Original Research

International Journal of Impotence Research (2005) 17, 27–32. doi:10.1038/sj.ijir.3901269 Published online 28 October 2004

Phentolamine relaxes human corpus cavernosum by a nonadrenergic mechanism activating ATP-sensitive K+ channel

L F G Silva1, N R F Nascimento2, M C Fonteles2, G de Nucci3, M E Moraes1, P R L Vasconcelos1 and M O Moraes1

  1. 1Surgery Department, Federal University of Ceara, Fortaleza, Ceara, Brazil
  2. 2Veterinary College, State University of Ceara, Fortaleza, Ceara, Brazil
  3. 3Department of Pharmacology, UNICAMP, Campinas, Brazil

Correspondence: LF Silva, Surgery Department, Federal University of Ceara, Rua Dr Jose Lino 141 apto 1002, Fortaleza, Ceara 60.165-270, Brazil. E-mail: luciofl@secrel.com.br

Received 14 December 2003; Revised 7 September 2004; Accepted 9 September 2004; Published online 28 October 2004.

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Abstract

To investigate the pharmacodynamics of phentolamine in human corpus cavernosum (HCC) with special attention to the role of the K+ channels. Strips of HCC precontracted with nonadrenergic stimuli and kept in isometric organ bath immersed in a modified Krebs–Henseleit solution enriched with guanethidine and indomethacine were used in order to study the mechanism of the phentolamine-induced relaxation. Phentolamine caused relaxation (approximately50%) in HCC strips precontracted with K+ 40 mM. This effect was not blocked by tetrodotoxin (1 muM) (54.6plusminus4.6 vs 48.9plusminus6.4%) or (atropine (10 muM) (52.7plusminus6.5 vs 58.6plusminus5.6%). However, this relaxation was significantly attenuated by L-NAME (100 muM) (59.7plusminus5.8 vs 27.8plusminus7.1%; P<0.05; n=8) and ODQ (100 muM) (62.7plusminus5.1 vs 26.8plusminus3.9%; P<0.05; n=8). Charybdotoxin and apamin (KCa-channel blockers) did not affect the phentolamine relaxations (54.6plusminus4.6 vs 59.3plusminus5.2%). Glibenclamide (100 muM), an inhibitor of KATP-channel, caused a significant inhibition (56.7plusminus6.3 vs 11.3plusminus2.3%; P<0.05; n=8) of the phentolamine-induced relaxation. In addition, the association of glibenclamide and L-NAME almost abolished the phentolamine-mediated relaxation (54.6plusminus5.6 vs 5.7plusminus1.4%; P<0.05; n=8). The results suggest that phentolamine relaxes HCC by a nonadrenergic–noncholinergic mechanism dependent on nitric oxide synthase activity and activation of KATP-channel.

Keywords:

phentolamine, pharmacodynamics, K+-channels, human corpus cavernosum smooth muscle, erectile dysfunction

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Introduction

Erectile dysfunction (ED) defined as an inability to achieve and/or maintain an erection sufficient for satisfactory sexual activity,1 is prevalent in 46.2% of the Brazilian male population.2 In a more recent publication it is estimated that 1 025 600 new cases of ED are expected to occur in Brazil, annually.3

Phentolamine a competitive nonselective antagonist acting on the alpha1- and alpha2-adrenoceptor with almost equal efficacy4 has been used in combination with other vasoactive agents to treat ED, since 1984.5

In 1998, Traish et al6 reported studies in organ bath chamber with strips from human and rabbit corpus cavernosum, using phentolamine mesylate to examine its biochemical and physiological mechanisms of action. They concluded that the amine besides adrenergic blockade also relaxes erectile tissue by an endothelium-derived nitric oxide pathway.

Vemulapalli and Kurowski7 demonstrated in rabbit corpus cavernous stimulated by transmural electrical field that phentolamine mesylate relaxes rabbit corpus cavernosum by activating NO synthase independent of alpha-adrenergic receptor blockade.

