Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction

Brioni, Jorge D.; Nakane, Masaki; Hsieh, Gin C.; Moreland, Robert B.; Kolasa, Teodozyj; Sullivan, J P

doi:10.1038/sj.ijir.3900801

Cited by 55 publications

(28 citation statements)

References 49 publications

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“…[7][8][9][10] Some drugs such as inhibitors of PDE 5 or other vasodilators, which can promote the relaxation of corpus cavernosum smooth muscle, can be potentially used to treat ED. [11][12][13][14][15][16][17][18][19] It has been shown that there are many Chinese traditional herbals that can enhance sexual activity. [20][21][22][23][24] Recently, there is an increasing interest in investigating their effective components.…”

Section: Introductionmentioning

confidence: 99%

Chuanxiongzine relaxes isolated corpus cavernosum strips and raises intracavernous pressure in rabbits

et al. 2009

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It has been shown that there are many Chinese traditional herbals that can enhance sexual activity. Chuanxiongzine is a vasoactive ingredient that has been isolated and purified from Ligusticum chuanxiong Hort. In previous studies, it has been found that chuanxiongzine was effective in relaxing rabbit corpus cavernosum smooth muscle. We determined the effects of chuanxiongzine on relaxation of isolated corpus cavernosum strips in vitro and on increase of intracavernous pressure (ICP) in vivo in rabbits. Chuanxiongzine caused a concentration-dependent relaxation of phenylephrine precontracted isolated corpus cavernosum strips (EC 50 1.58 Â 10 À4 mol l À1 ), which were endothelium independent and NO independent. However, the guanylyl cyclase inhibitor 1-H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one significantly shifted the chuanxiongzine concentration-response relationship to the right. Although there was no significant difference in the level of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) in isolated corpus cavernosum strips treated with chuanxiongzine or vehicle, chuanxiongzine caused a significant rise in the level of cGMP and cAMP in isolated corpus cavernosum strips pretreated with the activator of adenylyl cyclase forskolin and the source of NO sodium nitroprusside. In an in vivo study, chuanxiongzine dose-dependently raised ICP after the intracavernous injection of its cumulative doses (0.5, 1, 2 and 5 mg kg À1 ). The ICP increased from baseline to 19.1±3.7, 24.8±2.1, 30.2 ± 4.8 and 39.7 ± 6.1 mm Hg, respectively, and the duration of tumescence ranged from 8.5 ± 2.8 to 22.9 ± 7.3 min. Our results show that chuanxiongzine can relax isolated corpus cavernosum strips of rabbits in vitro and increase ICP of rabbits in vivo, which is neither endothelium dependent nor NO dependent, but may be partly mediated by the inhibition of cAMP phosphodiesterase or cGMP phosphodiesterase.

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Section: Introductionmentioning

confidence: 99%

Chuanxiongzine relaxes isolated corpus cavernosum strips and raises intracavernous pressure in rabbits

et al. 2009

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“…Although sildenafil is generally an efficacious agent for the treatment of ED, this drug has limited efficacy in a subpopulation of ED patients, e.g., diabetics. A PDE5 inhibitor cannot increase cGMP levels by itself unless there is release of NO that activates guanylate cyclase to increase cGMP levels (35). In this situation, PDE5 inhibitors can maintain cGMP levels by blocking the metabolism of cGMP.…”

