et al, 2001). Vardenafil and sildenafil are potent and selective PDE 5 inhibitors with approximate 50% inhibitory (IC50) values of 0.7 and 3.5 nM, respectively. Biochemical studies from our laboratory, using human penile corpus cavernosum smooth muscle cells, have shown that the equilibrium inhibition constants (Ki) for vardenafil and sildenafil were 4.5 and 14.7 nM, respectively (Kim et al, 2001). On the basis of the biochemical and pharmacological differences, it is expected that these 2 agents, at a given dose, would have different efficacy in facilitating penile erection. The objective of this study was to compare the efficacy of vardenafil and sildenafil in facilitating penile erection in response to submaximal electrical field stimulation of the pelvic nerve in an anesthetized rabbit model.
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Methods |
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Pelvic Nerve Stimulation
A 4-cm lower midline abdominal incision was fashioned to expose the pelvic
nerve, which can be identified on the posterolateral aspect of the rectum.
Bladder contents were aspirated through the bladder wall with an 18-gauge
needle and a 50-mL syringe. Under direct vision, a bipolar platinum wire
electrode was hooked onto the pelvic nerve without cutting the nerve.
Unilateral PNS was accomplished with a Grass S9 stimulator set at normal
polarity and repeat mode to generate a 30-second train of square waves with a
10-V pulse amplitude, an 0.8-ms pulse width, and suboptimal frequencies (2.5
or 6 Hz). The interval between stimulations was 3-5 minutes, which did not
produce nerve exhaustion until after 30 minutes in the control group, as
determined by peak amplitude of repeated stimulations.
Drugs
Vardenafil HCl was a generous gift from Dr Erwin Bischoff (Bayer AG,
Wuppertal, Germany). Sildenafil citrate was provided by Dr Farid Saad,
Jenapharm, Germany. All other drugs and reagents were obtained from
commercially available sources.
Intracavernosal Pressure Recording
The skin overlying the penis was incised, and the corpora cavernosa were
exposed at the root of the penis. A 23-gauge needle, filled with 4 U/mL
heparin solution and connected to PE-50 tubing, was inserted into the left
corpus cavernosum for pressure recording. All pressure measurements were
recorded by means of Grass PT-300 pressure transducers connected to PI-1-ACDC
signal conditioner modules and a Grass 7400 physiological recorder
(Astro-Med). The change in intracavernosal pressure (ICP) was monitored with
each drug dose, and all pressure responses were allowed to return to baseline
before the subsequent dose.
Drug Administration
Vardenafil and sildenafil were dissolved in 0.9% NaCl and were administered
through an indwelling 23-gauge butterfly needle into the ear vein in a volume
of 0.5 mL/kg. For intracavernosal (IC) drug administration, a 30-gauge needle
filled with 4 U/mL heparin solution and connected to PE-10 tubing was inserted
into the right corpus cavernosum. IC drugs were administered in a volume of
0.1 mL.
Data Analysis
Physiological parameters (ICP and response duration) were measured at
baseline and after PNS with IV or IC administration of vardenafil and
sildenafil. Changes in ICP were expressed as a fractional change in corporal
pressure in relation to systemic arterial pressure (SAP) (ie, ICP:SAP).
Comparisons between the effects of drugs on response duration and fractional
ICP over time were carried out using analysis of variance and Student's
t test.
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Results |
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Effects of IC Administration of Vardenafil or Sildenafil on Penile
ICP
On the basis of the results described in
Figure 1, we then tested the
effects of direct IC administration of increasing doses (1, 3, 10, and 30
µg/kg) of vardenafil or sildenafil on penile ICP without pelvic nerve
stimulation (PNS). As shown in Figure
3, both vardenafil and sildenafil caused significant
dose-dependent increases in ICP without PNS. However, at equivalent doses of
1-10 µg/kg, vardenafil was significantly more effective in increasing ICP
than was sildenafil. We also investigated the effects of IC administration of
vardenafil and sildenafil on ICP in response to suboptimal stimulation (2.5
Hz) of the pelvic nerve. IC administration of 10 µg/kg of vardenafil or
sildenafil followed by PNS caused a significant increase in ICP by both
agents. A comparison of erectile response induced by a combination of PNS and
IC vardenafil or sildenafil (10 µg/kg) showed that vardenafil was more
potent than sildenafil in increasing ICP
(Figure 4).