Recent evidences from several experiments with penile erectile tissues have stressed the involvement of K+-channels in the function/regulation of erection.8, 9, 10 At least, the calcium-sensitive (Kca) and the ATP-regulated (KATP) were demonstrated to be important modulators of human muscular corporal smooth muscle tone.11

The goal of this study was to confirm the role of phentolamine in the penile erectile NO/cGMP pathway, and mainly to investigate the participation of the K+ channels in the mechanism of action of phentolamine-induced relaxation in human corporal tissue.

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Materials and methods

All studies were performed according to a protocol approved by the ethics committee of research with human subjects of the Ceará Federal University and the National Committee of Ethics of Research of the Brazilian Health Ministry.

Human corpus cavernosum (HCC) erectile tissues were obtained from donor cadaver (n=16) during surgery for organ transplantation. A total of 64 strips (4/each donor) of human corporeal smooth muscle were excised.

After removal, the tissue was placed immediately in ice-cold transportation buffer (Collin's solution), maintained at 4°C and used within 24 h after operation.

Each fragment was cut into approximately 3 times 3 times 8 mm3 strips and vertically mounted in 5 ml organ chambers containing Krebs–Henseleit medium, with the following composition (mM): NaCl 114.6, KCl 4.96, MgSO4 1.3, CaCl2 2.0, NaH2PO4 1.23, NaHCO3 25 and 3.6 glucose and enriched with 10 muM guanethidine and 10 muM indomethacin (pH 7.4, 37°C gassed with 5% CO2 and 95% O2). The experiments were carried out in baths containing guanethidine and indomethacin in order to provide an environment free of adrenergic and prostanoid influences.

Thereafter, the tissues were equilibrated for 90 min. Contractions were measured isometrically with a model FT-60 (Narco Bio-System, Houston, TX, USA) force displacement transducer and recorded on a desk model polygraph (DMP-4B, Narco Bio-Systems).

Phentolamine hydrochloride, guanethidine, indomethacin, phenylephrine, 5-hydroxytryptamine (5-HT), prostaglandin F2alpha methyl ester (PGF-2alpha), 1H-[1,2,4] oxadiazole [4,3-a]quinoxalin-1-one (ODQ), N-omega-nitro-L-arginine methyl ester (L-NAME), tetrodotoxin (TTX), atropine, charybdotoxin, apamin, glibenclamide and ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetra acetic acid (EGTA) were purchased from Sigma/Aldrich Chemical Co., and dissolved in saline the day of the esperiment. Indomethacin was diluted in bicarbonate buffer solution in order to make 1 mM stock solutions.

After an equilibration period in the bath chambers, the tissues were contracted with a high-potassium depolarizing solution (K+40 mM) obtained by isosmotic replacement of NaCl in the standard solution by KCl. The maximal amplitude of the phasic component of this contraction was determined for each strip before starting the experiments as an internal control and in order to test viability and reproducibility of the contractile responses. The phasic component was considered the peak deflection after 3 s exposure to the high potassium solution.

Thereafter, concentration–response curves to phentolamine (10-9–10-2 M) were performed on strips tonically precontrated with either K+ (40 mM), PGF-2alpha (100 muM), 5-HT (10 muM) or Phenylephrine (10 muM).

The phentolamine-induced relaxation (100 muM) was compared with the effects of several relaxant agents (Acetylcholine (Ach; 1 muM), nitric oxide from sodium nitrate at pH 2 (NO; 10 muM), sodium nitroprusside (SNP; 1 muM), transmural electric field stimulation (EFS: 20 V, 0.5 ms, 20 Hz), in HCC strips tonically precontracted with K+ (40 mM).

In other set of experiments, once stable tonic contraction to K+ (40 mM) was attained, phentolamine (100 muM) was added to the organ bath chambers in the absence or presence of 100 muM tetrodotoxin, 10 muM atropine, 100 muM L-NAME, 100 muM ODQ, 100 nM charybdotoxin plus 10 muM apamin, or 100 muM glibenclamide. All the pharmacological blockers were incubated in the bath chamber during 5 min before adding phentolamine. The tonic contractile component of the high potassium solution is considered the peak deflection after the phasic component has faded away.

In order to test if phentolamine would relax HCC by blocking voltage-dependent calcium channels, a study was carried out on HCC strips, comparing the pretreatment with phentolamine or nifedipine against the phasic component of the contraction induced by K+ (40 mM), that is mainly dependent on calcium influx through these channels. This hypothesis was tested after 5-min incubation with phentolamine or nifedipine.

