The NO-cGMP-PKG pathway in skeletal remodeling.

The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway plays a critical role in skeletal homeostasis. Preclinical data using NO and its donors and genetically modified mice demonstrated that NO was required in bone remodeling and partly mediated the anabolic effects of mechanical stimuli and estrogen. However, the off-target effects and tachyphylaxis of NO limit its long-term use, and previous clinical trials using organic nitrates for osteoporosis have been disappointing. Among the other components in the downstream pathway, targeting cGMP-specific phosphodiesterase to promote the NO-cGMP-PKG signal is a viable option. There are growing in vitro and in vivo data that, among many other PDE families, PDE5A is highly expressed in skeletal tissue, and inhibiting PDE5A using currently available PDE5A inhibitors might increase the osteoanabolic signal and protect the skeleton. These preclinical data open the possibility of repurposing PDE5A inhibitors for treating osteoporosis. Further research is needed to address the primary target bone cell of PDE5A inhibition, the contribution of direct and indirect effects of PDE5A inhibition, and the pathophysiological changes in skeletal PDE5A expression in aging and hypogonadal animal models.

Phosphodiesterase 5 Associates With ß2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts.

Background In murine heart failure models and in humans with diabetic-related heart hypertrophy, inhibition of phosphodiesterase 5 (PDE5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between PDE5 and ß2 adrenergic receptor (ß2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild-type and ß2AR knockout mice fed a high fat diet (HFD) were treated with sildenafil, and echocardiogram analysis was performed. Cardiomyocytes were isolated for excitation-contraction (E-C) coupling, fluorescence resonant energy transfer, and proximity ligation assays; while heart tissues were implemented for biochemical and histological analyses. PDE5 selectively associates with ß2AR, but not ß1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances ß adrenergic receptor (ßAR)-stimulated cGMP and cAMP signals in HFD myocytes. Consequently, inhibition of PDE5 leads to protein kinase G-, and to a lesser extent, calcium/calmodulin-dependent kinase II-dependent improvements in adrenergically stimulated E-C coupling. Deletion of ß2AR abolishes sildenafil's effect. Although the PDE5-ß2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the ß2AR-PDE5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the ß2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances ß2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.

Testosterone Deficiency and Endothelial Dysfunction: Nitric Oxide, Asymmetric Dimethylarginine, and Endothelial Progenitor Cells.

INTRODUCTION: Testosterone deficiency is known to induce endothelial dysfunction, which can lead to erectile dysfunction and/or vascular dysfunction. In some basic and clinical reports, testosterone has been shown to regulate the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway and thereby influence endothelial function and endothelial progenitor cells (EPCs), which are key for the endothelial repair system. AIM: To review the association between testosterone and endothelial dysfunction focusing on NO and EPCs. METHODS: A review of relevant literature up to September 2018 was performed via PubMed. MAIN OUTCOME MEASURES: We reviewed the association between testosterone and endothelial dysfunction focusing on NO derived from endothelial NO synthase, phosphodiesterase type 5 (PDE-5), asymmetric dimethylarginine (ADMA), inflammation, and EPCs. RESULTS: Numerous articles describing the association between testosterone deficiency and endothelial dysfunction have been published. Some reports have shown that testosterone deficiency decreases NO production by altering the expression and activity of NO synthase and by regulating ADMA expression. Testosterone also regulates the expression of phosphodiesterase type 5. In addition, some basic and clinical studies have shown that testosterone affects the function and number of EPCs. However, some inconsistencies among these reports have been noted. CONCLUSION: Testosterone deficiency might cause endothelial dysfunction by decreasing NO levels through regulating the expression and activity of NO synthase and increasing ADMA expression. In addition, testosterone might affect the endothelial repair system by regulating the proliferation and migration of EPCs. Testosterone replacement therapy might be useful for treating endothelial dysfunction, considering that some reports have shown that this therapy improved NO bioavailability and EPC function. Hotta Y, Kataoka T, Kimura K. Testosterone Deficiency and Endothelial Dysfunction: Nitric Oxide, Asymmetric Dimethylarginine, and Endothelial Progenitor Cells. Sex Med Rev 2019;7:661-668.

Lower urinary tract symptoms/benign prostatic hypertrophy and vascular function: Role of the nitric oxide-phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate pathway.

