Updates on Pityriasis Rubra Pilaris: A Scoping Review.

Pityriasis rubra pilaris (PRP) is a rare, inflammatory papulosquamous skin disease with unknown exact etiology. Historically, PRP has been challenging to diagnose, especially during the acute phase, and to treat, due to its unclear pathogenesis. To better inform clinical practice, a literature review was conducted employing a broad search strategy to capture PRP-related published studies between January 1, 2012 to October 31, 2022. Two hundred twenty-one studies were identified, which were categorized into 9 themes: (1) potential causes and triggering factors, (2) comorbidities, (3) diagnostic difficulties, (4) genetics, (5) clinical manifestations and laboratory values, (6) treatment, (7) treatment-related adverse events, (8) quality of life, and (9) other. COVID-19 infection, COVID-19 vaccination, and malignancy were the most commonly reported potential triggering factors. Misdiagnosis is very common during the early acute stages. Pathogenesis and genetic studies have further implicated caspase recruitment domain family member 14 (CARD14) mutations in the development of familial PRP (Type V) and have underlined the overlap between psoriasis and PRP. To date, there are currently no specific and validated scoring systems or tools to assess the severity of PRP. While large, randomized trials are still lacking, biologic agents remain the most effective therapy.

Treatment Options for Juvenile Pityriasis Rubra Pilaris.

Pityriasis rubra pilaris represents a group of familial and acquired disorders of cornification that affect both adult and pediatric patients. Treatment options are difficult to assess through clinical trials, given the rarity of the disorder and its tendency for spontaneous remission. Case reports and case series are therefore the primary means of assessment. Because of the heterogeneity of the disease, there is no universal approach to treatment, and multiple agents may need to be trialed to achieve disease control. At present, topicals are used for most pediatric patients, though monotherapy with topicals is only effective for less severe disease. Despite concerns over their side-effect profiles, oral retinoids are generally accepted as a first-line systemic therapy. However, interleukin-17 inhibitors and ustekinumab, an interleukin-12 and interleukin-23 inhibitor, may soon become first-line systemic treatment as well, given their efficacy and relative safety in trials thus far. Ustekinumab, in particular, is emerging as a first-line agent for patients with pityriasis rubra pilaris with CARD14 gene variations. When these therapies fail, second-line and adjunctive therapies to consider include tumor necrosis factor-alpha inhibitors, methotrexate, and phototherapy. However, further investigation is necessary to assess the safety and efficacy of many of these agents in juvenile pityriasis rubra pilaris.

Successful treatment with ustekinumab in CARD14-associated papulosquamous eruption in a Brazilian child.

CARD14-associated papulosquamous eruption (CAPE) was proposed in 2018 to describe the clinical features of psoriasis and pityriasis rubra pilaris with CARD 14 mutations. We report a 5-month-old female infant who developed CAPE-associated erythroderma. Although she did not respond to conventional therapies, she responded well to ustekinumab treatment at the age of 4 years.

Generalized Pustular Psoriasis: A Review of the Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment.

Generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis that is characterized by the abrupt widespread onset of small pustules accompanied by systemic manifestations of inflammation. It can arise in patients with a history of psoriasis as well as in those without, sometimes due to medication initiation or withdrawal, pregnancy, or infection. Generalized pustular psoriasis is thought to be driven primarily by innate immunity and unrestrained IL-36 cytokine activity. Recent genetic analyses have identified 3 genetic mutations that are associated with GPP-IL36RN, CARD14, and AP1S3-though these mutations only account for a minority of cases. There are many cutaneous pustular diseases that must be ruled out in the evaluation of a patient with suspected GPP, especially acute generalized exanthematous pustulosis (AGEP), and histologic analysis is the cornerstone of diagnosis. Although the quality of evidence to generate treatment recommendations for GPP is limited, management often includes utilization of systemic agents and/or biologics, usually with adjunctive topical treatment. Accumulating evidence suggests that biologic agents, especially infliximab, may be considered as first-line treatment of GPP, especially in severe acute cases, due to their abrupt onset of action and favorable side-effect profiles compared with oral systemic agents.

Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC.

BACKGROUND: Oxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential. METHODS: We aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592). RESULTS: Mosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model. CONCLUSION: Inhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.