In another set of experiments the relaxation induced by phentolamine in strips tonically precontracted with PGF-2alpha was assayed in normal Krebs–Henseleit solution with 2 mM calcium and then compared with the relaxation obtained when the tissues were contracted by the same agonist but in a medium with zero nominal calcium ('Ca2+-free' solution), in the presence of EGTA (100 muM).

The relaxation data were normalized as a percent of the tonic component of the contraction elicited by K+ (40 mM) for each preparation and expressed as meanplusminuss.e.m., and compared with the response obtained by isovolumetric addition of vehicle. Each protocol was made separated.

The statistical differences among doses and in relation to control were analyzed by the variance test one-way ANOVA with Tukey test as post hoc, with 5% significance.

Differences among the relaxation obtained before and after the specific blockers were compared by paired two-tailed Student t-test with significance level set at 5%.

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Results

In a first series of experiments, phentolamine elicited dose-dependent relaxations in HCC strips precontracted with several agonists (Figure 1).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Effect of phentolamine in human corpus cavernosum precontracted submaximally with phenylephrine 10 muM, K+ 40 mM, prostaglandin PGF2alpha 100 muM or 5-hydroxytryptamine (5-HT) 10 muM. Data are expressed as meanplusminuss.e.m. (ngreater than or equal to5). Relaxation is expressed as percent of previous contraction.

Full figure and legend (19K)

The relaxation to phentolamine (100 muM) was compared with the actions of several other relaxant agents in HCC strips precontracted with K+ (40 mM), and it was observed that this component corresponds to approximately50% of the relaxation induced by acetylcholine (1 muM) and sodium nitroprusside (1 muM) (Figure 2).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Effects of several relaxant agents in human corpus cavernosum strips precontracted with 40 mM K+. Phento=Phentolamine (100 muM); Ach=acetylcholine (1 muM); NO=nitric oxide from sodium nitrate at pH 2 (10 muM); SNP=sodium nitroprusside (1 muM); EFS=transmural electric field stimulation (20 V; 0.5 ms; 20 Hz). Data are expressed as meanplusminuss.e.m. (n=6). P<0.05, ANOVA, a vs b.

Full figure and legend (37K)

The phentolamine (100 muM)-induced relaxation in HCC precontracted with K+ (40 mM) was not blocked by tetrodotoxin (100 muM) or 10 muM atropine (54.6plusminus4.6 vs 48.9 times 6.4%) and (52.7plusminus6.5 vs 58.6plusminus5.6%) (P>0.05; n=6) (Figure 3).

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Effect of Phentolamine (Phento) (100 muM) in human corpus cavernosum strips precontracted with 40 mM K+ in the absence or presence of tetrodotoxin (TTX) (100 muM) or atropine (ATR) (10 muM). P<0.05, (n=6), unpaired Student t-test (treated vs control).

Full figure and legend (30K)

To investigate if phentolamine induces relaxation on HCC via activation of the NO/sGC/cGMP pathway, experiments were performed in the presence of L-NAME (100 muM) (NO synthase inhibitor) (59.7plusminus5.8 vs 27.8plusminus7.1%) (P<0.001; n=8) and ODQ (100 muM), a potent inhibitor of the soluble guanylyl cyclase (62.7plusminus5.1 vs 26.8plusminus3.9%) (P<0.05; n=8) (Figure 4).

Figure 4.
Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Effect of Phentolamine (Phento) (100 muM) in human corpus cavernosum strips precontracted with 40 mM KCl in the absence or presence of L-NAME (100 muM) or ODQ (100 muM). P<0.05, (n=8) unpaired Student's t-test (treated vs control). L-NAME=NG-nitro-L-arginine methyl ester, ODQ=1H-[1,2,4] Oxadiazole [4,3-a]quinoxalin-1-one.

Full figure and legend (22K)

In order to analyze if phentolamine has any role in the L-type calcium function, the 40 mM K+-induced contraction was compared in HCC strips pretreated with phentolamine or nifedipine, a specific inhibitor of this channel. While nifedipine effectively blocked the K+-induced contraction, phentolamine was ineffective (0.64plusminus0.0 vs 95.8plusminus0.5%) (P<0.001; n=4) (Figure 5a).

