digoxin and Sleep-Apnea-Syndromes

Heart failure remains a major health problem in the United States, affecting 5.8 million Americans. Its prevalence continues to rise due to the improved survival of patients. Despite advances in treatment, morbidity and mortality remain very high, with a median survival of about 5 years after the first clinical symptoms. This article describes the causes, classification, and management goals of heart failure in Stages A and B.

Topics: Adrenergic beta-Antagonists; Alcohol Drinking; Angiotensin-Converting Enzyme Inhibitors; Cardiac Pacing, Artificial; Cardiotonic Agents; Cardiotoxins; Coronary Artery Disease; Defibrillators, Implantable; Diabetic Cardiomyopathies; Digoxin; Dyslipidemias; Early Diagnosis; Endocrine System Diseases; Heart Failure; HIV Infections; Humans; Hypertension; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Risk Factors; Sedentary Behavior; Sleep Apnea Syndromes; Smoking; Tachycardia

Recent studies about renal function and volume regulating hormones in obstructive sleep apnea (oSAS) indicate complex disturbances in volume homeostasis. Increased nocturnal secretion of atrial natriuretic peptide (ANP) and decreased renin secretion during apnea looks similar to a situation seen during hypervolemia or increased cardiac volume load. Increased venous return induced by pathologically high negative intrathoracic pressure during obstructive apnea may be the cause. Since during wakefulness no true hypervolemia is present, a "pseudohypervolemia" or "central hypervolemia" must exist caused by volume shift from the peripheral to the central compartment during apnea. Since volume homeostasis and blood pressure regulation are complexly connected the question arises whether disturbances in volume homeostasis play a role in the pathogenesis of arterial hypertension in sleep apnea. In a subgroup of hypertensive patients hypertension is salt-sensitive and volume dependent; it is called volume-expanded or low-renin hypertension. An inhibitor of the Na+/K(+)-ATPase acting via the digitalis receptor - called digitalis like factor (DLF) - is regarded as the causative agent for the development of hypertension in these cases. From this background, we were interested in the question whether DLF may be the linkage between disturbances in volume homeostasis and the pathogenesis of hypertension in sleep apnea. We could demonstrate a decrease of nocturnal urinary excretion of DLF during nasal continuous positive air pressure (nCPAP) therapy. Since a positive correlation between changes in diuresis respectively natriuresis and DLF excretion was found, we suggested DLF to be involved in changes of renal function in sleep apnea besides ANP. In 3 patients we measured nocturnal plasma levels of DLF and renin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Digoxin; Diuresis; Homeostasis; Humans; Kidney; Natriuresis; Plasma Volume; Renin; Saponins; Sleep Apnea Syndromes; Sodium-Potassium-Exchanging ATPase

Sleep-disordered breathing with recurrent apnea is associated with intermittent hypoxia (IH). Cardiovascular morbidities caused by IH are triggered by increased generation of reactive oxygen species (ROS) by pro-oxidant enzymes, especially NADPH oxidase-2 (Nox2). Previous studies showed that (i) IH activates hypoxia-inducible factor 1 (HIF-1) in a ROS-dependent manner and (ii) HIF-1 is required for IH-induced ROS generation, indicating the existence of a feed-forward mechanism. In the present study, using multiple pharmacological and genetic approaches, we investigated whether IH-induced expression of Nox2 is mediated by HIF-1 in the central and peripheral nervous system of mice as well as in cultured cells. IH increased Nox2 mRNA, protein, and enzyme activity in PC12 pheochromocytoma cells as well as in wild-type mouse embryonic fibroblasts (MEFs). This effect was abolished or attenuated by blocking HIF-1 activity through RNA interference or pharmacologic inhibition (digoxin or YC-1) or by genetic knockout of HIF-1α in MEFs. Increasing HIF-1α expression by treating PC 12 cells with the iron chelator deferoxamine for 20 h or by transfecting them with HIF-1alpha expression vector increased Nox2 expression and enzyme activity. Exposure of wild-type mice to IH (8 h/day for 10 days) up-regulated Nox2 mRNA expression in brain cortex, brain stem, and carotid body but not in cerebellum. IH did not induce Nox2 expression in cortex, brainstem, carotid body, or cerebellum of Hif1a(+/-) mice, which do not manifest increased ROS or cardiovascular morbidities in response to IH. These results establish a pathogenic mechanism linking HIF-1, ROS generation, and cardiovascular pathology in response to IH.

Topics: Animals; Carotid Body; Central Nervous System; Deferoxamine; Digoxin; Enzyme Inhibitors; Fibroblasts; Furans; Gene Expression Regulation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Indazoles; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; NADPH Oxidase 2; NADPH Oxidases; PC12 Cells; Peripheral Nervous System; Rats; Reactive Oxygen Species; Siderophores; Sleep Apnea Syndromes