We examined the inactive to active renin in the renin granules of the cadaver kidneys and the plasma in patients with diabetic nephropathy. The inactive renin in the break-through fraction when the plasma or the renin from the renin granules was put into a pepstatin column was determined. The inactive renin in this fraction was activated by trypsin. Concerning plasma, the inactive to active renin ratio was 90 in the patients and 9 in the normal subjects. On the other hand, this ratio was 0.29 in the patients' kidneys and 0.28 in the control kidneys. These results suggest that the increase of the inactive to active renin ratio in plasma of diabetic nephropathy does not result from the change of the renin storage in the kidneys.

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The effect of diltiazem on left ventricular isovolumic relaxation time was examined in 11 patients with hypertrophic obstructive and non-obstructive cardiomyopathy in a combined study using phonocardiograms and echocardiograms. Five to 10 min after intravenous injection of diltiazem (0.2 mg/kg, body weight), a prolonged isovolumic left ventricular relaxation time, which was measured from aortic component of the second heart sound to the mitral opening on the echocardiogram, decreased from 63.1 ± 26.0 to 46.9 ± 28.0 msec (p < 0.01). This study suggests that diltiazem, one of the calcium blocking agents, may ameliorate the impaired left ventricular diastolic function in patients with hypertrophic cardiomyopathy.

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In 11 of 13 cynomolgus monkeys inoculated with coxsackievirus B3 and/or B4, myocarditis was proved histologically. Myocarditis was evident the first 10 days after inoculation and left chronic sequelae ; moderate myocardial celluar hypertrophy with an increase of connective tissue with focal distribution, and some residual inflammatory foci were found 5 months after viral inoculation. Virus was recovered from the heart on the 4th day but not on the 10th day, while serum neutralizing antibody rose significantly over 2 or 3 weeks in most of the inoculated monkeys. Electrocardiographic abnormalities were found in all 11 monkeys in which the myocarditis was proved histologically. These abnormalities were usually transient and were detected most often in the ST-T segment of the right-side chest leads, corresponding to the anatomical distribution of the myocarditis.

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We studied, with microelectrodes, the effect of lidocaine and 1-verapamil on the upstroke phase of action potentials and conduction velocity in incompletely depolarized ventricular papillary muscle (resting potential, -58 ± 1 mV) perfused in a high K⁺ (16.7 mM) Tyrode's solution. The action potential upstroke had a slur and the maximum rate of rise (V^^·_max) consisted of 2 components : the first large (32 ± 7 V/sec ; V^^·_{max, fast}) and the second small (10 ± 2 V/sec, V^^·_{max, slow}). The conduction velocity was slow and ranged about 30-35 cm/sec. Isoproterenol and noradrenaline increased V^^·_{max, slow} and decreased V^^·_{max, fast}, in a concentration dependent manner (10^-8 - 10^-5 M). These effects were abolished by following application of a β-blocker, pindolol (1μg/ml). Thus, the dominant ionic channel responsible for the the slow conduction seemed to alter from the depressed fast channel to the slow channel as the catecholamine concentration was increased. In the absence of isoproterenol, lidocaine (2μg/ml) depressed V^^·_max with a resultant decrease of conduction velocity to 16.4 ± 4.2 cm/sec and which was followed by a conduction block, while 1-verapamil was without effect. In the presence of isoproterenol (5 × 10^-7 M), 1-verapamil (1μg/ml) depressed the V^^·_max and decreased the conduction velocity to 16.9 ± 4.2 cm/sec, just before development of the conduction block, while lidocaine was without effect. These results suggest that the dominant ionic channel responsible for the slow conduction in high K media (16.7 mM), can be readily altered by changes in extracellular catecholamine concentrations and that the slowest possible conduction velocity was approximately the same (about 16 cm/sec) between the depressed fast channel-dependent and the slow channel-dependent conductions. Clinical implications of these findings were discussed.

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For the purpose to evaluate the effects of lidocaine on the ventricular arrhythmias occurring as complications of actute myocardial ischemia or infarction, the electrophysiological actions of lidocaine were estimated, as compared with those of procainamide, on the right ventricular papillary muscle of the rabbit heart superfused with hypoxic, hyperkalemic and/or acidic Krebs-Ringer solution. Lidocaine (1 to 5 ×10^-5 M) and procainamide (1.7 to 3.4 ×10^-5 M) depressed the maximum rate of action potential upstroke (V^^·_max) and prolonged both of the effective refractory period (ERP) and the diastolic interval needed for the premature V^^·_max to recover to 98% in magnitude of the basic V^^·_max (98% recovery time) dose-dependently, without decreasing the resting potential. Among the ischemic components, low pH (pH 6.9) and high potassium (10 mM) extracellular environments potentiated the depressant actions of lidocaine in synergic manner, but no significant enhancement of the actions of procainamide were observed under exposure to any components of ischemia. Mechanisms underlying the difference of the depressant actions on ischemic myocardium between lidocaine and procainamide were discussed in the light of recent concepts of actions of local anesthetics, and came to the conclusion that lidocaine is the most preferable antiarrhythmic agent for the management of ventricular arrhythmias during ischemia or infarction.