Figure 5.
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Effect of pretreatment of corpus cavernosum strips with phentolamine (phento) or nifedipine (100 muM) in the K+ 40 mM-induced contraction in human corpus cavernosum strip (a) and effect of calcium removal from the medium (Ca2+-free solution) in the relaxation induced by phentolamine in PGF2alpha precontracted strips (b). *P<0.05, (n=6) paired Student's t-test (treated vs control). Ca2+=Ca2+-free solution.

Full figure and legend (50K)

We also tested the effects of 100 muM phentolamine in strips precontracted with 100 muM PGF-2alpha, in a Ca2+-free medium. The phentolamine-induced relaxation was attenuated in 74.3plusminus6.2 (43.6plusminus6.2 vs 11.2plusminus2.3) (Figure 5b), and this blockade was reversed by washout and performing the phentolamine relaxation assay in normal Krebs–Henseleit solution (43.6plusminus6.2 vs 34.8plusminus4.3) (Figure 5b).

On the other hand, pretreatment of tissues with apamin (1 muM) plus charybdotoxin (100 nM), potent inhibitors of KCa-channel (small and large conductance, respectively) did not change the relaxation elicited by phentolamine in HCC strips precontracted with K+ 40 mM (54.6plusminus4.6 times 59.3plusminus5.2%) (P>0.05) (Figure 6a).

Figure 6.
Figure 6 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Effect of the combination of 1 muM apamin (Apam) and 100 nM charybdotoxin (Charybd) in the phentolamine-induced relaxation in human corpus cavernosum (HCC) is shown in panel (a). Panel (b) shows the effect of 100 muM phentolamine (Phento) in HCC strips precontracted with 40 mM KCl in the absence or presence of 100 muM glibenclamide (GLI) or L-NAME+glibenclamide (100 muM-L-N+GLI-100 muM). *P<0.05, (n=6) paired Student's t-test (treated vs control). Apam=Apamin, Charybd=charybdotoxin, L-N=L-NAME (NG-nitro-L-arginine methyl ester), GLI=glibenclamide, NS=not significant.

Full figure and legend (38K)

To examine the role of KATP-channels on the phentolamine-induced relaxation, tissues were pretreated with 100 muM glibenclamide, an ATP sensitive K+ channel blocker. Additionally a blockade was made with the pretreatment with 100 muM L-NAME plus 100 muM glibenclamide. An inhibition (80.1plusminus2.3) in the phentolamine-induced relaxation was shown (56.7plusminus6.3 vs 11.3plusminus2.3%; P<0.05) or phentolamine+glibenclamide+L-NAME (54.6plusminus5.6 vs 5.7plusminus1.4%) (P<0.05) (Figure 6b).

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Discussion

Phentolamine mesylate has been used since 1984 with other vasoactive drugs, by intracavernous injection, for the treatment of ED. Later, the observations of Gwinup12 formed the basis for the use of an oral formulation of phentolamine to treat ED.6, 13 Phentolamine mesylate is an effective alpha1 and alpha2 adrenergic blocker both in human and rabbit corpus cavernosum.6

Some studies have shown the relative efficacy of this formulation for long-term preventive pharmacological treatment of ED for men with mild to moderate ED.14, 15, 16 One study has shown no difference in the success rate of sexual intercourse of patients treated with phentolamine or sildenafil.17

The inhibition of the physiologic sympathetic tonus by phentolamine leads to relaxation of the HCC.6 Nevertheless, this does not seem to be the only mechanism of the relaxation induced by phentolamine, at least in in vitro conditions.

Traish et al6 and Vemulapalli and Kurowski7 demonstrated a nonadrenergic noncholinergic component of the relaxation induced by phentolamine mesylate in rabbit corpus cavernosum.

Our study shows a similar result. Phentolamine relaxes HCC by a mechanism independent on adrenergic receptors blockade, since its effect remains even when the contraction is induced by nonadrenergic agonists (ie, K+ 40 mM, 5-HT, PGF-2alpha) in a medium containing a sympatholytic agent (guanethidine) (Figure 1).

