Search

The aim of the study was to assess the relationships between oxidative stress, cardiac remodelling and fibrosis on an experimental model of heart failure with adrenergic stimulation. Large myocardial infarction (approximately 50% of the left ventricle myocardium) was obtained by ligation of the left coronary artery of normotensive male Wistar rats. Sham animals were submitted to left thoracotomy without coronary ligation. In order to perform cardiac stimulation by catecholamines, mini-osmotic pumps were implanted in animals 10 weeks after surgery to deliver noradrenalin for a 2-week period. At the end of this period, the following investigations were performed: haemodynamics, morphometry, fibrosis quantification, plasma and tissue catecholamine assay and oxidative stress status. Coronary ligation induced dilatation of left ventricle with compensatory hypertrophy of the right ventricle and of the remaining left ventricle myocardium. This remodelling process was associated in non-infarcted myocardium with increased collagen infiltration and increased oxidative stress. Ten weeks after surgery, the chronic administration of noradrenalin for 2 weeks did not increase oxidative stress. Noradrenalin, however, induced inotropic stimulation and myocardial hypertrophy, but to a lesser extent in infarcted rats compared to sham rats. Our results suggest that noradrenalin infusion to levels in excess of those seen post-infarction is associated with fibrosis and oxidative stress. Moreover, noradrenalin in infarcted animals caused additional fibrosis without further increasing oxidative stress. The mechanism of catecholamine-induced fibrosis may thus involve different processes such as ischaemia, increased mechanical stress, cytokines and neurohormones.

1. Evaluation of cardiac beta 1-adrenergic sensitivity in heart failure should provide instructive therapeutic as well as prognostic information. We set up a non-invasive test in healthy volunteers to evaluate beta 1-adrenergic reactivity using dobutamine as a preferential agonist. 2. The range of i.v. bolus doses was 3.2 to 12.2 micrograms kg-1. The test was well tolerated. The parameters that were most sensitive and best correlated to dobutamine doses were systolic blood pressure and the rate-corrected electromechanical systole (QS2i). The reproducibility of the test over 48 h and over 1 month was satisfactory for most parameters, with a mean variation coefficient ranging from 9 to 26%, and was better for QS2i than for heart rate. 3. Slope of log dose-response for heart rate and QS2i was similar with dobutamine and with isoprenaline, corresponding to stimulation of the same type of beta-adrenergic receptors (beta 1-subtype). This result was obtained despite a higher vagal stimulation with dobutamine. We conclude that the left ventricular contractile response assessed by QS2i provided the best parameter for evaluation of beta 1-adrenergic cardiac effects either with dobutamine or with isoprenaline. 4. In heart failure patients such a dobutamine test should allow separation of altered contractility and beta-adrenergic desensitization, since alteration of inotropic response to dobutamine should depend on both altered contractile function and adrenergic desensitization but heart rate response should only depend on the latter phenomenon.

The purpose of this work was to study the consequences of an intracellular depletion of pyridoxal-phosphate (PLP) in rat heart cells in culture submitted to oxygen deficiency. Glucose (GLc) and 4'-deoxypyridoxine (DOP) effects were separately evaluated after 150 mn of partial oxygen deprivation (N2) with regard to enzyme leakage, beating rates, intracellular concentrations of PLP and the ratio glycogen phosphorylase activity (-5'-AMP/+5'-AMP). PLP concentrations were higher in the air-GLc group than in the air group. alpha-Hydroxybutyrate dehydrogenase (alpha-HBDH) and creatine kinase (CK) leakages were observed in the N2 group, whereas 1.17 +/- 0.17 mM GLc prevented leakage. Beatings stopped in the N2 group, slightly decreased in the N2-GLc group; the ratio (-5'-AMP/+5'--AMP) increased only in the N2 group. With a 1 mM DOP pretreatment a significant decline of PLP was observed either with or without GLc in the culture medium. The ratio (-5'-AMP/+5'-AMP) was lower in the air-DOP group than in the air group, whereas beatings, alph-HBDH and CK activities were identical to the control group. ImM DOP in the N2-DOP group partially prevented alpha-HBDH and CK leakages into the medium but did not prevent the decrease in contractile activity. Surprisingly, PLP concentration increased in the N2-DOP group/air-DOP group and the increase in ratio (-5'-AMP/+5'-AMP) was higher in the N2-DOP group than in the N2 group when compared to the respective control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Human serum, obtained within 24 hours after the onset of septic shock, was evaluated for its effects on the chronotropic response of cultured rat myocardial cells to isoproterenol. Transmembrane action potential (AP) was measured in some experiments. Sera obtained after the first four to five hours, when central venous pressure (CVP) was normal or high, inhibited increased cell beats, while this property was not evidenced for samples taken soon after septic shock when CVP was low. Sera were also found to alter AP in much the same way as Sotalol, an adrenergic beta-blocking drug. These two effects were never observed with control sera obtained from healthy male adults at rest. These findings demonstrate that sera from patients in septic shock depress the beta-adrenergic response of rat myocardial cells, after the early phase of septic shock characterized by sympathoadrenergic activity. They strongly suggest the mediation of unidentified humoral factors, which might interfere in the pathogenesis of myocardial dysfunction during the intermediate phase of septic shock.

In heart of genetically obese (fa/fa) 12-week-old Zucker rats, ventricle contractility (4 mM KCl medium), amplitude and duration of slow action potentials (14 mM KCl medium) were less increased by isoprenaline than in heart of non obese (Fa/fa) rats. This difference could be related to a lower reactivity of beta-adrenoceptors in obese rat heart.

Three concentrations (0.5, 1 and 2 per 1000, w/v) of a single batch of trypsin were compared regarding their influence on cultured cardiac cell of newborn rats. All three allowed to obtain cardiac cells in good conditions, as evidence by beating frequencies and [16-14C]-palmitate beta-oxidation. However the 0.5 per 1000 concentration appeared to be the optimal one, inducing a smaller loss of cells during the first two days in culture.

Rat serum at different concentrations added to cultured Rat heart cells medium increased spontaneous beating frequency of myoblasts. This increase occurred instantaneously and lasted more than 24 hrs. It was related to the serum concentration used. Electrophysiological recording showed a decrease in the iso-electric phase duration of membrane potential, with no change in action potential. In spite of the beating frequency increase, cells remained sensitive to the chronotrope positive action induced by Isoprenaline. There was no difference between male and female sera. The global results could partly be explained by the action of Ca++ in Rat serum.