It is well known that there is an association of lower urinary tract symptoms/benign prostatic hypertrophy with cardiovascular disease, suggesting that lower urinary tract symptoms/benign prostatic hypertrophy is a risk factor for cardiovascular events. Vascular function, including endothelial function and vascular smooth muscle function, is involved in the pathogenesis, maintenance and development of atherosclerosis, leading to cardiovascular events. Vascular dysfunction per se should also contribute to lower urinary tract symptoms/benign prostatic hypertrophy. Both lower urinary tract symptoms/benign prostatic hypertrophy and vascular dysfunction have cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes mellitus, aging, obesity and smoking. Inactivation of the phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate-nitric oxide pathway causes lower urinary tract symptoms/benign prostatic hypertrophy through an enhancement of sympathetic nervous activity, endothelial dysfunction, increase in Rho-associated kinase activity and vasoconstriction, and decrease in blood flow of pelvic viscera. Both endogenous nitric oxide and exogenous nitric oxide act as vasodilators on vascular smooth muscle cells through an increase in the content of cyclic guanosine 3',5'-monophosphate, which is inactivated by phosphodiesterase type 5. In a clinical setting, phosphodiesterase type 5 inhibitors are widely used in patients with lower urinary tract symptoms/benign prostatic hypertrophy. Phosphodiesterase type 5 inhibitors might have beneficial effects on vascular function through not only inhibition of cyclic guanosine 3',5'-monophosphate degradation, but also increases in testosterone levels and nitric oxide bioavailability, increase in the number and improvement of the function of endothelial progenitor cells, and decrease in insulin resistance. In the present review, the relationships between lower urinary tract symptoms/benign prostatic hypertrophy, the phosphodiesterase type 5-nitric oxide-cyclic guanosine 3',5'-monophosphate pathway, vascular function and cardiovascular outcomes are examined.

Use of sildenafil or other phosphodiesterase inhibitors and risk of melanoma.

BACKGROUND: Phosphodiesterase 5A inhibitors (PDEIs), a common treatment for erectile dysfunction, were recently linked to an increased risk of melanoma. METHODS: We conducted two parallel case-control studies, using the Danish Nationwide Health Registries (DNHR) and the Kaiser Permanente Northern California (KPNC) electronic health records. Identifying men with histologically verified melanoma (cases) matched on birth year to 10 cancer-free controls, we estimated odds ratios (OR) for melanoma associated with high use of PDEIs (⩾100 tablets filled), adjusting for available confounders. RESULTS: We identified 7045 DNHR and 2972 KPNC cases with invasive melanoma. The adjusted OR for invasive melanoma associated with high PDEI use was 1.22 (95% confidence interval (CI), 0.99-1.49) in DNHR and 0.95 (95% CI, 0.78-1.14) in KPNC. Odds ratios were highest for localised invasive melanoma in DNHR (OR, 1.21) and melanoma in situ in KPNC (OR, 1.15), and lowest for non-localised disease in both populations (ORs 0.75 and 0.61, respectively). The increased ORs were slightly attenuated upon adjustment for markers of health-care utilisation. CONCLUSIONS: We found little evidence for a causal association between PDEI use and risk of melanoma. The marginally increased risk of early stage disease likely resulted from more frequent health-care contacts among PDEI users.

The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure.

The right ventricle (RV) is the major determinant of functional state and prognosis in pulmonary arterial hypertension. RV hypertrophy (RVH) triggered by pressure overload is initially compensatory but often leads to RV failure. Despite similar RV afterload and mass some patients develop adaptive RVH (concentric with retained RV function), while others develop maladaptive RVH, characterized by dilatation, fibrosis, and RV failure. The differentiation of adaptive versus maladaptive RVH is imprecise, but adaptive RVH is associated with better functional capacity and survival. At the molecular level, maladaptive RVH displays greater impairment of angiogenesis, adrenergic signaling, and metabolism than adaptive RVH, and these derangements often involve the left ventricle. Clinically, maladaptive RVH is characterized by increased N-terminal pro-brain natriuretic peptide levels, troponin release, elevated catecholamine levels, RV dilatation, and late gadolinium enhancement on MRI, increased (18)fluorodeoxyglucose uptake on positron emission tomography, and QTc prolongation on the ECG. In maladaptive RVH there is reduced inotrope responsiveness because of G-protein receptor kinase-mediated downregulation, desensitization, and uncoupling of ß-adrenoreceptors. RV ischemia may result from capillary rarefaction or decreased right coronary artery perfusion pressure. Maladaptive RVH shares metabolic abnormalities with cancer including aerobic glycolysis (resulting from a forkhead box protein O1-mediated transcriptional upregulation of pyruvate dehydrogenase kinase), and glutaminolysis (reflecting ischemia-induced cMyc activation). Augmentation of glucose oxidation is beneficial in experimental RVH and can be achieved by inhibition of pyruvate dehydrogenase kinase, fatty acid oxidation, or glutaminolysis. Therapeutic targets in RV failure include chamber-specific abnormalities of metabolism, angiogenesis, adrenergic signaling, and phosphodiesterase-5 expression. The ability to restore RV function in experimental models challenges the dogma that RV failure is irreversible without regression of pulmonary vascular disease.

Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice.

Age-related cognitive decline is accompanied by an increase of neuronal apoptosis and a dysregulation of neuroplasticity-related molecules such as brain-derived neurotrophic factor and neurotoxic factors including beta amyloid (Aß) peptide. Because it has been previously demonstrated that phosphodiesterase-5 inhibitors (PDE5-Is) protect against hippocampal synaptic dysfunction and memory deficits in mouse models of Alzheimer's disease and physiological aging, we investigated the effect of a treatment with the PDE5-I, sildenafil, on cell death, pro- and antiapoptotic molecules, and Aß production. We demonstrated that chronic intraperitoneal injection of sildenafil (3 mg/kg for 3 weeks) decreased terminal deoxyuridine triphosphate nick end labeling-positive cells in the CA1 hippocampal area of 26-30-month-old mice, downregulating the proapoptotic proteins, caspase-3 and B-cell lymphoma 2-associated X, and increasing antiapoptotic molecules such as B-cell lymphoma protein-2 and brain-derived neurotrophic factor. Also, sildenafil reverted the shifting of amyloid precursor protein processing toward Aß42 production and the increase of the Aß42:Aß40 ratio in aged mice. Our data suggest that PDE5-I might be beneficial to treat age-related detrimental features in a physiological mouse model of aging.

Presence of phosphodiesterase type 5 in the spinal cord and its involvement in bladder outflow obstruction related bladder overactivity.

PURPOSE: Phosphodiesterase type 5 inhibitors were recently introduced as a new treatment option for men with lower urinary tract symptoms. Safety and clinical effectiveness are well documented but the mode of action is still unclear. We determined and compared the expression of phosphodiesterase type 5 in the spinal cord of normal (sham operated) rats and rats with partial urethral obstruction induced bladder overactivity. We also assessed the urodynamic effects of intravenously and intrathecally administered sildenafil in the rats to determine whether phosphodiesterase type 5 inhibitors exert effects on the sacral spinal cord. MATERIALS AND METHODS: A total of 65 male Sprague-Dawley rats were used for molecular/morphological and functional experiments. Bladder overactivity was induced via surgical partial urethral obstruction in 39 of 65 rats. Spinal phosphodiesterase type 5 expression was assessed by histology and polymerase chain reaction. The effects of sildenafil administered intravenously or intrathecally were studied urodynamically. RESULTS: Phosphodiesterase type 5 was expressed in various regions of the lumbosacral spinal cord, including the sacral regions of micturition control. Expression was similar in normal rats and rats with partial urethral obstruction/bladder overactivity. In normal rats intravenous and intrathecal sildenafil had no urodynamic effect. When administered intravenously and intrathecally to rats with partial urethral obstruction/bladder overactivity, sildenafil decreased micturition frequency and bladder pressure. Doses tested intrathecally had no effect when given intravenously. CONCLUSIONS: Phosphodiesterase type 5 is expressed in the rat spinal cord. Intravenous sildenafil may exert part of its urodynamic effect in rats with partial urethral obstruction/bladder overactivity via an effect on the sacral spinal cord.

Direct androgen regulation of PDE5 gene or the lack thereof.