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Effects of Vardenafil or Sildenafil on the Duration of ICP and
Systemic Blood Pressure
We investigated the effects of vardenafil and sildenafil, administered
intravenously at a dose of 10 µg/kg with suboptimal nerve stimulation at
2.5 Hz or at 30 µg/kg with nerve stimulation at 6 Hz, on the response
duration (the time between maximal rise in ICP and its return to baseline). As
shown in Figure 5, both agents
enhanced response duration relative to control (93 ± 3 seconds). The
duration of response was consistently greater with vardenafil (169 ± 23
seconds) than with sildenafil (137 ± 31 seconds) at 10 µg/kg but was
similar at the 30-µg/kg dose. IC administration of these drugs (1-30
µg/kg) significantly enhanced response durations (ca 12-104 minutes) in a
dose-dependent manner and lasted more than 5 times that of IV drug
administration (ca 2-3 minutes). IC vardenafil consistently enhanced response
duration to a greater extent than sildenafil, reaching or approaching
significance at all doses tested (Figure
5). Further, we noted that IV administration of either vardenafil
or sildenafil reduced the mean SAP (70 ± 0.6 mm Hg) by 8-13 and 9-11 mm
Hg, respectively.
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Discussion |
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In our animal model, the data indicate that vardenafil is approximately 3 times more effective than sildenafil in facilitating penile erection, irrespective of the route of administration or PNS. This increased efficacy may be attributed to the differences in the intrinsic binding properties of these 2 inhibitors to PDE 5 (ie, association and dissociation rates of the inhibitors from the PDE enzyme). This is in agreement with our previous work in cultured human penile smooth muscle cells, in which we showed differences in the inhibition constants between vardenafil (Ki = 4.5 nM) and sildenafil (Ki = 14.7 nM) (Kim et al, 2001). The observations from the biochemical and in vivo studies (Bischoff et al, 2001; Kim et al, 2001) suggest that vardenafil is a more effective inhibitor of PDE 5 than sildenafil.
It has been generally accepted that sildenafil has no direct effect on cavernosal smooth muscle relaxation and that sildenafil does not cause penile erection in the absence of sexual stimulation (Noto et al, 2000). Recently, McAuley et al (2001) reported that sildenafil caused dose-related increases in ICP after IC injection in rabbits (0.3-1.3 mg/3.5-4 kg). Similar observations were reported in cats (0.3-30 µg/3.5-4.4 kg) (Doherty et al, 2001). In this study, we also observed that vardenafil and sildenafil (1-30 µg/kg) caused dose-related increases in ICP after IC injection without PNS. Other PDE inhibitors (PDE 3: milrinone; PDE 4: rolipram; and PDE 5: zaprinast) also showed increases in ICP after IC injection in cats (Bivalacqua et al, 1999). Until now, few studies have investigated the effect of IC injections of specific PDE inhibitors on penile erection, and their mechanisms of action are not fully understood.
Since it is believed that vardenafil and sildenafil enhance penile erectile function only subsequent to sexual stimulation, which is preceded by release of NO from the nerves, it is unclear why these PDE 5 inhibitors (vardenafil and sildenafil) increased ICP without stimulation of the pelvic nerve. It is possible that IC administration of these drugs may activate other pathways independent of nerve stimulation. One possibility is that endothelial NO synthase may increase NO production in response to mechanical stimuli as a result of drug injection. Endothelium-derived NO could then activate guanylyl cyclase to stimulate the production of cGMP. Since vardenafil and sildenafil enhance trabecular smooth muscle relaxation by inhibition of cGMP hydrolysis, IC administration of these agents may result in penile tumescence.
Alternatively, these agents may be acting via a noncyclic GMP-mediated
mechanism when administered intracavernosally. Administration of high doses of
sildenafil directly into the rabbit erectile tissue without stimulation of the
pelvic nerve has been shown to cause penile erection in the presence of the NO
synthase inhibitor N(
)-L-arginine methyl ester (L-NAME;
McAuley et al, 2001).
Furthermore, the guanylate cyclase inhibitor
1H-[1,2,4]oxadiazolo[4,3-a]quinoxacline-1-one (ODQ) only partially attenuated
sildenafil-induced relaxation in organ bath preparations of penile cavernosal
tissue (McAuley et al, 2001). These mechanisms, which are apparently independent of the NO/cGMP pathway,
remain to be further elucidated.