This relaxation corresponds, in the higher concentration used (100 muM), to approximately50% of the relaxations induced by classical agonists, as acetylcholine (1 muM), nitric oxide (10 muM), transmural electrical field stimulation, or sodium nitroprusside (1 muM), and is time-dependent with maximal response attained 30 min after incubation. The participation of relaxant prostanoids in this effect is unlikely, since all the experiments were carried out under indomethacin blockade of the cyclooxygenase enzymes.

The nonadrenergic relaxation induced by phentolamine is not neurogenic in nature, since it is not sensitive to tetrodotoxin and is also not dependent on direct activation of muscarinic receptors, being atropine-insensitive.

This nonadrenergic component is not fully understood so far. Traish et al6 and Vemulapalli and Krouski7 working with rabbit corpora cavernosa showed that this component is partially dependent on endothelial and neuronal nitric oxide synthase activity. Nevertheless, Palea and Barras18 also working with rabbit corpus cavernosum, showed that this component is insensitive to 100 muM L-NAME and concluded that the relaxation induced by phentolamine is independent of nitric oxide.

The nonadrenergic component of the phentolamine-induced relaxation was shown, in the present study carried out with HCC, to be both dependent in the activity of nitric oxide synthase and soluble guanylyl cyclase, since it was partially inhibited by L-NAME and ODQ (Figure 4). This reinforces the data presented by Traish and Vemulapalli pointing to a NO/GMPc based mechanism. The contrast with the data presented by Palea and Barras is probably due to dose and specie differences. For instance, Palea used 10 muM phentolamine and we used a 10-fold higher dose.

Nevertheless, this partial blockade by L-NAME or ODQ does not fully explain the phenomenon. Another mechanism underlying phentolamine-induced relaxation was supposed to exist.

A calcium-channel blockade by phentolamine was discarded since this compound at the higher dose used, that is, 100 muM, did not inhibit the high-potassium induced contraction. This phasic contraction is highly dependent on calcium influx by voltage-dependent calcium channels19 and, in our experiments, was fully blocked by nifedipine (Figure 5a).

The addition of phentolamine to HCC precontracted with PGF-2alpha in a 'Ca2+-free' medium revealed that this drug does not act downstream in the calcium-signaling pathway, as in its release from internal stores, interaction with calmodulin, or any event in the action of calcium as a second messenger. Furthermore, it is unlikely that phentolamine would interact directly with the contractile machinery. The reversibility of this effect in a normal Krebs–Henseleit solution shows that phentolamine does not induce damage to the contractile machinery.

Otherwise, potassium channels are physiological regulators of the membrane electric potential and transmembrane calcium flux, thus they have a key role in the regulation of smooth muscle tone including HCC.20 Two isoforms of the channel, that is, the calcium-activated channels (Kca) and adenosine triphosphate-sensitive channel (KATP), are the main modulators of the tone of the erectile tissue.11 At least, injections of the KATP-channel openers cromakalim and pinacidil in rabbit corpus cavernosum leads to relaxation,8 intracavernosal injections of pinacidil, nicorandil, and lemakalim induces erection in cats, monkeys, and humans.9, 21, 22, 23, 24, 25

The blockade of Kca-channels (both high Maxi-K and low-conductance Kca), by charybdotoxin and apamin, respectively, did not affect the phentolamine-induced relaxation and therefore Kca-channels are not likely to be involved in this phenomenon (Figure 6a).

Nevertheless, the phentolamine-induced relaxation was highly (approximately90%) inhibited by glibenclamide, pointing to a KATP-channel role in this effect. In addition, the combination of glibenclamide and L-NAME were not additive showing that the NO/GC/cGMP pathway is probably linked to the activation of the KATP-channel, as demonstrated by Lin et al (Figure 6b).26

The role of KATP channels in the relaxation of the HCC are being studied and point to a role of KATP openers as second line alternatives in the management of drug refractory ED.11, 27 The chemical management of phentolamine, as a mother drug, would lead to compounds that could increment NO stimulating and KATP opening activity keeping the alpha-adrenergic blocker property.

Whatever the case, the present study reports for the first time that the nonadrenergic component of the relaxation induced by phentolamine in the HCC is highly dependent on KATP channel opening mechanism.

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