Inflammatory linear verrucous epidermal nevus (ILVEN) encompasses a spectrum of inflammatory mosaic disorders.

BACKGROUND: Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease characterized by pruritic erythematous scaly plaques distributed along the lines of Blaschko. Two cases of ILVEN with CARD14 mutations and one case with a GJA1 mutation have been previously reported. OBJECTIVE: To elucidate the genetic cause of a cohort of patients diagnosed based on clinical and histopathological evaluation with ILVEN. METHODS: We recruited patients diagnosed with ILVEN based on clinical and histopathological criteria. Exome sequencing of affected skin with or without blood/saliva was performed and germline and somatic pathogenic variants were identified. RESULTS: Five patients were enrolled. All had skin lesions from birth or early childhood. Two patients developed psoriasis vulgaris after the diagnosis of ILVEN. The first had a germline heterozygous CARD14 mutation and a post-zygotic hotspot mutation in KRT10. The histopathologic evaluation did not show epidermolytic hyperkeratosis. The second had a post-zygotic hotspot mutation in HRAS. Her ILVEN became itchy once psoriasis developed. One patient was re-diagnosed with linear porokeratosis based on a germline mutation in PMVK and a post-zygotic second-hit mutation. Two patients were re-diagnosed with congenital hemidysplasia with ichthyosiform nevus and limb defect nevus based on germline NSDHL mutations. CONCLUSION: ILVEN is a clinical descriptor for a heterogenous group of mosaic inflammatory disorders. Genetic analysis has the potential to more precisely categorize ILVEN and permits pathogenesis-directed therapies in some cases.

Pustular psoriasis of pregnancy: Clinical and genetic characteristics in a series of eight patients and review of the literature.

Pustular psoriasis of pregnancy (PPP) can lead to life-threatening complications. The objective of this study is to report clinical and genetic spectrum, prognostic factors and management options. A retrospective study was designed including eight PPP patients. Clinical data were collected, and performed genetic and statistical analysis to identify factors associated with fetal complications, resistance to treatment and post-partum flare extension. A systematic review of the literature was also carried out. Eight Tunisian patients, with a mean age of 23 ± 3.3 years, were included. They presented 14 flares (F) during pregnancies and one flare after delivery. Additional GPP flares outside pregnancy periods were noted in 2/8 of patients. The mean duration of PPP flares was 16.66 ± 7.8 weeks. The first flare occurred at a gestational age of 26 ± 5 weeks. Only 2/8 studied patients presented a homozygous mutation c.80 T > C (p.L27P) in IL36RN gene. Used treatments were topical steroids (n = 12F), systemic steroids (n = 5F), ciclosporin (n = 1F), UVB (n = 1F) and acitretin (in post-partum n = 6F). Complications were oligoamnios (n = 2), intra-uterine growth retardation (n = 1), fetal death in utero (n = 1), prematurity (n = 3), low weight at birth (n = 2). A significant association was found between (i) occurrence of fetal complications and early gestational age at the onset (p = 0.036), (ii) resistance to topical steroids and body surface affected area (p = 0.008), (iii) presence of mutation c.80 T > C in PPP flares and low serum levels of calcium (p = 0.01). Our systematic review of the literature identified 39 patients with 41 flares of PPP. Only 7/39 patients presented a causative mutation in IL36RN and CARD14 genes. PPP is characterized by a phenotypic heterogeneity and can be associated to IL36RN mutations. Its early onset can be associated with fetal complications. Systemic steroids and cyclosporine remain the most used therapies.

Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure.

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.

Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3',5'-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics.

Eficácia e segurança de Riociguate comparado ao placebo e a medicamentos disponíveis no sus para tratamento de hipertensão pulmonar tromboembólica crônica: revisão rápida de evidências / Effectiveness and safety of Riociguate compared to placebo and drugs available in brazilian public health for treatment of chronic thromboembolic pulmonary hypertension: rapid response review of evidence

