denopamine and Myocardial-Infarction

The aim of this study was to investigate the mechanism of beta-adrenergic preconditioning (BPC). The roles of adenosine and its receptor subtypes, the generation of oxygen free radicals (ROS) and activation of the K(ATP) channels as well as the phosphoinositide-3-kinase (PI(3)K)/PKB/Akt and extracellular signal-regulated kinase (ERK) signal transduction pathways during the triggering and mediation phases were evaluated. Using the isolated working rat heart, BPC was elicited by administration of denopamine (beta1 adrenergic receptor agonist, 10(-7) M), isoproterenol (beta1/beta2 adrenergic receptor agonist, 10(-7) M) or formoterol (beta2 adrenergic receptor agonist, 10(-9) M) for 5 min followed by 5 min washout. Index ischaemia was 35 min regional ischaemia and infarct size determined using the tetrazolium method. The role of adenosine was studied using adenosine deaminase and selective antagonists as well as the PI(3)K and ERK inhibitors, wortmannin and PD98,059, bracketing the triggering and mediating phases. Involvement of ROS, PKC, the mitochondrial K(ATP) channels, release of endogenous opioids and bradykinin was studied by administration of N-acetyl cysteine (NAC), bisindolylmaleimide, the K(ATP) channel blocker 5-hydroxydecanoate (5-HD), naloxone or HOE140, respectively. Activation of PKB/Akt and ERKp44/p42 during triggering and reperfusion was determined by Western blot. Preconditioning with all three beta-adrenergic receptor agonists caused a reduction in infarct size and an improvement in postischaemic function. BPC preconditioning with isoproterenol, denopamine or formoterol was abolished by the adenosine A3 receptor antagonist MRS1191 during both the triggering and mediation phases. Isoproterenol-induced preconditioning (beta1/beta2 PC) was attenuated by MRS1754, an adenosine A(2B) receptor antagonist, during the triggering phase and abolished during reperfusion. The mediation phase of beta1/beta2 PC was also abolished by ZM241385, an adenosine A(2A) antagonist. The free radical scavenger NAC caused a significant attenuation of cardioprotection induced by isoproterenol when administered during both trigger and mediation phases, while being effective during the trigger phase with denopamine and during reperfusion in formoterol preconditioned hearts. The mitochondrial K(ATP) channel blocker, 5-HD, was without effect on beta1/beta2 PC during both triggering and mediation phases. BPC in rat hearts is dependent on activation of the A(3) adenosine re

Topics: Adenosine; Animals; Ethanolamines; Extracellular Signal-Regulated MAP Kinases; Formoterol Fumarate; Ischemic Preconditioning, Myocardial; Isoproterenol; Myocardial Infarction; Phosphatidylinositol 3-Kinases; Potassium Channels; Protein Kinase C; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; Receptors, Adrenergic, beta; Receptors, Purinergic P1; Triazines; Triazoles

The present study was undertaken to determine whether cardiac response to beta 1-adrenergic agonists is altered in rats with chronic heart failure (CHF), and whether this alteration is related to beta-adrenergic receptor down-regulation in the viable tissue of the left ventricle of these rats. For this purpose, the cardiac response to denopamine, a selective beta 1-adrenergic agonist, and the change in cardiac beta-adrenoceptor density were examined in rats with CHF. A non-selective beta-adrenergic agonist, isoprenaline, was also examined as a comparison. Cardiac output and stroke volume indices were reduced 12 weeks after left coronary artery ligation, suggesting that CHF had developed at this time. Denopamine (2, 4 and 8 micrograms/kg i.v.), and isoprenaline (0.01 microgram/kg i.v.) increased the cardiac output and stroke volume indices in sham-operated rats, whereas such increases were attenuated in the CHF rat. The cardiac beta-adrenergic receptor density, measured by [3H]CGP-12177 binding assay, was reduced in homogenates and microsomal membranes in the viable tissue of the left ventricle of the CHF rat (homogenates: 29% reduction, microsomal membrane: 23% reduction). These results suggest that the cardiac responsiveness to denopamine is diminished in the CHF rat and this alteration is accounted for, in part, by a decrease in cardiac beta-adrenoceptor density.

Topics: Adrenergic beta-1 Receptor Agonists; Adrenergic beta-Agonists; Animals; Cardiac Output; Chronic Disease; DNA; Down-Regulation; Ethanolamines; Heart; Heart Failure; Hemodynamics; In Vitro Techniques; Isoproterenol; Male; Myocardial Infarction; Myocardium; Organ Size; Radioligand Assay; Rats; Rats, Wistar; Receptors, Adrenergic, beta-1; Stroke Volume

To evaluate right ventricular (RV) function in severe left ventricular (LV) failure, we measured RV and LV ejection fractions (EF) in 18 patients with old myocardial infarction (OMI) and in 18 with dilated cardiomyopathy (DCM) using cardiac blood pool scintigraphy. In patients with OMI, RVEF was significantly greater in stage II LV failure than in stage III (functional class of the New York Heart Association, 47 +/- 8% and 28 +/- 12%, respectively: p less than 0.01), and this correlated well with exercise tolerance by bicycle ergometer and mean pulmonary artery pressure (r = 0.83 and r = -0.71, respectively). In patients with DCM, however, there was no correlation between RVEF and these indexes. After the oral administration of denopamine (beta 1 effector), both RVEF and LVEF increased in patients with OMI (35 +/- 13% to 45 +/- 12%, and 27 +/- 9% to 30 +/- 10%: p less than 0.01), but they did not change significantly in patients with DCM. These results indicate that RVEF in patients with OMI correlates well with subjective symptoms, exercise tolerance and RV afterload, but these correlations were not apparent in patients with DCM. We concluded that RV function in cases of severe LV failure has a different meaning between OMI and DCM.

Topics: Adult; Cardiomyopathy, Dilated; Cardiotonic Agents; Ethanolamines; Exercise Test; Heart Ventricles; Humans; Middle Aged; Myocardial Infarction; Radionuclide Angiography; Stroke Volume

Topics: Animals; Cardiotonic Agents; Dogs; Dopamine; Drug Evaluation; Ethanolamines; Isoproterenol; Myocardial Infarction