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Effect of phosphodiesterase 5 inhibitor on alteration in vascular smooth muscle sensitivity and renal function in rats with liver cirrhosis.

Previous studies suggested that increased activity of phosphodiesterase (PDE)5 in the kidneys of cirrhotic rats contributes to sodium retention. This study examined the role of PDE5 in the changes in vascular reactivity, hemodynamics, and sodium excretion in rats with liver cirrhosis. Four weeks after bile duct ligation (BDL) or sham operation (SO), in vitro reactivity of aortic rings to various agents and in vivo effects of a PDE5-selective inhibitor [1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo[3,4d]-pyrimidin-4-(5H)-one, DMPPO] were studied. The vasodilator responses to n

Synthesis and biological activity of 3,3-diamino-sulfonylacrylonitriles as novel inhibitors of glucose induced insulin secretion from beta cells.

Pinacidil analogues, for example, N-cyano-N'-(3,5-dichlorophenyl)-N"-(3-methylbutyl)guanidine, 1, have previously been described as potassium channel openers on beta cells and smooth muscle cells. In the present study 3,3-diamino-sulfonylacrylonitrile, a new bioisostere of the cyanoguanidine group, was investigated. 3,3-Diamino-sulfonylacrylonitriles were prepared in a two step synthesis from the corresponding isothiocyanates and sulfonylacetonitriles. Single crystal X-ray crystallography and NMR spectroscopy were used to establish the structure of 2-(4-chlorophenylsulfonyl)-3-cyclobutylamino-

Review of Hematology-Oncology Emergencies for Internal Medicine Residents.

The prevalence of cancer continues to grow globally every year. With therapeutic advances over the recent decades, the prevalence of individuals living with cancer continues to increase. Internal medicine residents can see patients admitted to the hospital for cancer-related emergencies. Early identification and appropriate management of these emergencies have been shown to improve mortality and morbidity. In this article, we aim to review the recent updates in the management of commonly encountered oncologic emergencies in the practice of internal medicine residents. This review will cover sp

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… Medical management of insulinoma includes diazoxide, octreotide, or lanreotide. Diazoxide decreases insulin secretion but can cause marked edema and hirsutism [ 20 ]. Diazoxide and somatostatin analogs do not play a role in non-islet cell tumors. … Diazoxide treatment for insulinoma: a national UK survey. Gill GV, Rauf O, MacFarlane IA. Postgrad Med J. 1997;73:640–641. doi: 10.1136/pgmj.73.864.640. 21. Management of non-islet-cell tumor hypoglycemia: a clinical review. Bodnar TW, Acevedo MJ, Pietropaolo M. …

Diabetes and hypoglycaemia in young children and mutations in the Kir6.2 subunit of the potassium channel: therapeutic consequences.

ATP-sensitive potassium channels (K(ATP)) couple cell metabolism to electrical activity by regulating potassium movement across the membrane … nent inactivation of the K(ATP) channels provokes inappropriate insulin secretion, despite low ATP. Diazoxide, used efficiently in certain cases of HI, opens the K(ATP) channels and therefore overpass the mutation effect on the insulin secretion. Conversely, several studies reported sequencing of KCNJ11, coding for Kir6.2, in patients with permanent neonata …

The role of 18F-DOPA PET/CT in the diagnosis of the congenital focal form of hyperinsulinism in children.

BACKGROUND: Congenital hyperinsulinism (CHI) is a neuroendocrine disease with focal or diffuse abnormalities in pancreas. While drug-resistant diffuse forms require near-total pancreatectomy or prolonged pharmacotherapy, focal CHI may be treated by targeted surgical resection. We evaluated the usefulness of 18F-DOPA PET/CT to identify the focal pancreatic form. SUBJECTS AND METHODS: Nineteen children (11 boys, 8 girls, aged 2-54 months) with clinical signs of neonatal CHI and positive genetic examinations were enrolled in the study. After i.v. administration of 18F-DOPA, early PET and late PE

Early opening of sarcolemmal ATP-sensitive potassium channels is not a key step in PKC-mediated cardioprotection.

ATP-sensitive potassium (KATP) channels are abundantly expressed in the myocardium. Although a definitive role for the channel remains elusive they have been implicated in the phenomenon of cardioprotection, but the precise mechanism is unclear. We set out to test the hypothesis that the channel protects by opening early during ischemia to shorten action potential duration and reduce electrical excitability thus sparing intracellular ATP. This could reduce reperfusion injury by improving calcium homeostasis. Using a combination of contractile function analysis, calcium fluorescence imaging and

Respiratory uncoupling by increased H(+) or K(+) flux is beneficial for heart mitochondrial turnover of reactive oxygen species but not for permeability transition.

BACKGROUND: Ischemic preconditioning has been proposed to involve changes in mitochondrial H(+) and K(+) fluxes, in particular through activation of uncoupling proteins and ATP-sensitive K(+) channels (MitoKATP). The objectives of the present study were to explore how increased H(+) and K(+) fluxes influence heart mitochondrial physiology with regard to production and scavenging of reactive oxygen species (ROS), volume changes and resistance to calcium-induced mitochondrial permeability transition (mPT). RESULTS: Isolated rat heart mitochondria were exposed to a wide concentration range of th

Voltage-gated and ATP-sensitive K+ channels are associated with cell proliferation and tumorigenesis of human glioma.