Tecnologia: Riociguate e outros medicamentos de controle da hipertensão pulmonar. Indicação: Tratamento de Hipertensão Pulmonar Tomboembólica Crônica (HPTEC). Pergunta: Há superioridade em eficácia e segurança do riociguate, comparado a medicamentos disponíveis no SUS, no tratamento de HPTEC inoperável ou operada com hipertensão pulmonar residual? Métodos: Revisão rápida de evidências (overview) de revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada com AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews). Resultados: Foram selecionadas 4 e incluídas 2 revisões sistemáticas. Conclusão: Comparado ao placebo, em tratamento de curto prazo de HPTEC, riociguate melhora a tolerância ao exercício, aumenta a chance de melhora da classificação funcional e tem similar risco de eventos adversos sérios, porém não reduz a mortalidade. Treprostinil tem efeitos similares a riociguate. Entretanto, ambrisentana, bosentana, macitentana ou sildenafila não diferem do placebo no tratamento de HPTEC

Technology: Riociguat and other drugs to control pulmonary hypertension. Indication: Treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Question: Is riociguat more effective and safe than other drugs available in the Brazilian Public Health System for the treatment of inoperable or recurrent CTEPH? Methods: Rapid review of evidence (overview) from systematic reviews, with a bibliographic search in the PUBMED database, using a structured strategy. The methodological quality of systematic reviews was assessed with AMSTAR-2 (Methodological Quality Assessment of Systematic Reviews). Results: Four systematic reviews were selected and two included in this study. Conclusion: Compared to placebo, in the short-term treatment of CTEPH, riociguat improves exercise tolerance, increases the chance of improving functional classification, and has a similar risk of serious adverse events, but does not reduce mortality. Treprostinil has similar effects to riociguat. However, ambrisentan, bosentan, macitentan or sildenafil do not differ from placebo in the treatment of CTEPH

[Diagnosis and treatment of pulmonary hypertension]. / Diagnostiek en behandeling van pulmonale hypertensie.

Pulmonary hypertension is defined as a mean pulmonary artery pressure of more than 25 mmHg. There are many possible causes of pulmonary hypertension; pulmonary hypertension has a poor prognosis, irrespective of the underlying cause. The most frequent causes of pulmonary hypertension are left heart failure and lung disease. The diagnostic work up of pulmonary hypertension starts with investigations into left heart failure and lung disease. If these reveal no cause, ventilation perfusion scintigraphy should be carried out so that chronic thrombo-embolic pulmonary hypertension can be demonstrated or excluded. In most cases, chronic thrombo-embolic pulmonary hypertension can be treated curatively by means of pulmonary endarterectomy. If chronic thrombo-embolic pulmonary hypertension is also ruled out, then we speak of pulmonary arterial hypertension. Prostacyclins, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and soluble guanylyl cyclase stimulators have been shown to be effective in patients with pulmonary arterial hypertension. This condition should be treated at specialist centres.

Pulmonary arterial hypertension in adults: novel drugs and catheter ablation techniques show promise? Systematic review on pharmacotherapy and interventional strategies.

This systematic review aims to provide an update on pharmacological and interventional strategies for the treatment of pulmonary arterial hypertension in adults. Currently US Food and Drug Administration approved drugs including prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and soluble guanylate-cyclase stimulators. These agents have transformed the prognosis for pulmonary arterial hypertension patients from symptomatic improvements in exercise tolerance ten years ago to delayed disease progression today. On the other hand, percutaneous balloon atrioseptostomy by using radiofrequency perforation, cutting balloon dilatation, or insertion of butterfly stents and pulmonary artery catheter-based denervation, both associated with very low rate of major complications and death, should be considered in combination with specific drugs at an earlier stage rather than late in the progression of pulmonary arterial hypertension and before the occurrence of overt right-sided heart failure.

From Escherichia coli heat-stable enterotoxin to mammalian endogenous guanylin hormones.

The isolation of heat-stable enterotoxin (STa) from Escherichia coli and cholera toxin from Vibrio cholerae has increased our knowledge of specific mechanisms of action that could be used as pharmacological tools to understand the guanylyl cyclase-C and the adenylyl cyclase enzymatic systems. These discoveries have also been instrumental in increasing our understanding of the basic mechanisms that control the electrolyte and water balance in the gut, kidney, and urinary tracts under normal conditions and in disease. Herein, we review the evolution of genes of the guanylin family and STa genes from bacteria to fish and mammals. We also describe new developments and perspectives regarding these novel bacterial compounds and peptide hormones that act in electrolyte and water balance. The available data point toward new therapeutic perspectives for pathological features such as functional gastrointestinal disorders associated with constipation, colorectal cancer, cystic fibrosis, asthma, hypertension, gastrointestinal barrier function damage associated with enteropathy, enteric infection, malnutrition, satiety, food preferences, obesity, metabolic syndrome, and effects on behavior and brain disorders such as attention deficit, hyperactivity disorder, and schizophrenia.