In summary, in an anesthetized animal model, vardenafil appears to be a more efficacious PDE 5 inhibitor than sildenafil in facilitating penile erection. The increases in ICPs occurred more quickly, were of larger magnitude, and were sustained for longer durations for vardenafil than for sildenafil. The effects of IC vardenafil or sildenafil on penile erection suggest that IC injection of PDE 5 inhibitors may be useful in treating some patients who do not respond to oral administration of these drugs. On the basis of the available biochemical data from previous studies and the physiological responses from this study, further clinical evaluation of vardenafil vs sildenafil as a treatment for erectile dysfunction is warranted.
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Footnotes |
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References |
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Andersson KE, Wagner G. Physiology of penile erection.
Physiol Rev.
1995; 75:
191
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Bischoff E, Niewoehner N, Haning H, Es Sayed M, Schenke T, Schlemmer H. The oral efficacy of vardenafil hydrochloride for inducing penile erection in a conscious rabbit model. J Urol. 2001; 165: 1316 -1318.[Medline]
Bivalacqua TJ, Champion HC, Rajasekaran M, Sikka SC, Kadowitz PJ, Doherty PC, Hellstrom WJ. Potentiation of erectile response and cAMP accumulation by combination of prostaglandin E1 and rolipram, a selective inhibitor of the type 4 phosphodiesterase (PDE4). J Urol. 1999;162: 1848 -1855.[Medline]
Boolell M, Allen MJ, Ballard SA, Gepi Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C. Sildenafil. An orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res. 1996; 8: 47 -52.[Medline]
Chung AT, Strauss JD, Steers WD, Murphy RA. cGMP mediates corpus cavernosum smooth muscle relaxation with altered cross-bridge function. Life Sci. 1998;63: 185 -194.[Medline]
Doherty PC, Bivalacqua TJ, Champion HC, Kadowiz PJ, Greenwood-Van Meerveld B, Berzetei-Gurske I, Hellstrom WJ. Direct effects of selective type 5 phosphodiesterase inhibitors alone or with other vasodilators on the erectile response in cats. J Urol. 2001; 165: 1004 -1009.[Medline]
Fawcett L, Baxendale R, Stacey P, et al. Molecular cloning and
characterization of a distinct human phosphodiesterase gene family: PDE11A.
Proc Natl Acad Sci USA.
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Kim NN, Huang YH, Goldstein I, Bischoff E, Traish AM. Inhibition of cyclic GMP hydrolysis in human corpus cavernosum smooth muscle cells by vardenafil, a novel, selective phosphodiesterase type 5 inhibitor. Life Sci. 2001;69: 2249 -2256.[Medline]
Klotz T, Sachse R, Heidrich A, Jockenhovel F, Rohde G, Wensing G, Horstmann R, Englemann R. Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J Urol. 2001; 19: 32 -39.[Medline]
Kuthe A, Wiedenroth A, Mager H, Uckert S, Forssmann W, Stief G, Jonas U. Expression of different phosphodiesterase genes in human cavernous smooth muscle. J Urol. 2001; 165: 280 -283.[Medline]
McAuley IW, Kim NN, Min K, Goldstein I, Traish AM. Intracavernosal sildenafil facilitates penile erection independent of the nitric oxide pathways. J Androl. 2001; 22: 623 -628.[Abstract]
Moreland RB, Goldstein I, Kim NN, Traish A. Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor. Trends Endocrinol Metab. 1999;10: 97 -104.[Medline]
Noto T, Inoue H, Ikeo T, Kikkawa K. Potentiation of penile
tumescence by T-1032, a new potent and specific phosphodiesterase type V
inhibitor, in dogs. J Pharmacol Exp Ther.
2000; 294:
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Porst H, Rosen R, Padma-Nathan H, Goldstein I, Giuliano F, Ulbrich E, Bandel T. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impot Res. 2001;13: 192 -199.[Medline]
Stark S, Sachse R, Liedl T, Hensen J, Rohde G, Wensing G, Horstmann R, Schrott KM. Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose. Eur Urol. 2001;40: 181 -190.[Medline]
Stief CG, Noack T, Andersson KE. Signal transduction in cavernous smooth muscle. World J Urol. 1997; 15: 27 -31.[Medline]
Taher A, Mayer M, Stief CG, Jonas U, Forssmann WG. Cyclic nucleotide phosphodiesterase in human cavernous smooth muscle. World J Urol. 1997; 15: 32 -35.[Medline]
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.05) than responses in the presence of
vehicle (control). Data are mean plus or minus standard error of the mean.
*P 
