Teruo Fukumoto

Diltiazem and verapamil reduce the loss of adenine nucleotide metabolites from hypoxic hearts

The present study was undertaken to elucidate possible mechanisms for a protection of myocardial cells from hypoxia-induced derangements in cardiac function and metabolism by calcium antagonists. For this purpose, rabbit hearts were perfused for 20 min under hypoxic conditions in the presence of 312 ng/ml diltiazem or 125 ng/ml verapamil, and then for 45 min under reoxygenated conditions. Metabolic changes in the myocardium and the perfusate were examined throughout. Hypoxia induced a marked decline in myocardial high-energy phosphates and an immediate release of ATP metabolites, such as adenosine, inosine and hypoxanthine, from the perfused heart. These changes were effectively depressed by diltiazem and verapamil. Hypoxia and subsequent reoxygenation resulted in a release of creatine phosphokinase from the heart, which was completely inhibited by the treatment with either diltiazem or verapamil. Myocardial calcium contents were increased by 20 min-hypoxic perfusion. Both diltiazem and verapamil are capable of preventing hypoxia-induced increase in the transmembrane flux of cellular components, which may be beneficial for the preservation of substances necessary for the ATP regeneration after hypoxia and for the inhibition of calcium overload in cardiac cells.

Effects of oral diltiazem on ventricular premature contractions.

The effects of oral diltiazem (90-180 mg/day for four weeks) on ventricular premature contractions (VPCs) were studied in 16 patients with frequent VPCs using 24-hour ambulatory ECG recordings. VPC frequency was evaluated as a function of underlying heart rate. Plots of VPC frequency vs. heart rate were made at 1-beat/min intervals for all heart rates recorded for at least five minutes during 24 hours. Patterns of correlation between VPC frequency and heart rate observed before diltiazem therapy included: 1) a relatively linear increase in VPCs with heart rate (positive correlation) in ten patients, 2) a linear decrease (negative correlation) in one patient, and 3) an increase at low heart rates and a decrease at high heart rates (bidirectional correlation) in five patients. Diltiazem significantly reduced the mean VPC frequency per 24 hours for patients with a positive correlation, but induced no significant change for patients with a negative or a bidirectional correlation. At the 65% level of VPC reduction, diltiazem was effective in eight of ten patients with a positive correlation but was not effective in the six patients with other correlations (p less than 0.01). These results suggest that an evaluation of VPC frequency as a function of heart rate predicts the response of VPCs to diltiazem.

The effects of VDT work on urinary excretion of catecholamines.

The mental components of 2 hours of VDT work for three age groups of volunteers were investigated using urinary excretions of noradrenaline and adrenaline. After the work of searching for target words, the noradrenaline excretion showed a tendency to decrease in the young group, a significant increase in the middle-aged and a tendency to increase in the elderly. There was no change in adrenaline excretion in any age group. The elderly had a slower work speed than the young or middle-aged. Noradrenaline excretion showed a significant increase after VDT work using small letters, no significant change with large letters and a tendency to decrease after hard-copy work. The adrenaline excretion, did not change. The work speed was slower during the VDT work with small letters than during the hard-copy work These data suggest that the elevated level of sympathetic nervous activity resulting from VDT work is not caused by the VDT itself but by the intensity of the VDT work, and suggest that the effect of the VDT ...

Enhancement of post-hypoxic contractile and metabolic recovery of perfused rat hearts by dl-propranolol: Possible involvement of non-beta-receptor mediated activity

The present study was undertaken to elucidate a possible role of non-beta-receptor mediated effects in dl-propranolol-induced enhancement of post-hypoxic contractile and metabolic recovery in perfused rat hearts. The rat hearts were perfused for 30 min under reoxygenated conditions following 15 min-substrate free-hypoxic perfusion, and the cardiac performance and myocardial metabolism were examined. Hypoxia induced complete cessation of cardiac contractile force, depletion of myocardial high-energy phosphates, release of ATP metabolites and creatine kinase from the heart. Subsequent reoxygenation produced little recovery of cardiac contractile activity and tissue high-energy phosphates, further enhancement of the release of creatine kinase and the accumulation of tissue calcium. Treatment of the hypoxic hearts with dl-propranolol, d-propranolol and atenolol was performed during 5 to 15 min of hypoxic perfusion. dl-Propranolol and d-propranolol at the concentration of 45 microM elicited a significant recovery of cardiac contractile activity and restoration of myocardial high-energy phosphates. This treatment also resulted in a suppression of the release of creatine kinase and ATP metabolites and the tissue calcium accumulation observed during hypoxia and/or reoxygenation. However, such beneficial effects were not seen in hearts treated with 45 microM atenolol. dl-Propranolol and atenolol, but not d-propranolol, in a concentration of 45 microM have been shown to reveal beta-adrenoceptor blocking action. Thus, the results suggest the involvement of non-beta-receptor mediated effects of propranolol in the enhanced post-hypoxic contractile and metabolic recovery of the perfused rat heart. The non-beta-receptor mediated activity of these drugs appears to be related to their ability to suppress the maximal driving frequency of left atrial preparations.

