Higenamine mediates cardiotonic, vascular relaxation and bronchodilator effects. The relaxation effects and the mechanism of action of higenamine on the rat corpus cavernosum (CC) were assessed to investigate the effect of higenamine on penile erection. Strips of CC and aorta were used in organ baths for isometric tension studies. Tension was measured with isometric force transducers, and muscle relaxation was expressed as the percent decrease in precontraction induced by phenylephrine (PE). The relaxation reactions were investigated in an endothelial-denuded group and groups pretreated with N(G)-nitro-L-arginine methyl ester (NO synthesis inhibitor), propranolol (β-receptor blocker), indomethacin (COX inhibitor), glibenclamide (K+ATP channel inhibitor), 4-aminopyridine (membrane potential-dependent potassium channel inhibitor) and methylene blue (guanylyl cyclase inhibitor) for 30 min. Intracavernous pressure (ICP) was assessed in rats after the intravenous administration of higenamine, and changes in guanosine 3′,5′-cyclic monophosphate and adenosine 3′,5′-cyclic monophosphate (cAMP) concentrations were measured on the basis of the higenamine concentration. Also, the combined reaction of higenamine and the phosphodiesterase type-5 (PDE-5) inhibitors was assessed. Higenamine induced relaxation of the CC and the aortic strips precontracted with PE in a dose-dependent manner. The CC was significantly more relaxed than the aortic rings in response to the same higenamine concentration (P<0.05). The CC relaxation reaction was suppressed by the β-receptor blocker propranolol. The cAMP concentration increased gradually with increased higenamine concentration (P<0.05). The ICP also increased with increased higenamine concentration in vivo (P<0.05). In the group pretreated with 10−7 M higenamine, the relaxation reaction of CC induced by the PDE-5 inhibitor increased significantly, compared with CC exposed to the PDE-5 inhibitor but not pretreated with higenamine (P<0.05). In conclusion, higenamine induced relaxation of the rat CC in a dose-dependent manner. The effect may be mediated through β-adrenoceptors. The results suggest that higenamine may be valuable as a new lead compound for treating erectile dysfunction.
With the development of medicines and improvements in general hygiene, the average lifespan has been prolonged and several problems concerning the quality of life that were not considered important previously have appeared. Among them, male erectile dysfunction (ED) is a disease that greatly affects the quality of life.
The incidence of ED in males older than 40 is 52% according to the Massachusetts Male Study.1 Additionally, the incidence of ED increases with age. That is, many males past middle age have ED.
Recently developed phosphodiesterase type-5 (PDE-5) inhibitors have been widely used as first-line therapeutics for treating ED. Although large multicenter clinical trials have shown the efficacy and tolerability of these drugs in ED with various etiologies and a broad range of severity, 30–35% of patients fail to respond. The reported 62% prescription renewal rate at 3-4 months of follow-up, which drops to approximately 30% by 6-12 months, suggests that patients stop taking the drug for reasons other than treatment failure.2, 3 The use of PDE-5 inhibitors may result in side effects, such as visual disturbance, headache, facial flushing, rhinitis and indigestion. Other treatments for ED include injection therapy within the penis or penile implants. However, such methods are invasive and irreversible, and have not been used widely.4 Thus, there is a continuing need for the development of new non-invasive and effective therapies for patients with ED.
Kosuge et al.5 purified a substance from the perennial Aconiti tuber plant belonging to Ranunculaceae, which has an active cardiotonic component, characterized its chemical structure, and named it ‘higenamine.’ Higenamine mediates cardiotonic,5, 6 vascular relaxation,7 bronchodilator8 and anti-thrombotic effects,9, 10 and reduces apoptotic cell death in vivo,11 suggesting that higenamine has various actions on the cardiovascular system and that it may have an effect on penile erection.
In this study, we investigated the effect of higenamine on relaxation of the corpus cavernosum (CC) in rats. The mutual action of higenamine and PDE-5 inhibitors was also assessed.