Inhibition of phosphodiesterase-5 (PDE5) is a well-known mechanism for the effective treatment of erectile dysfunction (ED). Androgen supplementation has also been prescribed for treating ED. However, it has been widely accepted that androgen can upregulate PDE5 expression, and thus creating a paradox in which a positive regulator of erectile function (androgen) could possibly increase the level of a negative regulator (PDE5). To solve this paradox, we conducted a systematic search of the PubMed and a non-systematic search of the Internet using PDE5, erectile, penis, testosterone and androgen as keywords. The retrieved papers were analyzed for data concerning the expression and regulation of PDE5 by androgens. Human and rat PDE5A gene sequences were retrieved from GenBank and computer-analyzed. The results showed that a putative androgen-response element (ARE) was reported in a study of human PDE5A gene promoter, and this prompted a separate study on whether androgen regulates PDE5 expression. The positive outcome in the latter study has since been cited in 17 review and editorial articles as the underlying mechanism for androgen's therapeutic effects on ED. In addition, five other research studies also reached the same conclusion. On the other hand, two independent studies on the genome-wide searches for androgen-regulated genes did not find PDE5A as a candidate. Sequence analysis conducted in this study also failed to find ARE in rat PDE5A gene. Two independent studies on Leydig cells also failed to find positive regulation of PDE5 expression by androgen. Two other studies found concomitant reduction of cavernous smooth muscle and PDE5 expression in castrated rats. One of these studies also found no effect of androgen on PDE5 expression in cultured cavernous smooth muscle cells. Thus, it appears that reduced PDE5 expression in castrated animals is due to reduced smooth muscle content and that PDE5A gene is not directly regulated by androgens.

Phosphodiesterase-5 expression and function in the lower urinary tract: a critical review.

Both clinical and preclinical studies have mostly shown beneficial effects for Phosphodiesterase-5 (PDE-5) inhibitors in the treatment of lower urinary tract symptoms. Molecular studies have consistently shown abundant PDE-5 expression in bladder smooth muscle. Data concerning urethral PDE-5 expression have been surprising because striated muscle was not only positively identified, but also found to express more PDE-5 than the smooth muscle. In the prostate, highly variable results have been obtained. For PDE-5 expression, the data have ranged from extremely low to highly abundant. PDE-5 has been found in the glandular epithelium, vascular smooth muscle, endothelium, and fibromuscular stroma.

Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: indications for central and peripheral mechanisms.

A promising target for memory improvement is phosphodiesterase type 5 (PDE5), which selectively hydrolyzes cyclic guanosine monophosphate (cGMP). In rodents, PDE5 inhibitors (PDE5-Is) have been shown to improve memory performance in many behavioral paradigms. However, it is questioned whether the positive effects in animal studies result from PDE5 inhibition in the central nervous system or the periphery. Therefore, we studied the effects of PDE5 inhibition on memory and determined whether compound penetration of the blood-brain barrier (BBB) is required for this activity. Two selective PDE5-Is, vardenafil and UK-343,664, were tested in the object recognition task (ORT) in both a MK-801- and scopolamine-induced memory deficit model, and a time-delay model without pharmacological intervention. Compounds were dosed 30 min before the learning trial of the task. To determine if the PDE5-Is crossed the BBB, their concentrations were determined in plasma and brain tissue collected 30 min after oral administration. Vardenafil improved object recognition memory in all three variants of the ORT. UK-343,664 was ineffective at either preventing MK-801-induced memory disruption or time-dependent memory decay. However, UK-343,664 attenuated the memory impairment of scopolamine. Vardenafil crossed the BBB whereas UK-343,664 did not. Further, co-administration of UK-343,664 and scopolamine did not alter the brain partitioning of either molecule. This suggests that the positive effect of UK-343,664 on scopolamine-induced memory decay might arise from peripheral PDE5 inhibition. The results herein suggest that there may be multiple mechanisms that mediate the efficacy of PDE5 inhibition to improve memory performance in tasks such as the ORT and that these involve PDE5 located both within and outside of the brain. To further elucidate the underlying mechanisms, the cellular and subcellular localization of PDE5 needs to be determined.

cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.

Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.

New insights into the pathophysiology of sickle cell disease-associated priapism.

