In isolated papillary muscles of cats the changes in Ca inward current and isometric contractile force following a decrease of extracellular pH from 7.4 to 5.5 were studied. The Ca current was analyzed (a) by measuring the upstroke velocity of Ca-mediated action potentials and (b) in voltage clamp experiments using the double sucrose gap technique. 1. At a pH of 5.5 the upstroke velocity of the Ca-mediated action potential decreased to 65% of the control, while overshoot and action potential duration remained almost unchanged. Furthermore, the relative refractory period was prolonged and in some cases, a "Wenckebach-like" phenomenon occurred. In voltage clamp experiments, the slow inward current was found to be diminished to 50-60% of the initial control value and over a broad voltage range the current voltage relationship curve was shifted to weaker currents. Acidosis did not influence the steady state inactivation but altered the kinetics of inactivation of the slow inward current and induced an increase of tauinactivation and taurecovery. This indicates that acidosis exerts a complex effect on the slow membrane channel. 2. The normal response of the Ca current towards variations of the extracellular Ca concentration (0.5-4 mM) or towards the addition of the beta-stimulating compound isoproterenol (2 mg/l) was not altered by the lowered extracellular pH. 3. In the acid medium, isometric contractile force declined to 40% of the control value within 25 min and, thus, reacted stronger than the Ca current. This indicates that those forms of acidosis used in the present experiments caused their negative inotropic effect not exclusively via a depression of the Ca current. Rather an additional intracellular effect has to be assumed which finally leads to a reduced activity of the contractile system. 4. At pH 5.5 excess Ca (4 mM) induced the same quantitative response of the contractile system as obtained at normal pH. In contrast, the positive-inotropic effect of 2 mg/l isoproterenol was more pronounced, whilst the sensitivity of the Ca inward current towards this beta-stimulating compound remained unchanged.

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The role of calcium accumulation in the pathogenesis of Duchenne muscular dystrophy (DMD) has already been discussed. Several trials with different calcium-blocking drugs have revealed no clinical benefit. In addition, the present study includes histological investigations and computer tomography to verify therapeutic effects. In a randomized placebo-controlled double-blind study, 13 DMD patients aged from 3-10 years (mean, 7 years) were treated with 5 mg/kg diltiazem daily for 1 year. Compared with before therapy, the number of calcium-positive muscular fibres was remarkably reduced in the treated DMD patients, but not in the placebo group. The evaluation of all other biochemical and clinical parameters revealed no significant effects of the diltiazem therapy. The muscular X-ray density measured by computer tomography decreased under treatment. After the evaluation of the double-blind study, the code was broken. Therapy, however, was continued in the treated group and started in the placebo group. After 3 years of diltiazem therapy the clinical status of all 26 patients of the study and 20 additional DMD patients who were treated with diltiazem was compared with 46 untreated DMD patients of the same age and stage in our department. No obvious clinical benefit of diltiazem therapy could be observed.

In isolated perfused guinea-pig hearts the threshold for ventricular fibrillation was determined applying DC or sinusoidal 50-cycle AC pulses during the vulnerable period. The results were compared with the threshold for single responses during diastole.Using rectangular pulses from 0.5 to 40 msec the threshold for fibrillation as well as for single responses exhibited a nearly linear relationship between strength and duration of impulses when plotted in a log-log-scale. As compared with the threshold for single responses the fibrillation threshold was shifted in parallel to a higher intensity level.Vulnerability of the ventricles was independent on stimulus duration. When the hearts were beating in AV-rhythm maximal vulnerability appeared about 150 msec after the beginning of ventricular excitation.Alteration of the physical conditions by increasing the magnitude ~f the electrodes and changing their position resulted in an increase of the threshold for single diastolic responses accompanied by a decrease of the fibrillation threshold, both curves being shifted in parallel retainig their slope. Using the same electrode arrangement, the threshold for electrical defibrillation exhibited a similar characteristic as the fibrillation threshold, however on a higher intensity level.With sinusoidal 50-cycle AC pulses an increase of stimulus duration beyond 1 period caused no further change to the threshold for single responses, whereas the threshold for fibrillation declined continously until a total duration of about 6 periods was attained.The results are interpreted in terms of the re-entry mechanism of fibrillation.Die Wirksamkeit des elektrischen Stroms f(ir die Ausl6sung yon Vorhofbzw. Kammerflimmern des Herzens ist von zahlreichen physikalischen und biologischen Gegebenheiten abh~ingig (14, 24, 26, 29, 36, 41, 42). Als physikalische Bedingungen kommen haupts~ichlich in Betracht:1. die Stromdichte im Herzen: Sie ist abh/ingig yon der angelegten Spannung, der Gr61~e und Position der Elektroden und den Widerstands-verhMtnissen

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Alkalosis (pH 7.8) produced by reduction of CO2 concentration augmented both upstroke velocity of Ca action potentials and isometric contractile force of mammalian heart muscle. If the increase of pH to 7.8 was achieved by a raise of HCO3 concentration (with simultaneous reduction of CO2 concentration), the positive inotropic response was not accompanied by an augmented Ca current. Obviously, the well-known positive inotropic effect of alkalosis does not only depend upon the enhancement of transmembrane Ca influx during excitation, but can be mediated alone by affecting intracellular Ca movements as well.

In small specimens prepared from the atrioventricular node of rabbits, the influence of hypoxia and metabolic inhibitors (Na-cyanide, 2.4 dinitrophenol, 2-desoxyglucose) on the av-node action potential was studied. The action potentials in these specimens proved to be of slow response type regardless of their origin, either the N or the NH-region of the node. 1. Following superfusion with O2-poor Tyrode solution, Vmax of the atrioventricular action potential gradually declined within 90 min and attained finally a new steady state. A mean decrease of 30.2 +/- 9.4% was obtained. Frequency a automatic impulse formation went down by almost the same amount within only 20 min. On return to an oxygenated Tyrode solution, or in the continued presence of O2 deficiency after an increase of the external glucose concentration from 11 mM to 33 mM, full recovery of these effects occurred. 2. After administration of Na-cyanide (1 X 10(-3) M), a similar Vmax decrease of 29.0 +/- 7.0% appeared. It took only 20 min for full development and was accompanied by a decrease reversible within 10-20 min on return to a cyanide-free medium. Poisoning the atrioventricular cell with 2.4 dinitrophenol (1 X 10(-3) M) led to the same result. Treatment with 2-desoxyglucose (3 X 10(-2) M) evoked a more pronounced Vmax diminution of 50%. 3. The inhibitor of K conductance, 4-aminopyridine (2 X 10(-3) M) did not remove the metabolically induced changes of Vmax of the atrioventricular action potential. After poisoning of oxydative phosphorylation, this compound caused in some cases evan a further reduction of Vmax. 4. The beta-adrenergic compound isoproterenol (9.2 X 10(-6) M) restored the hypoxia or cyanide-induced suppression of both Vmax and frequency of automatic impulse formation. The particularly pronounced response of Vmax led to an increase far exceeding the initial control values obtained under normal metabolic conditions of the atrioventricular cell.