Materials and methods
Organ-bath study of the CC
We sectioned the CC of male Sprague Dawley rats, 9–11 weeks old, weighing 280–320 g; eight animals per group were used. The rats were killed by cervical dislocation, the penis was dissected immediately, and 2 × 2 × 6-mm sections of the CC were prepared. The thoracic aorta was extracted, connective tissues were removed, and aortic rings of 3 mm in length were prepared. CC sections and aortic rings were transferred to an organ bath; one end was connected to a muscle fixation ring and the other end was connected to an isometric tension transducer (SG-10). The signals were relayed to a physiography instrument (PowerLab ADI Instruments, Sydney, Australia) and measured. Chart 5 software (ADI Instruments) was used for real-time monitoring of tension. Krebs–Hanseleit (KH) solution was used for the organ bath at 37 °C and pH 7.4, and gassed continuously with 95% O2/5% CO2. When the initial tension of each section was maintained at approximately 2 g, the KH solution was changed approximately every 30 min (total equilibration period: 2 h) and allowed to reach a stable condition. Once a stable condition was reached, phenylephrine (PE) was added and the contraction level was observed. Each section was progressively stretched to the optimal point on its length-tension curve as determined by the active tension developed to PE. Afterwards, a stable condition was restored by washing the preparation with KH solution three more times. Such manipulation was repeated, and contracture within 100±10% of the previous contraction was defined as the ideal resting optimal isometric tension. Although maintaining the resting optimal isometric tension, tissues were contracted by pretreatment with PE (5 × 10−6 M) within the bath, higenamine in five-fold dilutions from 10−7 to 10−5 M was added, and the relaxation level was assessed by observing the change in the tension curve.
The relaxation reactions were investigated in endothelial-intact or endothelial-denuded groups to examine the mechanism of higenamine-induced relaxation of the CC. Endothelial-intact or -denuded tissues from the CC were incubated for 30 min in KH solution containing various drugs. After incubation, the tissues were contracted with PE (5 × 10−6 M), during which period the plateau state contraction was attained. The relaxation reaction following the addition of increasing concentrations of higenamine was then observed. Drug probes included N(G)-nitro-L-arginine methyl ester (L-NAME; 10−5 M, NO synthesis inhibitor), propranolol (10−5 M, β-receptor blocker), indomethacin (3 × 10−5 M, COX inhibitor), glibenclamide (10−5 M, K+ATP channel inhibitor), 4-aminopyridine (10−5 M, membrane potential-dependent potassium channel inhibitor) and methylene blue (10−5 M, guanyl cyclase inhibitor).12, 13, 14 Eight sections were used for each group. CC sections were pretreated with 3 ml 0.3% 3-[(3-cholamide propyl)]-1-propane sulfonate (CHAPS) for 20 s to remove vascular endothelial cells. The sections were rubbed lightly using the thumb and index finger for 20 s, washed with KH solution, and the cells were removed by rolling gently on dry paper. The removal of vascular endothelial cells was confirmed by the failure of the loss of tissue contraction induced by acetylcholine (10−5 M) in response to PE (5 × 10−6 M).
Measurement of guanosine 3′,5′-cyclic monophosphate (cGMP) and adenosine 3′,5′-cyclic monophosphate (cAMP) in the rat CC
Contraction of the smooth muscle sections was equalized for 1 h in KH solution, induced with PE (5 × 10−6 M), and the tissues were exposed to higenamine for 10 min. Then, the tissues were frozen rapidly in liquid nitrogen and homogenized in ice-cold 6% trichloroacetic acid. The homogenized tissues were centrifuged for 15 min, and cellular proteins in the supernatant were separated by conventional methods. Samples were divided into a normal CC group and groups of 10−7, 10−6 and 10−5 M according to the concentration of higenamine, and the concentrations of released cGMP (n=8/group) and cAMP (n=8/group) were measured by immunoassay. The immunoassay was based on the competitive binding technique in which cGMP and cAMP present in a sample compete with a fixed amount of horseradish peroxidase-labeled cGMP and cAMP for sites on a rabbit polyclonal antibody. During the incubation, the polyclonal antibody becomes bound to the goat anti-rabbit antibody coated on the microplate. Following a wash to remove excess conjugate and unbound sample, a substrate solution is added to the wells to determine the bound enzyme activity. The color development is stopped and the absorbance is read at 450 nm. The intensity of the color is inversely proportional to the concentration of cGMP and cAMP in the sample.