INTRODUCTION: Priapism is defined as an erectile disorder, in which erection persists uncontrollably without sexual purpose. The precise mechanisms involved in the development of sickle cell disease-associated priapism are ill defined. AIM: To summarize the recent developments that increase our understanding of the molecular mechanisms of priapism. METHODS: This article reviews the literature (Medline search 2000-2010) that relates the key molecular signaling pathways that contribute to the development of priapism associated with sickle-cell disease. It focuses on basic science investigations using multiple animal models. MAIN OUTCOME MEASURES: The reader will be informed of the most current research regarding the role of endothelial nitric oxide synthase, phosphodiesterase type 5 (PDE5), adenosine, RhoA/Rho-kinase (ROCK), and opiorphins in the pathophysiology of priapism. RESULTS: New concepts in the field of priapism research suggest that priapism often results from altered vascular homeostatic actions in the penis and is associated with deficient erection control mechanisms on a molecular level. A leading proposal in this regard is the notion of aberrant signaling of the endothelium-derived nitric oxide and PDE5 signal transduction pathway in the penis. Additionally, dysfunctional regulatory control of signal transduction systems which interact with this pathway such as adenosine and RhoA/Rho-kinase may contribute to the development of priapism. Recent investigations of opiorphins also demonstrate a role in regulating corporal smooth muscle tone and thereby dysregulation of erection physiology in priapism. These advances have paved the way for understanding this disorder as having a molecular pathogenesis. CONCLUSIONS: As the science underlying priapism further emerges, increasingly effective therapeutics for sickle cell disease-associated priapism is certain to follow.

cGMP-dependent protein kinase contributes to hydrogen sulfide-stimulated vasorelaxation.

A growing body of evidence suggests that hydrogen sulfide (H2S) is a signaling molecule in mammalian cells. In the cardiovascular system, H2S enhances vasodilation and angiogenesis. H2S-induced vasodilation is hypothesized to occur through ATP-sensitive potassium channels (K(ATP)); however, we recently demonstrated that it also increases cGMP levels in tissues. Herein, we studied the involvement of cGMP-dependent protein kinase-I in H2S-induced vasorelaxation. The effect of H2S on vessel tone was studied in phenylephrine-contracted aortic rings with or without endothelium. cGMP levels were determined in cultured cells or isolated vessel by enzyme immunoassay. Pretreatment of aortic rings with sildenafil attenuated NaHS-induced relaxation, confirming previous findings that H2S is a phosphodiesterase inhibitor. In addition, vascular tissue levels of cGMP in cystathionine gamma lyase knockouts were lower than those in wild-type control mice. Treatment of aortic rings with NaHS, a fast releasing H2S donor, enhanced phosphorylation of vasodilator-stimulated phosphoprotein in a time-dependent manner, suggesting that cGMP-dependent protein kinase (PKG) is activated after exposure to H2S. Incubation of aortic rings with a PKG-I inhibitor (DT-2) attenuated NaHS-stimulated relaxation. Interestingly, vasodilatory responses to a slowly releasing H2S donor (GYY 4137) were unaffected by DT-2, suggesting that this donor dilates mouse aorta through PKG-independent pathways. Dilatory responses to NaHS and L-cysteine (a substrate for H2S production) were reduced in vessels of PKG-I knockout mice (PKG-I⁻/⁻). Moreover, glibenclamide inhibited NaHS-induced vasorelaxation in vessels from wild-type animals, but not PKG-I⁻/⁻, suggesting that there is a cross-talk between K(ATP) and PKG. Our results confirm the role of cGMP in the vascular responses to NaHS and demonstrate that genetic deletion of PKG-I attenuates NaHS and L-cysteine-stimulated vasodilation.

Tadalafilo: nuevos aspectos de la inhibición de la fosfodiesterasa tipo 5 en el tratamiento de la hipertensión pulmonar / Tadalafil: Novel aspects of phosphodiesterase-5 inhibition in the treatment of pulmonary hypertension

Desde 2009, el tadalafilo, un potente y selectivo inhibidor de la fosfodiesterasa tipo 5 (PDE5), puede representar una nueva alternativa terapéutica eficaz y segura para pacientes con hipertensión pulmonar (HP) en clases funcionales II y III de la Organización Mundial de la Salud (OMS) —como detallan las «Guías de práctica clínica para el diagnóstico y tratamiento de la HP» de la Sociedad Europea de Cardiología (ESC) y de la European Respiratory Society (ERS)—, en términos de beneficios en ejercicio, en retraso del deterioro clínico y en calidad de vida. Por otra parte, dado su mayor vida media, que permite su dosificación única diaria oral de 40 mg, podría mejorar el cumplimiento terapéutico —facilitando una mayor adhesión al tratamiento— de los pacientes con HP (AU)