From Escherichia coli heat-stable enterotoxin to mammalian endogenous guanylin hormones

The isolation of heat-stable enterotoxin (STa) from Escherichia coli and cholera toxin from Vibrio cholerae has increased our knowledge of specific mechanisms of action that could be used as pharmacological tools to understand the guanylyl cyclase-C and the adenylyl cyclase enzymatic systems. These discoveries have also been instrumental in increasing our understanding of the basic mechanisms that control the electrolyte and water balance in the gut, kidney, and urinary tracts under normal conditions and in disease. Herein, we review the evolution of genes of the guanylin family and STa genes from bacteria to fish and mammals. We also describe new developments and perspectives regarding these novel bacterial compounds and peptide hormones that act in electrolyte and water balance. The available data point toward new therapeutic perspectives for pathological features such as functional gastrointestinal disorders associated with constipation, colorectal cancer, cystic fibrosis, asthma, hypertension, gastrointestinal barrier function damage associated with enteropathy, enteric infection, malnutrition, satiety, food preferences, obesity, metabolic syndrome, and effects on behavior and brain disorders such as attention deficit, hyperactivity disorder, and schizophrenia.

[New directions in the therapy of pulmonary arterial hypertension]. / Nowe kierunki w leczeniu tetniczego nadcisnienia plucnego.

Recent years are the time of dynamic development of pulmonary arterial pressure pharmacotherapy. By introducing the goal oriented therapy the survival in this group of patients has significantly increased. Apart from the pharmacotherapy used according to the ESC guidelines, new attempts of interventional treatment based on denervation of pulmonary artery have also been taken. Constantly, the new clinical trials (tests?) of drugs acting via new metabolic pathways have been conducted. They include for example: soluble guanylate cyclase stimulators, tyrosine kinase inhibitors, serotonin receptors inhibitors, Rhokinase inhibitors, VIP analogues. One of the newmedicines is riociguat, the effectiveness and safety of which have been confirmed in the PATENT and CHEST study. However, the small number and clinical diversity in the group of the PAH patients cause significant difficulties with the extrapolation of the results of trials according to the guidelines of the therapy.

Modulation of soluble guanylate cyclase for the treatment of erectile dysfunction.

Nitric oxide (NO) is the principal mediator of penile erection, and PDE-5 inhibitors are the first-line agents used to treat erectile dysfunction (ED). When NO formation or bioavailability is decreased by oxidative stress and PDE-5 inhibitors are no longer effective, a new class of agents called soluble guanylate cyclase (sGC) stimulators like BAY 41-8543 will induce erection. sGC stimulators bind to the normally reduced, NO-sensitive form of sGC to increase cGMP formation and promote erection. The sGC stimulators produce normal erectile responses when NO formation is inhibited and the nerves innervating the corpora cavernosa are damaged. However, with severe oxidative stress, the heme iron on sGC can be oxidized, rendering the enzyme unresponsive to NO or sGC stimulators. In this pathophysiological situation, another newly developed class of agents called sGC activators can increase the catalytic activity of the oxidized enzyme, increase cGMP formation, and promote erection. The use of newer agents that stimulate or activate sGC to promote erection and treat ED is discussed in this brief review article.

NOS-2 signaling and cancer therapy.