The effects of VDT work on the regulation of hemodynamics compared with aging

Urinary excretions of aldosterone, blood pressure, and heart rate were examined for three age groups of volunteers searching for target words on VDT for two hours. Aldosterone excretion did not change in the young and middle-aged groups, but increased in the elderly group. Blood pressure decreased midway through the work in the young group, and increased during the work in the middle-aged and elderly groups. Aldosterone excretion did not increase during hard-copy work or during VDT work with large letters, but increased during VDT work with small letters. During VDT work with both large and small letters, blood pressure increased. During hard-copy work, neither blood pressure nor heart rate changed, although blood pressure increased after the work. These data suggest that the sympathetic nervous activation represented by the increases in aldosterone excretion and blood pressure occurred definitively during VDT work with small letters under the conditions of this study. It is also suggested that this effect is enhanced by aging.

THEOPHYLLINE INHIBITS ISOPROTERENOL-INDUCED CORONARY DILATATION IN THE ISOLATED PERFUSED RAT HEART

To study the role of endogenous adenosine in coronary dilatation induced by beta-adrenergic stimulation, isolated rat hearts were perfused at a constant flow rate. Perfusion of the heart with isoproterenol caused increases in the heart rate, left ventricular developed pressure, coronary dilatation, and release of adenosine and its degradation products. Theophylline inhibited isoproterenol-induced coronary dilatation without any significant effects on other contractile properties such as heart rate and left ventricular developed pressure. Coronary dilatation induced by exogenous adenosine was also inhibited by theophylline. These results suggest that beta-adrenergic stimulation induces coronary vasodilatation not only through direct beta-adrenergic responses, but also through increases in extracellular adenosine.

Clinical suppression of bradycardia dependent premature ventricular contractions by the potassium channel opener nicorandil

Objective To assess the clinical antiarrhythmic effect of nicorandil, a potassium channel opener, on premature ventricular contractions. Design and patients The effect of oral nicorandil (15 to 60 mg daily for four weeks) on premature ventricular contractions was investigated in 20 patients (11 female, nine male, mean (SD) age 63 (17) years) who underwent 24 hour ambulatory ECG. Patients were classified into two groups based on the relation between the frequency of premature ventricular contractions and heart rate: (1) those with a positive correlation (n = 9); and (2) those with a bidirectional correlation (n = 11), characterised by an increased frequency of premature contractions at low heart rates and a decreased frequency at high heart rates. Results Nicorandil reduced the frequency of premature ventricular contractions by 75% in five patients in group 2, but was not effective in any patient in group 1. The heart rate at which the frequency of premature ventricular contractions peaked was significantly lower in the five responders in group 2 than in the six non-responders (63.2 (3.7) v 76.3 (12.4) beats/min, p < 0.05). Conclusions Nicorandil may suppress premature ventricular contractions when they occur mainly at a low heart rate.

Effects of Hydrogen Ion on the Changes in Adenosine Production in the Isolated Rat Heart Perfused at a Constant Flow System

This study was designed to clarify the relationship between the change in H+ and the nucleoside concentration at a constant coronary flow rate using a Langendorff system. Wistar rat hearts were perfused with Krebs-Henseleit solution (control, pH 7.4) modified to be either acidotic or alkalotic. Coronary perfusion pressure (CPP), left ventricular pressure, and myocardial oxygen consumption were decreased in the acidotic perfusate. On the other hand, these parameters increased in the alkalotic perfusate. Adenosine production in the acidotic perfusate significantly decreased while it significantly increased in the alkalotic perfusate. Furthermore, there was a significant positive correlation between both the percent change in adenosine production and the percent change in CPP in acidosis and alkalosis. It is suggested from these results that the hydrogen ion affects the adenosine metabolism and that the change in coronary blood flow by H+ is at least partly regulated by adenosine.

Real-time measurement of the spatial magnitude of the ST segment with the automated vectorcardiographic ST segment analyzer.

ST segment deviation has been used as an indicator of the degree of myocardial ischemic injury. An automated vectorcardiograph, i.e., an ST segment analyzing system developed in our laboratory, was applied to experimental coronary artery occlusion in dogs, and continuous real-time measurements of ST segment deviation were undertaken. ST segment deviations of the X, Y and Z leads of the Frank lead system were measured and averaged during eight-second periods (STX, STY and STZ). From the ST segment deviation in three dimensions, the spatial ST magnitude and the direction of ST segment deviation (azimuth and elevation) were computed with the use of a microcomputer. The spatial changes of the ST segment after the occlusion of the coronary arteries in the experimental animals were quite compatible with the site of the occlusion. In addition, various interventions influenced the spatial magnitude of the ST segment resulting from coronary artery occlusion.