Induction of an erection by electrical stimulation
The 32 Sprague-Dawley male rats were divided into four groups (n=8 each): group 1, normal control; group 2, intravenously injected 0.0005 mg kg−1 higenamine; group 3, intravenously injected 0.001 mg kg−1 higenamine; and group 4, intravenously injected 0.002 mg kg−1 higenamine.
Experimental rats were anesthetized with ketamine (50 mg kg−1) injected into the peritoneal cavity. Animals were placed in the supine position on an operation table, a catheter (polyethylene-50 tube) was inserted into the carotid, and blood pressure (BP) was monitored. The prostate was exposed with a midline incision of the abdomen. Additionally, the pelvic ganglion located in the posterolateral side of the prostate was assessed, and the pertinent pelvic nerves and cavernosal nerves were assessed and dissected without injuring the nerves. After intravenous injection of higenamine through the internal jugular vein, the cavernosal nerves were stimulated using an electric stimulator and platinum electrodes after about 10–15 min. To assess an erection in response to electrical stimulation of the nerves, the penis was dissected up to the penile crura, the tunica albuginea of the penis was assessed by dissecting the ischial CC muscles surrounding the penile crura and a 25-gauge needle was installed (polyethylene-50 tube pretreated with 250 U ml−1 heparin) into the CC.15
The BP and the intracavernosal pressure (ICP) were measured using a BP manometer transducer and recorder (PowerLab, ADI Instruments). Chart 5 software (ADI Instruments) was used for real-time BP monitoring. Electrical stimulation was performed at a voltage of 5 V and duration of 60 s.
To examine the hemodynamic reaction in response to autonomic nerve stimulation, pressure was measured prior to nerve stimulation, during stimulation and after stimulation. Additionally, to examine the reactions induced by nerve stimulation, the percentage of the maximal ICP/mean systemic arterial BP (max ICP/MAP × 100) was measured by stimulating the CC nerves, and differences among the groups were compared.
Combined effects of higenamine and the PDE-5 inhibitors on the CC
The relaxation effects of the PDE5 inhibitor on precontracted CC strips with PE (5 × 10−6 M) were assessed for any synergistic effect of combined PDE5 inhibitor and higenamine treatment. The PDE5 inhibitor and combinations diluted five-fold from 10−5 to 5 × 10−4 M were added and relaxation was assessed. The minimal concentration of higenamine inducing relaxation of the CC was obtained from the above experiment. The CC sections were contracted by pretreatment with higenamine for 20 min at the minimal concentration obtained from the above experiment, the PDE-5 inhibitor was added and the relaxation level was observed.
Drugs and solutions
PE, L-NAME, glibenclamide, 4-aminopiridine, indomethacin, methylene blue, propranolol and CHAPS were purchased from Sigma (St Louis, MO, USA). The cGMP immunoassay kit (KGE003) and cAMP immunoassay kit (KGE002) were purchased from R&D Systems (Minneapolis, MN, USA). The PDE5 inhibitor (udenaphyl) was supplied by Dong-A Pharmaceuticals (Seoul, South Korea). The composition of the KH solution was (mM l−1) NaCl, 118.1; NaHCO3, 25; KCl, 4.6; KH2PO4, 1.2; CaCl2, 2.5; MgSO4, 1.2 l; glucose, 11.0; and pH 7.4. Higenamine was synthesized and purified as described in Chang et al.16, 17
Statistical significance was analyzed by Student's t-test and one-way analysis of variance with Scheffe's F-test using SPSS software (version 14.0; SPSS, Chicago, IL, USA). Results are expressed as the mean±s.d. A P-value <0.05 was deemed to indicate statistical significance.
