cardiovascular-agents and cariporide

The Annual Scientific Sessions of the American Heart Association is the leading scientific conference in the cardiovascular field, both for basic and clinical research in cardiology and related disclipines. This report covers the outcome of major clinical trials that were presented in the 'late-breaking' clinical trial sessions. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) investigated the angiotensin receptor blocker valsartan, the angiotensin-converting enzyme inhibitor captopril, and their combination in 14,703 survivors of an acute myocardial infarction with a reduced left ventricular ejection fraction on clinical outcome. The study demonstrated that valsartan and captopril where equally effective, whereas the combination was associated with an increased risk of side effects without further benefit. VALIANT is a landmark trial because it was the first large study that compared the combination of an angiotensin receptor blocker with an angiotensin-converting enzyme inhibitor in the setting of acute myocardial infarction. Other trials that will be summarised in this report are the Na + /H + Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions Trial (EXPEDITION; cariporide in coronary artery bypass graft surgery), the Reversal of Atherosclerosis with Aggressive Lipid Lowering Trial (REVERSAL; atorvastatin and pravastatin for atherosclerosis reversal), the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation V (SPORTIF V; ximelagatran and warfarin for stroke prevention in atrial fibrillation), the Prophylactic Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularisation (PAPABEAR; amiodarone for the prevention of postoperative atrial fibrillation), the Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist in Congestive Heart Failure (ACTIV in CHF; vasopressin 2 antagonist tolvaptan in congestive heart failure) and Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT; fosinopril and pravastatin in microalbuminuric subjects without hypertension or hypercholesterolemia).

Topics: American Heart Association; Arrhythmias, Cardiac; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Guanidines; Humans; Sulfones; United States

The NHE-1 isoform of the Na+/H+ exchanger is excessively activated in cardiac cells during ischemia. Hence NHE-1 specific inhibitors are being developed since they could be of beneficial influence under conditions of cardiac ischemia and reperfusion. In this study, the Cytosensortrade mark microphysiometer was used to measure the potency of four new drug molecules, i.e., EMD 84021, EMD 94309, EMD 96785 and HOE 642 which are inhibitors of the isoform 1 of the Na+/H+ exchanger. The experiments were performed with Chinese hamster ovary cells (CHO K1) which are enriched in the NHE-1 isoform of the Na+/H+ antiporter. The Na+/H+ exchanger was stimulated with NaCl and the rate of extracellular acidification was quantified with the Cytosensor. The proton exchange rate was measured as a function of the NaCl concentration in the range of 10-138 mm NaCl stimulation. The proton exchange rate followed Michaelis-Menten kinetics with a KM = 30 +/- 4 mm for Na+. Addition of either one of the four inhibitors decreased the acidification rate. The IC50 values of the four compounds could be determined as 23 +/- 7 nm for EMD 84021, 5 +/- 1 nm for EMD 94309, 9 +/- 2 nm for EMD 96785 and 8 +/- 2 nm for HOE 642 at 138 mm NaCl, in good agreement with more elaborate biological assays. The IC50 values increased with the NaCl concentration indicating competitive binding of the inhibitor. The microphysiometer approach is a fast and simple method to measure the activity of the Na+/H+ antiporter and allows a quantitative kinetic analysis of the proton excretion rate.

Topics: Animals; Cardiovascular Agents; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Erythrocytes; Fibroblasts; Guanidines; Hydrogen-Ion Concentration; Mice; Microchemistry; Osmolar Concentration; Protein Isoforms; Protons; Rabbits; Sodium; Sodium-Hydrogen Exchangers; Sulfones

Topics: Abciximab; Alanine; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal; Aspirin; Benzamidines; Biphenyl Compounds; Cardiology; Cardiovascular Agents; Clinical Trials as Topic; Clopidogrel; Combined Modality Therapy; Coronary Disease; Dalteparin; Defibrillators, Implantable; Double-Blind Method; Enalapril; Endothelial Growth Factors; Fatty Acids, Omega-3; Guanidines; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunoglobulin Fab Fragments; Laser Therapy; Lymphokines; Metoprolol; Multicenter Studies as Topic; Myocardial Revascularization; Platelet Aggregation Inhibitors; Pyrrolidines; Randomized Controlled Trials as Topic; Simvastatin; Sodium-Hydrogen Exchangers; Stents; Sulfones; Thrombolytic Therapy; Ticlopidine; Tissue Plasminogen Activator; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vitamin E