ABSTRACT
Atrial fibrillation (AF) is one of the most commonly occurring arrhythmias and a major modifiable risk factor for stroke, especially in women. While its prevalence is similar in both men and women, women unfortunately face a greater intrinsic AF-related risk of stroke than men do. This is likely one of the reasons that more women than men die from strokes, in addition to experiencing more new and recurrent strokes. Therefore, in women especially, it is imperative to diagnose and treat AF as early as possible. While its unreliable symptom profile and possible intermittent nature can make AF difficult to detect, proactive identification of risk factors and improved detection methods can help. Additionally, the use of risk stratification schemes for anticoagulant therapy, along with the efficacy of nonvitamin K antagonist anticoagulants can enable appropriate therapy to prevent stroke occurrence.
Subject(s)
Anticoagulants/administration & dosage , Anticoagulants/therapeutic use , Atrial Fibrillation/diagnosis , Atrial Fibrillation/drug therapy , Stroke/complications , Administration, Oral , Atrial Fibrillation/complications , Atrial Fibrillation/prevention & control , Brain Ischemia/complications , Brain Ischemia/drug therapy , Electric Countershock , Female , Fibrinolytic Agents/pharmacology , Fibrinolytic Agents/therapeutic use , Heart Rate/drug effects , Humans , Male , Myocardial Infarction/complications , Myocardial Infarction/drug therapy , Risk Assessment , Risk Factors , Stroke/drug therapy , Stroke/prevention & controlABSTRACT
P2X purinergic receptors, activated by extracellular ATP, mediate a number of cardiac cellular effects and may be important under pathophysiological conditions. The objective of the present study was to characterize the P2X receptor-mediated ionic current and determine its role in heart failure using the calsequestrin (CSQ) model of cardiomyopathy. Membrane currents under voltage clamp were determined in myocytes from both wild-type (WT) and CSQ mice. The P2X agonist 2-methylthio-ATP (2-meSATP) induced an inward current that was greater in magnitude in CSQ than in WT ventricular cells. The novel agonist, MRS-2339, an N-methanocarba derivative of 2-chloro-AMP relatively resistant to nucleotidase, induced a current in the CSQ myocyte similar to that by 2-meSATP. When administered via a miniosmotic pump (Alzet), it significantly increased longevity compared with vehicle-injected mice (log rank test, P = 0.02). The improvement in survival was associated with decreases in the heart weight-to-body weight ratio and in cardiac myocyte cross-sectional area [MRS-2339-treated mice: 281 +/- 15.4 (SE) mum(2), n = 6 mice vs. vehicle-treated mice: 358 +/- 27.8 mum(2), n = 6 mice, P < 0.05]. MRS-2339 had no vasodilator effect in mouse aorta ring preparations, indicating that its salutary effect in heart failure is not because of any vascular unloading. The cardiac P2X current is upregulated in the CSQ heart failure myocytes. Chronic administration of a nucleotidase-resistant agonist confers a beneficial effect in the CSQ model of heart failure, apparently via an activation of the cardiac P2X receptor. Cardiac P2X receptors represent a novel and potentially important therapeutic target for the treatment of heart failure.
Subject(s)
Adenine Nucleotides/pharmacology , Calsequestrin/metabolism , Cardiac Output, Low/prevention & control , Cardiomyopathies/drug therapy , Myocytes, Cardiac/drug effects , Purinergic P2 Receptor Agonists , Adenine Nucleotides/therapeutic use , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Triphosphate/analogs & derivatives , Adenosine Triphosphate/pharmacology , Animals , Benzenesulfonates/pharmacology , Calsequestrin/genetics , Cardiac Output, Low/etiology , Cardiomyopathies/complications , Cardiomyopathies/metabolism , Cardiomyopathies/pathology , Disease Models, Animal , Disease Progression , Membrane Potentials/drug effects , Mice , Mice, Transgenic , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Patch-Clamp Techniques , Pyridoxal Phosphate/analogs & derivatives , Pyridoxal Phosphate/pharmacology , Receptors, Purinergic P2/drug effects , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X4 , Thionucleotides/pharmacologyABSTRACT
BACKGROUND: Recent in vitro studies have shown that disturbed flow and oxidative conditions induce the expression of bone morphogenic proteins (BMPs 2 and 4) in cultured endothelial cells. BMPs can stimulate superoxide production and inflammatory responses in endothelial cells, raising the possibility that BMPs may play a role in vascular diseases such as hypertension and atherosclerosis. In this study, we examined the hypothesis that BMP4 would induce hypertension in intact animals by increasing superoxide production from vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and an impairment of vasodilation responses. METHODS AND RESULTS: BMP4 infusion by osmotic pumps increased systolic blood pressure in a time- and dose-dependent manner in both C57BL/6 mice (from 101 to 125 mm Hg) and apolipoprotein E-null mice (from 107 to 146 mm Hg) after 4 weeks. Cotreatment with the BMP antagonist noggin or the NADPH oxidase inhibitor apocynin completely blocked the BMP4 effect. In addition, BMP4 infusion stimulated aortic NADPH oxidase activity and impaired vasorelaxation, both of which were prevented either by coinfusing noggin or by treating the isolated aortas with apocynin. BMP4, however, did not cause significant changes in maximum relaxation induced by the endothelium-independent vasodilator nitroglycerin. Remarkably, BMP4 infusion failed to stimulate aortic NADPH oxidases, increase blood pressure, and impair vasodilation responses in p47phox-deficient mice. CONCLUSIONS: These results suggest that BMP4 infusion induces hypertension in mice in a vascular NADPH oxidase-dependent manner and the subsequent endothelial dysfunction. We suggest that BMP4 is a novel mediator of endothelial dysfunction and hypertension and that noggin and its analogs could be used as therapeutic agents for treating vascular diseases.