Effect of higenamine on aortic rings and CC
As the concentration of higenamine increased from 10−7 M, the aortic rings and CC pre-contracted with PE relaxed. The first relaxation reaction occurred at a concentration of 10−7 M and increased according to the increase in the higenamine concentration. When the concentration of higenamine was 10−5 M, relaxation of the aortic ring and CC was approximately 35.3±2.6 and 92.5±6.9%, respectively.
Higenamine induced relaxation of the CC, and the aortic rings contracted in response to PE in a dose-dependent manner (P<0.05). The CC group (n=8) showed significantly more relaxation than the aortic-ring group (n=8) in response to the same concentration of higenamine (P<0.05; Figure 1).
Mechanism of the relaxation reaction induced by higenamine
The relaxation reaction of the CC was suppressed only by the β-adrenoreceptor blocker propranolol. When the concentration of higenamine was 10−5 M, maximal relaxation was approximately 92.6±6.9% in the control group, but it was 42.1±7.3% after pretreatment in the propranolol group (P<0.05; Figure 2).
However, pretreatment with L-NAME, indomethacin, glibenclamide, 4-aminopyridine and methylene blue for 30 min, as well as the results of endothelial-denuded tissues did not suppress the relaxation of the CC by higenamine (Figure 2).
Concentration of cGMP and cAMP in the CC according to the concentration of higenamine
Concentrations of cGMP and cAMP in normal and higenamine-treated CC were measured using immunoassays. The cAMP concentrations were 26.17±5.69 pmol per mg protein in the normal CC without higenamine, 34.48±4.65 pmol per mg protein in the 10−7 M higenamine group, 43.95±9.01 pmol per mg protein in the 10−6 M higenamine group and 49.59±6.36 pmol per mg protein in the 10−5 M higenamine group. The cAMP concentration increased gradually as the higenamine concentration increased, and the concentration of cAMP in the 10−6 and 10−5 M higenamine groups showed statistically significant increases compared with the control group (P<0.05; Figure 3a). The cGMP concentrations were 0.63±0.26 pmol per mg protein in normal CC without higenamine, 1.38±0.59 pmol per mg protein in the 10−7 M higenamine group, 2.00±1.13 pmol per mg protein in the 10−6 M higenamine group and 3.86±2.07 pmol per mg protein in the 10−5 M higenamine cGMP group. The cGMP concentration increased gradually as the higenamine concentration increased, but this was not statistically significant (P>0.05; Figure 3b).
Effect of higenamine on ICP
The mean systemic arterial BPs and heart rates of the control group and the experimental groups prior to and after electrical stimulation of the cavernosal nerve were not statistically different. Before cavernosal nerve stimulation, the mean baseline ICP/MAP did not show a statistically significant difference in four groups (group 1: 10.2±2.7%, group 2: 10.0±2.4%, group 3: 9.3±2.1% and group 4: 10.1±1.7%). At the time of cavernosal nerve stimulation, the mean ICP of group 1 (control) was 72.9±11.7 mm Hg, and the max ICP/MAP × 100 was 59.2±6.6%. The mean ICP of group 2 (0.0005 mg kg−1 higenamine) was 67.3±13.0 mm Hg and the max ICP/MAP × 100 was 59.3±10.4%. The mean ICP of group 3 (0.001 mg kg−1 higenamine) was 87.7±14.4 mm Hg and the max ICP/MAP × 100 was 74.5±8.4%. The mean ICP of group 4 (0.002 mg kg−1 higenamine) was 87.8±14.1 mm Hg and the max ICP/MAP × 100 was 76.0±5.1%. The max ICP/MAP × 100 of groups 3 and 4 were statistically higher than that of the control group (P<0.05). However, group 2 (0.0005 mg kg−1 higenamine) did not show a statistically significant difference from the control group (P=0.19; Figure 4).
