2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Heart-Failure

Tumor necrosis factor (TNF)-alpha plays a role in congestive heart failure (CHF). A2A adenosine receptor (A(2A)R) activation on immune cells putatively reduces the release of cytokines contributing to CHF progression. The study is aimed at determining the role of the A(2A)R in the modulation of TNF-alpha production, and the ex vivo effect of TNF-alpha on A(2A)R in peripheral blood mononuclear cells (PBMC) from CHF patients.. Plasma levels of TNF-alpha and TNF-alpha production from lipopolysaccharide (LPS)-stimulated PBMC were evaluated in 26 CHF patients in comparison to controls. The effects of the A(2A)R agonist CGS-21680 and antagonist ZM-241385 on TNF-alpha production from PBMC were also evaluated. Finally, reverse transcriptase-polymerase chain reaction and Western blot analyses of A(2A)R in PBMC were performed in TNF-alpha-treated and untreated cells. TNF-alpha production from LPS-stimulated PBMC was enhanced in CHF patients with respect to controls. CGS-21680 blunted TNF-alpha production in both groups; ZM-241385 reverted this effect. A(2A)R expression in PBMC was higher in CHF patients than in controls. TNF-alpha addition produced an increase in A(2A)R in PBMC from controls but not in PBMC from CHF patients.. PBMC from CHF patients show an upregulation of A(2A)R-mediated inhibition of TNF-alpha, which may represents a mechanism of protection against inappropriate cytokine production.

Topics: Adenosine; Blotting, Western; Female; Heart Failure; Humans; Lipopolysaccharides; Male; Middle Aged; Neutrophils; Phenethylamines; Receptor, Adenosine A2A; Receptors, Purinergic P1; Reverse Transcriptase Polymerase Chain Reaction; Triazines; Triazoles; Tumor Necrosis Factor-alpha; Up-Regulation

1. The effects of CGS 21680, a selective A2A adenosine receptor agonist, on cardiac output, blood pressure, mean circulatory filling pressure (Pmcf), arterial and venous resistances, heart rate and left ventricular end-diastolic pressure were assessed in rats with acute heart failure by means of coronary artery occlusion. 2. Animals (n=6 in each group) were divided into five groups: group I, sham-operated vehicle-treated (0.9% saline; 0.018 mL min(-1)); groups II-V, subject to coronary artery occlusion and treated with vehicle (0.9% saline; 0.018 ml min(-1)) and CGS 21680 (0.1, 0.3 and 1.0 microg kg(-1) min(-1)), respectively. Haemodynamic measurements were taken one hour after completion of surgery, ninety minutes after coronary artery occlusion (except in group I), and fifteen minutes after infusion of saline or CGS 21680. 3. Baseline haemodynamic measurements before occlusion were found not to differ significantly between the different groups of animals. However, after occlusion, cardiac output, rate of rise in left ventricular pressure (+ dP/dt) and blood pressure were significantly reduced when compared to corresponding values in sham-operated animals. In addition, occlusion of the coronary artery resulted in a significant elevation in venous resistance, Pmcf and left ventricular end-diastolic pressure as compared to corresponding values in sham-operated animals. 4. Infusion with CGS 21680 at the highest dose significantly reduced blood pressure, arterial resistance and left ventricular end-diastolic pressure when compared to occluded vehicle-treated animals (group II). Administration of CGS 21680 at the highest dose also significantly increased cardiac output (28%) and heart rate (10%) in comparison to occluded vehicle-treated animals. In addition, the highest dose of CGS 21680 significantly reduced Pmcf (9%) and venous resistance (62%) in comparison to occluded vehicle-treated animals. Administration of CGS 21680 did not significantly affect +dP/dt when compared to occluded vehicle-treated animals. 5. The results from the present investigation indicate that occlusion of the coronary artery in rats results in a state of heart failure characterized by reduced arterial pressure and cardiac output, and increased venous resistance, Pmcf and left ventricular end-diastolic pressure. Administration of CGS 21680 to animals with acute heart failure resulted in increased cardiac output which was due to reduced venous resistance, as well as increased heart rat

Topics: Acute Disease; Adenosine; Anesthesia; Animals; Antihypertensive Agents; Blood Pressure; Cardiac Output; Heart Failure; Heart Rate; Male; Microspheres; Phenethylamines; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Vascular Resistance; Ventricular Function, Left

1. Recently we demonstrated that the administration of an A2A adenosine receptor agonist, CGS 21680, to anaesthetized rats with acute heart failure (1 h post-coronary artery ligation) resulted in an increase in cardiac output. In the present investigation, the effects of CGS 21680 on cardiac output, vascular resistance, heart rate, blood pressure and mean circulatory filling pressure (Pmcf) were investigated in anaesthetized rats with chronic heart failure (8 weeks post-coronary artery ligation). 2. Experiments were conducted in five groups (n = 6) of animals: sham-operated vehicle-treated (0.9% NaCl; 0.037 mL kg(-1) min(-1)) animals in which the occluder was placed but not pulled to ligate the coronary artery; coronary artery-ligated vehicle-treated animals; and coronary artery-ligated CGS 21680-treated (0.1. 0.3 or 1.0 microg kg(-1) min(-1)) animals. 3. Baseline blood pressure, cardiac output and rate of rise in left ventricular pressure (+dP/dt) were significantly reduced in animals with coronary artery ligation when compared to sham-operated animals. Coronary artery ligation resulted in a significant increase in left ventricular end-diastolic pressure, Pmcf and venous resistance when compared to sham-operated animals. 4. Administration of CGS 21680 at 0.3 and 1.0 microg kg(-1) min(-1) significantly (n = 6; P<0.05) increased cardiac output by 19+/-4% and 39+/-5%, and heart rate by 14+/-2% and 15+/-1%, respectively, when compared to vehicle treatment in coronary artery-ligated animals. Administration of CGS 21680 also significantly reduced blood pressure and arterial resistance when compared to coronary artery-ligated vehicle-treated animals. Infusion of CGS 21680 also significantly reduced venous resistance when compared to vehicle-treated coronary artery-ligated animals. 5. The results show that heart failure is characterized by reduced cardiac output, and increased left ventricular end-diastolic pressure, venous resistance and Pmcf. Acute treatment with CGS 21680 in animals with chronic heart failure decreased left ventricular end-diastolic pressure and increased cardiac output. This increase in cardiac output was the result of reduced arterial and venous resistances and increased heart rate.

Topics: Adenosine; Anesthesia; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiac Output; Coronary Disease; Heart Failure; Heart Rate; Hemodynamics; Ligation; Male; Organ Size; Phenethylamines; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Time Factors; Vascular Resistance