Penile erection requires association of soluble guanylyl cyclase with endothelial caveolin-1 in rat corpus cavernosum

2006 ◽  
Vol 290 (5) ◽  
pp. R1302-R1308 ◽  
Author(s):  
A. Elizabeth Linder ◽  
Romulo Leite ◽  
Kimberly Lauria ◽  
Thomas M. Mills ◽  
R. Clinton Webb
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Guanylyl Cyclase ◽  
Penile Erection ◽  
Muscle Relaxation ◽  
Corpus Cavernosum ◽  
Soluble Guanylyl Cyclase ◽  
Smooth Muscle Relaxation ◽  
Membrane Cholesterol ◽  
Caveolin 1

Erectile dysfunction is caused by a variety of pathogenic factors, particularly impaired formation and action of nitric oxide (NO). NO released from nerve endings and corpus cavernosum endothelial cells plays a crucial role in initiating and maintaining increased intracavernous pressure, penile vasodilatation, and penile erection. Classically, these effects are dependent on cGMP synthesized during activation of soluble guanylyl cyclase (sGC) by NO in smooth muscle cells. The enzyme NO synthase in endothelial cells has been localized to caveolae, small invaginations of the plasma membrane rich in cholesterol. Membrane cholesterol depletion impairs acetylcholine-induced relaxation in arteries attributed to an alteration in caveolar structure. It has been shown that sGC may be activated in endothelial caveolae contributing to vasodilation. We hypothesized that caveolae are the platform for sGC/cGMP signaling in cavernosum smooth muscle eliciting erection. Methyl-β-cyclodextrin, a pharmacological tool to deplete membrane cholesterol and disassemble caveolae, impaired rat erectile responses in vivo and cavernosum smooth muscle relaxation induced by the NO donor sodium nitroprusside and the sGC activator 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole in vitro. Methyl-β-cyclodextrin had no effect on cavernosum smooth muscle relaxation induced by NO released upon nerve stimulation or by exogenous cGMP. Furthermore, sGC and caveolin-1, the major coat protein of caveolae, were colocalized in rat corpus cavernosum sinusoidal endothelium. Electron microscopy indicated caveolae disruption in corpus cavernosum treated with methyl-β-cyclodextrin. In summary, our results provide evidence of compartmentalization of sGC in the caveolae of cavernosal endothelial cells contributing to NO signaling mediating smooth muscle relaxation and erection.

Soluble guanylyl cyclase expression is reduced in allergic asthma

2006 ◽  
Vol 290 (1) ◽  
pp. L179-L184 ◽  
Author(s):  
Andreas Papapetropoulos ◽  
Davina C. M. Simoes ◽  
Georgia Xanthou ◽  
Charis Roussos ◽  
Christina Gratziou
Keyword(s):  
Smooth Muscle ◽  
Allergic Asthma ◽  
Guanylyl Cyclase ◽  
Muscle Relaxation ◽  
Soluble Guanylyl Cyclase ◽  
Airway Hyperreactivity ◽  
Smooth Muscle Relaxation ◽  
Mrna Levels ◽  
Bronchial Smooth Muscle Cells ◽  
Biochemical Analyses

Soluble guanylyl cyclase (sGC) is an enzyme highly expressed in the lung that generates cGMP contributing to airway smooth muscle relaxation. To determine whether the bronchoconstriction observed in asthma is accompanied by changes in sGC expression, we used a well-established murine model of allergic asthma. Histological and biochemical analyses confirmed the presence of inflammation in the lungs of mice sensitized and challenged with ovalbumin (OVA). Moreover, mice sensitized and challenged with OVA exhibited airway hyperreactivity to methacholine inhalation. Steady-state mRNA levels for all sGC subunits (α1, α2, and β1) were reduced in the lungs of mice with allergic asthma by 60–80%, as estimated by real-time PCR. These changes in mRNA were paralleled by changes at the protein level: α1, α2, and β1 expression was reduced by 50–80% as determined by Western blotting. Reduced α1 and β1 expression in bronchial smooth muscle cells was demonstrated by immunohistochemistry. To study if sGC inhibition mimics the airway hyperreactivity seen in asthma, we treated naïve mice with a selective sGC inhibitor. Indeed, in mice receiving ODQ the methacholine dose response was shifted to the left. We conclude that sGC expression is reduced in experimental asthma contributing to the observed airway hyperreactivity.

scholarly journals Erectile dysfunction: from biochemical pharmacology to advances in medical therapy

2000 ◽  
Vol 143 (2) ◽  
pp. 143-154 ◽  
Author(s):  
M Maggi ◽  
S Filippi ◽  
F Ledda ◽  
A Magini ◽  
G Forti
Keyword(s):  
Smooth Muscle ◽  
Erectile Dysfunction ◽  
Cyclic Nucleotide ◽  
Penile Erection ◽  
Muscle Relaxation ◽  
Corpus Cavernosum ◽  
Specific Inhibitor ◽  
Smooth Muscle Relaxation ◽  
Muscle Physiology ◽  
Orally Active