The role of NO and cGMP signaling in tumor biology has been extensively studied during the past three decades. However, whether the pathway is beneficial or detrimental in cancer is still open to question. We suggest several reasons for this ambiguity: first, although NO participates in normal signaling (e.g., vasodilation and neurotransmission), NO is also a cytotoxic or apoptotic molecule when produced at high concentrations by inducible nitric-oxide synthase (iNOS or NOS-2). In addition, the cGMP-dependent (NO/sGC/cGMP pathway) and cGMP-independent (NO oxidative pathway) components may vary among different tissues and cell types. Furthermore, solid tumors contain two compartments: the parenchyma (neoplastic cells) and the stroma (nonmalignant supporting tissues including connective tissue, blood vessels, and inflammatory cells) with different NO biology. Thus, the NO/sGC/cGMP signaling molecules in tumors as well as the surrounding tissue must be further characterized before targeting this signaling pathway for tumor therapy. In this review, we focus on the NOS-2 expression in tumor and surrounding cells and summarized research outcome in terms of cancer therapy. We propose that a normal function of the sGC-cGMP signaling axis may be important for the prevention and/or treatment of malignant tumors. Inhibiting NOS-2 overexpression and the tumor inflammatory microenvironment, combined with normalization of the sGC/cGMP signaling may be a favorable alternative to chemotherapy and radiotherapy for malignant tumors.

Selective mastoporan inhibition of muscarinic activation of bovine tracheal smooth muscle

Muscarinic activation of bovine tracheal smooth muscle (BTSM) leading to smooth muscle contraction involves the generation of two cGMP signals (20 and 60 s), being 20s peak associated with soluble (sGC) and the second (60s) to membrane-bound Natriuretic Peptide- receptor-Guanylylcy clases (NPR-GC). In this study, we showed that pre-incubation of isolated BTSM strips with mastoparan and superactive mastoparan (mastoparan 7) decreased significantly the muscarinic dependent contractile smooth muscle responses in dose-dependent and non-competitive manner. Moreover, mastoparan (50 nM) inhibited completely the BTSM-muscarinic contractile responses and affected dramatically the carbachol-dependent cGMP signals being the first cGMP signal inhibited in a 63 ± 5%, whereas the second signal disappeared. Mastoparan inhibition of muscarinic activation is specific since other spasmogens as serotonin and histamine fully contracted these BTSM strips under mastoparan treatment. Cyclic GMP levels were evaluated by exposing BTSM strips to activators of NO-sensitive sGC as Sodium Nitroprussiate (SNP) and Natriuretic Peptides as CNP-53 for membrane-bound NPR-GC. Thus, SNP and CNP increased in a binary way, in more than 20 fold cGMP levels at 30-40 s being both increments inhibited by mastoparan. Furthermore, the Gi/o-protein involvement on mastoparan inhibition of cGMP elevations induced by CNP and SNP is suggested by Pertussis toxin pre-treatment, which reversed mastoparan effects. These results indicate that muscarinic signal transduction cascades leading to airway smooth muscle contractions involved two different guanylyl cyclases being both regulated by mastoparan-sensitive G-proteins. ANP, Natriuretic Peptide type A; ASM, Airway Smooth Muscle; BTSM, Bovine Tracheal Smooth Muscle; CNP-53, Natriuretic Peptide type C-53; GPCR, G-Protein Coupled Receptor; Gq16, Heterotrimeric G protein subtype 16; Gi/o, Heterotrimeric G protein subtype...

La activación muscarínica del músculo liso de las vías aéreasrelacionada a la contracción de dicho músculo liso esta asociada a la generación de dos señales de GMPc (20 y 60 s), siendo la señal de los 20s relacionado a la activación de la guanililciclasa soluble mientras que el pico de los 60s a la guanililciclasa unida membranas y sensible a péptidos natriuréticos (NPR-GC). En este trabajo, nosotros mostramos que la pre-incubación de fragmentos del músculo liso traqueal de bovino (BTSM) con mastoparan y su análogo superactivo (mastoparan 7), en una forma dosis dependiente, son capaces de disminuir de manera significativa la actividad contráctil dependiente de agentes muscarinicos. Adicionalmente, mastoparan (50 nM) inhibió completamente la respuesta contráctil muscarinica del BTSM y afectó dramáticamente los picos de GMPc asociados a la activación muscarinica siendola primera señal inhibida en un 63 ± 5%, mientras que la segunda señal desapareció completamente. Esta inhibición del mastoparan de la activación muscarínica es especifica ya que otros espamogenos como la serotonina y la histamina fueron capaces de inducir respuestas máximas en presencia del mastoparan y su análogos. Este efecto del mastoparan sobre los niveles del GMPc fue evaluado en presencia de otros agentes generadores de este segundo mensajero como son el nitroprusiato de sodio (SNP) que activa la guanililciclasa soluble sensible a NO y los péptidos natriureticos como el CNP-53 (CNP) activador de la NPR-GC asociada a membranas plasmáticas. Tanto, el SNP como el CNP aumentaronen mas de 50 veces los niveles de GMPc a los 30-40 s en forma bifasica, siendo estos incrementos inhibidos de manera significativa por el mastoparan. Ademas, se sugiere la participación de proteínas Gi/o en los efectos inhibitoriosdel mastoparan, porque la Toxina pertussis revertió los efectos inhibitorios. Estos resultados indican que la cascada de activación muscarinica que conduce...