Tadalafil, which was commercialized in 2009, is a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, and may be a safe and effective therapeutic alternative for patients with class II and III pulmonary hypertension (PH) in the World Health Organization’s classification – as stated in the Clinical Practice Guidelines for the Diagnosis and Treatment of PH of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) – providing benefits in exercise tolerance, delaying clinical deterioration and improving quality of life. Given the greater half-life of this drug, allowing a single oral dose of 40 mg per day, tadalafil could improve therapeutic compliance – thus facilitating treatment adherence – among patients with PH (AU)

Evaluation of the therapeutic utility of phosphodiesterase 5A inhibition in the mdx mouse model of duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a devastating and ultimately fatal disease characterized by progressive muscle wasting and weakness. DMD is caused by the absence of a functional dystrophin protein, which in turn leads to reduced expression and mislocalization of dystrophin-associated proteins including neuronal nitric oxide (NO) synthase mu (nNOSµ). Disruption of nNOSµ signaling results in muscle fatigue and unopposed sympathetic vasoconstriction during exercise, thereby increasing contraction-induced damage in dystrophin-deficient muscles. The loss of normal nNOSµ signaling during exercise is central to the vascular dysfunction proposed over 40 years ago to be an important pathogenic mechanism in DMD. Recent preclinical studies focused on circumventing defective nNOSµ signaling in dystrophic skeletal and cardiac muscle by inhibiting phosphodiesterase 5A (PDE5A) have shown promising results. This review addresses nNOS signaling in normal and dystrophin-deficient muscles and the potential of PDE5A inhibition as a therapeutic approach for the treatment of cardiovascular deficits in DMD.

[Tadalafil: novel aspects of phosphodiesterase-5 inhibition in the treatment of pulmonary hypertension]. / Tadalafilo: nuevos aspectos de la inhibición de la fosfodiesterasa tipo 5 en el tratamiento de la hipertensión pulmonar.

Tadalafil, which was commercialized in 2009, is a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, and may be a safe and effective therapeutic alternative for patients with class II and III pulmonary hypertension (PH) in the World Health Organization's classification--as stated in the Clinical Practice Guidelines for the Diagnosis and Treatment of PH of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)--providing benefits in exercise tolerance, delaying clinical deterioration and improving quality of life. Given the greater half-life of this drug, allowing a single oral dose of 40 mg per day, tadalafil could improve therapeutic compliance--thus facilitating treatment adherence--among patients with PH.

[Regulation of cardiovascular functions by the phosphorylation of TRPC channels].

Calcium ions (Ca²(+)) play an essential role in homeostasis and the activity of cardiovascular cells. Ca²(+) influx across the plasma membrane induced by neurohumoral factors or mechanical stress elicits physiologically relevant timing and spatial patterns of Ca²(+) signaling, which leads to the activation of various cardiovascular functions, such as muscle contraction, gene expression, and hypertrophic growth of myocytes. A canonical transient receptor potential protein subfamily member, TRPC6, which is activated by diacylglycerol and mechanical stretch, works as an upstream regulator of the Ca²(+) signaling pathway required for pathological hypertrophy. We have recently found that the inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppresses agonist- and mechanical stretch-induced hypertrophy through inhibition of Ca²(+) influx in rat cardiomyocytes. The inhibition of PDE5 suppressed the increase in frequency of Ca²(+) spikes induced by receptor stimulation or mechanical stretch. Activation of protein kinase G by PDE5 inhibition phosphorylated TRPC6 proteins at Thr69 and prevented TRPC6-mediated Ca²(+) influx. Substitution of Ala for Thr69 in TRPC6 abolished the antihypertrophic effects of PDE5 inhibition. These results suggest that phosphorylation and functional suppression of TRPC6 underlies the prevention of cardiac hypertrophy by PDE5 inhibition. As TRPC6 proteins are also expressed in vascular smooth muscle cells and reportedly participate in vascular remodeling, TRPC6 blockade may be an effective therapeutic strategy for preventing pathologic cardiovascular remodeling.