Combined effects of higenamine and PDE-5 inhibitors in the CC
The effect of the PDE5 inhibitors based on the PE concentration of precontracted CC strips was examined. As the concentration of the PDE5 inhibitor was increased from 10−5 M, the CC showed dose-related relaxation effects. When the concentration of the PDE-5 inhibitor was 5 × 10−4 M, the mean relaxation was 84.3±13.9%. As the minimal concentration of higenamine effective for relaxing the CC was 10−7 M, the strips were pretreated with 10−7 M higenamine for 20 min. The strips were contracted with PE (5 × 10−6 M), and the PDE-5 inhibitor was then added. The results showed that in the group treated with 10−4 or 5 × 10−4 M PDE-5 inhibitor, the relaxation reaction of the CC increased significantly, compared with the PDE-5 inhibitor group without higenamine pretreatment (P<0.05; Figure 5).
Higenamine is a benzyltetrahydroisoquinoline-type drug derived from the Aconiti tuber.5 Higenamine acts as an adrenergic β-agonist to effectively treat heart failure. Thus, most studies of higenamine have focused on its chronotropic effects. Studies have been conducted on the adrenergic β-receptor expressed in blood vessels and smooth muscle. However, this is the first reported study that has assessed the reaction mechanism and relaxation effects of higenamine on CC tissue. Higenamine induced relaxation of the CC in a dose-dependent manner. Additionally, the CC responded more sensitively to the same higenamine concentration than the aorta, so the relaxation effects were greater. This confirms that higenamine acts preferentially on the CC rather than systemically.
Higenamine acts on the heart, the blood vessels and the bronchus through actions at the adrenergic β-receptor. The CC contracts in response to the activation of adrenergic α-receptors18, 19 and relaxes when adrenergic β-receptors are activated.20, 21 That is, activation of α-adrenoreceptors is involved in the flaccid state of the CC and suppression of penile erection.22 In contrast, activating β-adrenoreceptors is involved in an erection. Similarly, the relaxation effect of higenamine was efficiently suppressed by the non-selective adrenergic β-antagonist propranolol in our experiments. However, the nitric oxide synthesis inhibitor, L-NAME, the guanylate cyclase inhibitor methylene blue, the prostaglandin inhibitor indomethacin, the membrane potential-dependant K+ channel (KV) blocker 4-aminopyridine, the ATP-dependant K+ channel blocker glibenclamide and the presence or absence of endothelial cells did not affect relaxation of the CC induced by higenamine. After detecting the presence of β-adrenoceptors in the human CC, several animal experiments have been performed to examine which subtypes are involved in the primary reactions. In canine CC tissues, the β2 and β3 subtypes primarily mediate the relaxation reaction.23, 24 In contrast, mixed β1- and β2-adrenoceptors mediate relaxation reactions in the horse CC.21 Furthermore, atypical β-adrenoceptors and β2-adrenoceptors mediate the primary relaxation reaction in rabbits.25 However, in our study, the β-adrenoceptor subtype of the CC that higenamine mediated the major relaxation reaction could not be assessed using the non-selective adrenergic β-antagonist propranolol. Wong et al.8 suggested that β-adrenoceptors sensitive to higenamine are primarily located in the endothelial layer of vessels. However, our results showed that the relaxation effect of higenamine was not related to the presence or absence of the CC endothelial layer.