Transmembrane guanylate cyclase in intestinal pathophysiology.

PURPOSE OF REVIEW: Production of cyclic guanosine monophosphate (cGMP) by guanylate cyclase is of critical importance to gastrointestinal physiology. Tight regulation of cGMP concentration is necessary for proper intestinal secretion and intestinal epithelial cell proliferative and apoptotic homeostasis. This review focuses on recent work detailing the role of a subset of transmembrane guanylate cyclases in the pathophysiology of intestinal secretory and motility disorders and intestinal epithelial cell transformation. Also considered is the potential for therapeutic manipulation of intestinal guanylate cyclase/cGMP signaling for the correction of chronic constipation and gastrointestinal cancer. RECENT FINDINGS: Recent work in mice and humans suggests a role for transmembrane guanylate cyclases in intestinal fluid secretion as well as hormonal enteric-renal signaling which mediates postprandial natriuresis. Transmembrane guanylate cyclases are also important in gastrointestinal transit rate and motility. Ongoing clinical trials have found that guanylate cyclase activating peptides are safe and effective in the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. In addition, accumulating evidence indicates that membrane-associated guanylate cyclase receptors regulate intestinal epithelial cell homeostatic proliferation and apoptosis as well as gastrointestinal malignancy. The anticancer activity of cGMP signaling in animal studies suggests additional therapeutic applications for guanylate cyclase agonists. SUMMARY: Progress toward understanding gastrointestinal transmembrane guanylate cyclase/cGMP physiology has recently accelerated due to definitive in-vitro studies and work using gene-targeted animal models and has facilitated the development of safe and effective drugs designed to regulate cGMP production in the intestine. Current work should be directed toward a detailed understanding of cGMP effector pathways and the manner in which subcellular concentrations of cGMP regulate them to influence intestinal health and disease.

Increased cytochrome P4502E1 expression and altered hydroxyeicosatetraenoic acid formation mediate diabetic vascular dysfunction: rescue by guanylyl-cyclase activation.

OBJECTIVE: We investigated the mechanisms underlying vascular endothelial and contractile dysfunction in diabetes as well as the effect of HMR1766, a novel nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC). RESEARCH DESIGN AND METHODS: Two weeks after induction of diabetes by streptozotocin, Wistar rats received either placebo or HMR1766 (10 mg/kg twice daily) for another 2 weeks; thereafter, vascular function was assessed. RESULTS: Endothelial function and contractile responses were significantly impaired, while vascular superoxide formation was increased in the aortae from diabetic versus healthy control rats. Using RNA microarrays, cytochrome P4502E1 (CYP2E1) was identified as the highest upregulated gene in diabetic aorta. CYP2E1 protein was significantly increased (16-fold) by diabetes, leading to a reduction in levels of the potent vasoconstrictor 20-hydroxy-eicosatetraenoic acid (20-HETE). Induction of CYP2E1 expression in healthy rats using isoniazide mimicked the diabetic noncontractile vascular response while preincubation of aortae from STZ-diabetic rats in vitro with 20-HETE rescued contractile function. Chronic treatment with the sGC activator HMR1766 improved NO sensitivity and endothelial function, reduced CYP2E1 expression and superoxide formation, enhanced 20-HETE levels, and reversed the contractile deficit observed in the diabetic rats that received placebo. CONCLUSIONS: Upregulation of CYP2E1 is essentially involved in diabetic vascular dysfunction. Chronic treatment with the sGC activator HMR1766 reduced oxidative stress, decreased CYP2E1 levels, and normalized vasomotor function in diabetic rats.