Increasing evidence indicates that potassium (K+) channels play important roles in the growth and development of human cancer. In the present study, we investigated the contribution of and the mechanism by which K+ channels control the proliferation and tumor development of U87-MG human glioma cells. A variety of K+ channel blockers and openers were used to differentiate the critical subtype of K+ channels involved. The in vitro data demonstrated that selective blockers of voltage-gated K+ (K(V)) channels or ATP-sensitive K+ (K(ATP)) channels significantly inhibited the proliferation of U87-MG

Hypoxia-induced catecholamine release and intracellular Ca2+ increase via suppression of K+ channels in cultured rat adrenal chromaffin cells.

Hypoxia (5% O2) enhanced catecholamine release in cultured rat adrenal chromaffin cells. Also, the intracellular free Ca2+ concentration ([Ca2+]i) increased within 3 min in approximately 50% of the chromaffin cells under hypoxic stimulation. The increase depended on the presence of extracellular Ca2+. Nifedipine and omega-conotoxin decreased the population of the cells that showed the hypoxia-induced [Ca2+]i increase, showing that the Ca2+ influx was attributable to L- and N-type voltage-dependent Ca2+ channels. The membrane potential was depolarized during the perfusion with the hypoxic solut

Loss of imprinted genes and paternal SUR1 mutations lead to hyperinsulinism in focal adenomatous hyperplasia.

Two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in about 30% of operated sporadic cases, and a diffuse form can be observed in congenital hyperinsulinism, or Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI). In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted chromosomal region 11p15, restricted to the hyperplastic area of the pancreas, were observed. Similar mechanisms are observed in embryonal tumors and in the Beckwith-Wiedemann syndrome which is also associated with neonatal but transient hyper

Premature labour.

Prematurity is by far the commonest cause of neonatal morbidity and mortality. The management of premature labour is empirical because little is understood about the mechanism of labour. Effective uterine relaxant drugs have an important, albeit minor role. Phototherapy has reduced the complications of neonatal hyperbilirubinemia, and the beneficial effect of antepartum corticosteroid therapy in minimizing the risk of respiratory distress syndrome is now convincing. Prophylactic antibiotic therapy in premature rupture of the membranes does not alter perinatal mortality, although postpartum mat

Non-diabetic hypoglycemia: bridging gaps in diagnosis and treatment: a position statement report by the Arabic Association for the Study of Diabetes and Metabolism (AASD).

BACKGROUND: Non-diabetic hypoglycemia presents a substantial diagnostic challenge due to its diverse and often nonspecific symptomatology. The resultant delay in diagnosis can lead to a myriad of misdiagnoses. This misidentification not only prolongs patient suffering but also elevates the risk of severe complications, such as permanent neurologic damage and mortality. Recognizing the clinical nuances of non-diabetic hypoglycemia is paramount for timely and accurate diagnosis, which ultimately enhances patient outcomes and safety. MAIN BODY: A position statement has been formulated by the Ara

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… Medications that suppress insulin secretion, such as diazoxide, and somatostatin analogs (SSAs) are reserved for patients who refuse surgery, non-surgical candidates, or have non-localized tumors. … Treatment includes dietary management, medications (e.g., SSAs, diazoxide, immunosuppressants), and management of underlying conditions. …

Pharmacological characterization of urinary bladder smooth muscle contractility following partial bladder outlet obstruction in pigs.

Partial bladder outlet obstruction of the pig is considered as a valuable preclinical model for evaluating the profile of compounds for the treatment of bladder overactivity. In this study, we characterized the pharmacological properties of isolated bladder smooth muscle from pigs following partial outlet obstruction and its sensitivity to potassium channel openers. Bladder strips from obstructed animals showed significantly lower maximal efficacy (E(max)) and sensitivity to stimulation by ATP and carbachol, but not to those evoked by serotonin, compared to age-matched controls. Tissue strips

Alpha-lipoic acid as a trigger of insulin autoimmune syndrome: Current evidence, a case-based approach, diagnostic pitfalls, and practical management.

Insulin autoimmune syndrome (IAS), also known as Hirata disease, is a rare immune-mediated cause of endogenous hyperinsulinemic hypoglycemia characterized by circulating insulin autoantibodies (IAAs). It typically develops in individuals without prior exposure to exogenous insulin. Although IAS has been associated with viral infections and, less commonly, with autoimmune and hematologic disorders, medications and dietary supplements are considered the most frequent precipitating factors. Sulfhydryl-containing compounds are the most commonly implicated triggers. Methimazole represents the class

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… Diazoxide inhibits insulin secretion through activation of ATP-sensitive potassium (K_ATP) channels via binding to the sulfonylurea receptor 1 (SUR1) subunit, promoting β-cell hyperpolarization and thereby suppressing calcium-dependent insulin exocytosis. … However, diazoxide has shown variable efficacy in IAS, and its use may be limited by side effects including fluid retention, hypotension, and tachycardia [ 12 , 53 ]. …

Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells.

Glucagon-like peptide-1 (GLP-1) is a potent regulator of glucose-stimulated insulin secretion whose mechanisms of action are only partly understood. In the present paper, we show that at low (3 mM) glucose concentrations, GLP-1 increases the free intramitochondrial concentrations of both Ca(2+) ([Ca(2+)](m)), and ATP ([ATP](m)) in clonal MIN6 beta-cells. Suggesting that cAMP-mediated release of Ca(2+) from intracellular stores is responsible for these effects, increases in [ATP](m) that were induced by GLP-1 were completely blocked by the Rp isomer of adenosine-3',5'-cyclic monophosphothioate