Section: Figmentioning

confidence: 99%

Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

Brioni

Moreland

Cowart

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

107

105

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Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D4 receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D 4 receptor agonist that activates human dopamine D 4 receptors with an EC50 of 12.4 nM and 61% efficacy, with no effect on dopamine D 1, D2, D3, or D5 receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction. P enile erection is the result of a complex series of integrated neuronal and vascular events that leads to accumulation of blood in the penis to achieve rigidity. The coordination of several neural events is required to release endogenous mediators (i.e., nitric oxide) at the level of the penile smooth muscle to induce relaxation, whereas a disruption of this series of events can lead to erectile dysfunction (ED) (1, 2). Traditionally, drugs used for the treatment of ED have had a peripheral site of action, including phosphodiesterase (PDE)-5 inhibitors like sildenafil, but the recent demonstration that apomorphine can facilitate penile erection in ED patients has introduced a new approach to treatment, because apomorphine acts on central dopaminergic systems (3,4). Dopamine is the main catecholamine in the CNS and is involved in a variety of physiological functions, including sexual behavior, cognition, motor coordination, cardiovascular control, reward, hormonal regulation; abnormalities in dopaminergic neurotransmission have been implicated in Parkinson's disease, schizophrenia, attention-deficit disorder, depression, and drug abuse, among other disorders (5, 6). The regional distribution of the receptor subtypes, the recent generation of knock-out animals, and the availability of a large number of dopaminergic agents have aided researchers in clarifying the biological role of the dopamine receptors. Dopamine receptors in mammalian tissues have been classified as D 1 -like (D 1 and D 5 ) and D 2 -like (D 2 , D 3 , and D 4 ) based on their binding properties and their ability to activate or inhibit forskolin-induced adenylate cyclase activity, a classification supported by the cloning of the different subtypes during the last decade (7,8).Within the D 2 -like family, the D 2 receptor is highly expressed...

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“…5,7,9 The chambers were perfused with modified Krebs' solution at a constant flow of 1.0 ml/min by means of peristaltic pumps (Miniplus 2, Gilson). One end of the preparation was tied to a Grass FT 03C forcedisplacement transducer connected to a Linearcorder WR 3101 (Graphtec, Tokyo, Japan) for the registration of isometric changes in tension.…”

Section: Functional Studiesmentioning

confidence: 99%

“…NO-independent soluble guanylate cyclase (sGC) activators (BAY41-2272) and an NO-releasing derivative of sildenafil (sildenafil nitrate; NCX-911) are two such potential approaches to the medical management of ED. 8,9 Although the rat is an excellent model for diabetes research, our experience with its penile corpus cavernosum is that it is a difficult tissue to work with (ie spontaneous contractions and the size of the tissue) compared to the anococcygeus muscle. Anococcygeus and retractor penis muscles have been widely accepted as ideal smooth muscle models to study not only nitrergic neurotransmission but also other nonadrenergic noncholinergic neurotransmitters.…”

Section: Introductionmentioning

confidence: 99%

A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats

et al. 2004

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We compared the effects of a nitric oxide (NO)-releasing sildenafil (NCX-911), NO-independent soluble guanylate cyclase activator (BAY41-2272) and sildenafil on the anococcygeus muscle from streptozotocin-induced 16-weeks diabetic rats. NCX-911, BAY41-2272 and sildenafil reduced the phenylephrine-induced tone in the control group (EC 50 ¼ 1088.87165.0, 151.679.3 and 827.17167.3 nM, respectively). The potencies of NCX-911 and BAY41-2272 were not altered, but that of sildenafil was significantly reduced in the diabetic group. EC 50 values for NCX-911, BAY41-2272 and sildenafil in the diabetic group were 1765.97303.5, 209.7727.3 and 2842.27640.3 nM, respectively (Po0.05 for sildenafil). Nitrergic relaxation responses were significantly decreased in the diabetic group. The remaining nitrergic relaxation responses were potentiated by BAY41-2272 but not by sildenafil or NCX-911. These results confirm that endogenous NO derived from nitrergic nerves is significantly decreased in diabetes, and suggest that NO-releasing PDE5 inhibitors and NO-independent soluble guanylate cyclase activators could be more useful than PDE5 inhibitors in the treatment of ED in long-term diabetes.

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Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction

Cited by 55 publications

References 49 publications

Chuanxiongzine relaxes isolated corpus cavernosum strips and raises intracavernous pressure in rabbits

Chuanxiongzine relaxes isolated corpus cavernosum strips and raises intracavernous pressure in rabbits

Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats

A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats

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Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction

Cited by 55 publications

References 49 publications

Chuanxiongzine relaxes isolated corpus cavernosum strips and raises intracavernous pressure in rabbits

Chuanxiongzine relaxes isolated corpus cavernosum strips and raises intracavernous pressure in rabbits

Activation of dopamine D 4 receptors by ABT-724 induces penile erection in rats

A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats

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Activation of dopamine D ₄ receptors by ABT-724 induces penile erection in rats