Adrenergic nerves are suppressed when the penis is stimulated by the local reaction of prostaglandins and vasoactive intestinal peptide. The penile CC smooth muscles are relaxed due to reactions mediated by cholinergic or nonadrenergic-noncholinergic nerves and endothelium-derived relaxing factors released from vascular endothelial cells. Then, the artery expands and blood influx increases, resulting in an elevation of intra-penile pressure. The vein between the tunica albuginea and the expanded sinusoid is compressed, resulting in reduced blood efflux, so an erection occurs.26, 27, 28 cGMP and cAMP are second messengers involved in such a vascular smooth muscle relaxation reaction. Increases in such second messengers within the cells cause the dephosphorylation of myosin light chains, which induces relaxation of CC smooth muscle.29 PDE-5 inhibitors, currently used as first-line therapy for ED, suppress the hydrolysis of intracellular cGMP, raise cGMP concentration and thus, enhance an erection.30, 31 Nevertheless, numerous patients with ED have experienced treatment failure. In particular, low treatment success rates have been reported for patients with diabetes and patients who have undergone surgery for prostate cancer.32 Thus, the development of drugs that can compensate is required. In our study, higenamine increased the concentration of cGMP and cAMP in the CC tissues in a dose-dependent manner. Nonetheless, although intracellular cAMP increased significantly, the cGMP increase was not statistically significant. Similar to the results of studies conducted on other blood vessels,33 higenamine induced the relaxation reaction, mainly by increasing cAMP in the CC. Enhanced relaxation effects were observed when we examined the combined effects of a PDE-5 inhibitor and higenamine. Higenamine treatment significantly increased ICP, compared with the control group. According to the results of this study, higenamine activated the β-adrenoceptors. Also, it is well known that β-adrenoceptors increase the cAMP. So considering this phenomenon, it is suggested that β-adrenoceptors activated by higenamine increased the cAMP.6, 7 We do not have any data regarding the results of this study that higenamine has some PDE5 inhibitor activity. We guess that action mechanisms of higenamine and PDE-5 inhibitor showed synergistic effect have two signal pathways. One is β-adrenoceptors/cAMP pathway by higenamine and the other is guanylate cyclase/cGMP pathway by PDE-5 inhibitor. But Kim et al.34 reported that cAMP upregulated the intracellular levels of cGMP. They suggested several potential mechanisms for this regulation. Increased cAMP synthesis may lead to stimulation of guanylyl cyclase or to inhibition of PDE-5. These alterations of cyclase or phosphodiesterase activity could occur via direct interaction with cAMP or in an indirect manner via cyclic nucleotide-dependent protein kinase modulation of enzyme activity. Such results suggest that higenamine may be a useful drug for ED or a supplemental drug with PDE-5 inhibitors. Additional animal and clinical studies are required.
We investigated the relaxation effect of higenamine on the CC and characterized its mechanism of action. Additionally, this study was conducted to assess the possibility of using higenamine as a therapeutic for ED. The results show that higenamine induced more relaxation in the CC than in the aorta in a dose-dependent manner, and it enhanced the relaxation reaction of the CC induced by PDE-5 inhibitors. Furthermore, higenamine significantly increased ICP. However, studies to examine whether the higenamine concentration in the human CC could reach a maximal relaxation concentration and whether the higenamine concentration inducing an erection causes other side effects in humans are required.
Higenamine induced relaxation of the rat CC in a dose-dependent manner. The mechanism was a reaction involving β-adrenoreceptors in the CC. Higenamine induced relaxation of the CC by elevating intracellular cAMP. Such reactions were more specific in the CC than the aorta. Furthermore, higenamine elevated ICP and significantly augmented the relaxation reaction of the CC induced by PDE-5 inhibitors. Thus, higenamine may be valuable as a new lead compound for the treatment of ED.
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This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (Ministry of Education, Science and Technology; NRF-2009-0067889 and 2010-0017131).
The authors declare no conflict of interest.
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Kam, S., Do, J., Choi, J. et al. The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum. Int J Impot Res 24, 77–83 (2012). https://doi.org/10.1038/ijir.2011.48
- corpus cavernosum
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