Research on penile smooth muscle physiology has increased the number of drugs available for treating erectile dysfunction (ED). Penile erection involves the relaxation of smooth muscle in the corpus cavernosum. The key mediator of smooth muscle relaxation is nitric oxide (NO), which acts by increasing the cellular level of cGMP. Another cyclic nucleotide, cAMP, is involved in smooth muscle cell relaxation; cAMP formation is stimulated by a number of compounds, such as alprostadil. An increase in cAMP and/or cGMP levels can also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildenafil are PDE inhibitors. Papaverine is a non-specific inhibitor of these enzymes; sildenafil is an orally active, potent and selective inhibitor of GMP-specific PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the corpus cavernosum. Penile smooth muscle contraction, induced by adrenergic fibers through alpha(1) adrenoceptors, produces detumescence, thus making alpha adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed alpha(1)-alpha(2) adrenoceptor antagonist that works by a dual mechanism; it facilitates sexual arousal by acting on alpha(2) adrenoceptors in the central nervous system and blocks adrenergic influences at peripheral level.

Up-Regulation of NO/cGMP Signaling Pathway in Corpus Cavernosum of Sickle Cell Disease Transgenic Mice

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2495-2495
Author(s):  
Mário Angelo Claudino ◽  
Carla Fernanda Franco-Penteado ◽  
Marcus A.F. Corat ◽  
Luiz Augusto C Passos ◽  
Ana Paula Gimenes ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Sickle Cell Disease ◽  
Signaling Pathway ◽  
Penile Erection ◽  
Muscle Relaxation ◽  
Corpus Cavernosum ◽  
Smooth Muscle Relaxation ◽  
Control Group ◽  
Cell Disease ◽  
Cgmp Signaling

Abstract Priapism is defined as prolonged and persistent penile erection, unassociated with sexual interest or stimulation. This condition is common among males with sickle cell disease (SCD), however the molecular mechanisms involved in this syndrome are not well understood. Penile nitric oxide (NO), originating from both neurons and endothelium, modulates penile vascular and smooth muscle relaxation. NO, by binding sGC, converts cyclic guanosine triphosphate (cGTP) to cyclic guanosine monophosphate (cGMP), relaxing vascular smooth muscle and causing penile erection. The Berkeley mouse model is a well-accepted animal model of severe anemia that displays features of priapism similar to those seen in humans. These animals have a decreased activity of the enzyme responsible for cGMP hydrolysis, phosphodiesterase type 5A (PDE5) in the penis, suggesting that dysregulated NO signaling may lead to priapism in this mice model. Thus, the aim of this study was to evaluate the cavernosum smooth muscle relaxation mediated by the NO-cGMP signaling pathway in the SCD transgenic mouse. SS mice and normal C57BL/6 mice (control) penile tissues were removed at the level of attachment of the corporeal body; tunica albuginea was then carefully opened from its proximal extremity toward the penile shaft, and the erectile tissue within the corpus cavernosum (CC) was surgically dissected free. The strips were mounted in 10 ml organ baths containing Krebs solution at 37°C that was continuously bubbled with a mixture of 95% oxygen and 5% carbon dioxide (pH 7.4), and vertically suspended between two metal hooks. The tissues were stretched to a resting tension of 2.5 mN and allowed to equilibrate for 60 min. Changes in isometric force were recorded using a PowerLab 400 Data Acquisition System (Software Chart, version 5.2, AD Instruments, Colorado Springs, Colo). In a first set of experiments, cumulative concentration-response curves were constructed for a muscarinic agonist, acetylcholine (ACh; 0.001–1 μM), the NO donor compound, sodium nitroprusside (SNP; 0.001–10 μM) and the NO-independent stimulator of soluble guanylyl cyclase (sGC), BAY 41–2272 (0.001–10 μM), in corpus cavernosum (CC) precontracted with phenylephrine (PE; 10 μM). In a second set of experiments, to evaluate the nitrergic cavernosal relaxations, an electrical field stimulation (EFS; 1–32 Hz; 50 V; 10-s trains) was used. EFS were applied in strips placed between two platinum ring electrodes connected to a Grass S88 stimulator (Astro-Med Industrial Park, RI, U.S.A.). The endothelium-dependent NO-mediated relaxing responses to ACh induced concentration-dependent CC relaxations, and both potency (pEC50; 7.27 ± 0.09) and maximal responses (Emax; 78 ± 5%) were significantly higher in SS mice, compared with control mice (6.85 ± 0.07 and 60 ± 3%, respectively). EFS-induced relaxations in SS mice CC were significantly increased in all frequency studies compared to control mice. The endothelium-independent NOmediated relaxing responses to SNP produced concentration-dependent relaxation in isolated mice CC and both pEC50 (6.30 ± 0.09) and Emax (113 ± 6%) were significantly increased in the SS group when compared to the control group (5.80 ± 0.15 and 83 ± 4%, respectively). The NO-independent sGC stimulator, BAY 41–2272, induced significant increases in both pEC50 (7.07 ± 0.05) and Emax (124 ± 5 %) in the SS group when compared to the control group (6.78 ± 0.06 and 99 ± 2 %). In summary, these data demonstrate that SS mice exhibit an excessive relaxation response in CC, possibly by up-regulation of the NO-cGMP signaling pathway, reflecting in uncontrolled erection function. As such this dysregulated NO-pathway may constitute a potential therapeutic target to treat priapism in SCD individuals.

Sign in / Sign up

Export Citation Format

Share Document