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Antiarrhythmic effects and minimum antiarrhythimic plasma concentrations (min PC) were examined using three canine ventricular arrhythmia models, i.e., two-stage coronary ligation arrhythmia (Cor), halothane-adrenaline arrhythmia (Adr) and digitalis arrhythmia (Dig). Disopyramide suppressed these three arrhythmias and its min PCs were 5.3 ± 1.8 (Cor), 4.2 ± 1.1 (Adr) and 1.7 ± 0.4 μg/ml (Dig). Procainamide suppressed coronary ligation arrhythmia and its min PC was 27.1 ± 4.0 μg/ml, but was not effective on adrenaline arrhythmia. Aprindine was effective on three arrhythmias and its min PCs were 1.6 ± 0.3 (Cor), 1.0 ± 0.4 (Adr) and 0.8 ± 0.4μg/ml (Dig). Lidocaine was not effective on coronary ligation arrhythmia, but was effective on adrenaline arrhythmia and its min PC was 15 μg/ml. Phenytoin was effective on three arrhythmias and its min PCs were 9.8 ± 2.0 (Cor), 12.1 ± 3.1 (Adr) and 11.3 ± 3.0 μg/ml (Dig). It was not specifically effective on canine digitalis arrhythmia. Propranolol and other β-blockers were effective on adrenaline arrhythmia, but very high doses were necessary for suppressing coronary ligation and digitalis arrhythmias. Verapamil was only effective on adrenaline arrhythmia and its min PC was 0.03 ± 0.01 μg/ml. Canine min PCs of drugs were almost the same as those reported in man except for procainamide and lidocaine. Membrane stabilizing effects seem to be important for suppressing canine ventricular arrhythmias.

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The effects of the intravenous administration of three drugs, i.e., verapamil, disopyramide, and procainamide, on paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (Af) and atrial flutter (AF) were evaluated electrophysiologically. Efficacy on PSVT was 94.7% (36/38) with verapamil, 61.5% (13/18) with disopyramide and 100% (4/4) with procainamide. Efficacy on Af and AF was 9.1 % (1/11) with verapamil and 80.0% (12/15) with disopyramide. PSVT termination mechanisms were as follows : 1) Verapamil : A-H block in 5 cases and H-A block in 5 cases with Type 1 A-V nodal reentrant tachycardia (AVNRT). H-A block in 6 cases with Type 2 and Type 3. A-H block in 17 of 18 cases with A-V reciprocating tachycardia (AVRT). Cycle length alternans were observed in 13 of 34 cases. 2 ) Disopyramide : H-A block in 2 cases with AVNRT and V-A block in 2 cases with AVRT. 3) Procainamide : V-A block in 4 cases with AVRT. These results suggest that verapamil and disopyramide are most effective on PSVT and Af, respectively.

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We performed serial electrophysiological-pharmacological studies on 21 patients with recurrent sustained or non-sustained ventricular tachycardia (VT). In 8 of 11 patients with recurrent sustained VT, VT could be induced repeatedly by programmed electrical stimulation and terminated by ventricular burst pacing. In 13 of the 21 patients, repetitive ventricular response (RVR) was successfully induced. In the 8 patients with induced VT, the efficacy of several antiarrhythmic drugs intravenously administered was assessed. Procainamide prevented the initiation of VT in 57%, disopyramide in 50% and mexiletine in 40%. However, lidocaine, propranolol and verapamil could not prevent VT in any of 5, 3 and 6 patients, respectively. Verapamil in combination with quinidine prevented the initiation of VT in one case. Each of disopyramide, propranolol and verapamil increased the VT zone in 2 patients. The drugs belonging to the same group classified by their electrophysiological properties were not interchangeable in 2 patients. Their ability to terminate induced VT did not always correlate with that to prevent its initiation in 2 patients. The effects of specific drugs were rather variable and unpredictable in each patients, and especially those of combination regimens using more than 2 antiarrhythmic drugs were more unpredictable. In all patients, the induced VT was morphologically identical to the spontaneously occurring VT and its rate was ranged within 13% of that of the spontaneously VT. In 10 of 13 patients with RVR, QRS configuration of RVR was not similar to the spontaneously occurring arrhythmia. The pharmacological suppression of RVR as an index for prevention against spontaneous VT remains controversial. This study concludes that the serial electrophysiological-pharmacological study provides a rapid prediction of effectiveness of a particular regimen and combination and a rapid identification of the deleterious effects of certain drugs in patients with recurrent sustained VT.

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The effects of procainamide on the refractory periods of the accessory and normal pathways in the antegrade and retrograde directions with reference to the reciprocating tachycardia were studied in 31 patients with Wolff-Parkinson-White (WPW) syndrome. Right atrial, left atrial and right ventricular pacing (incremental pacing and extrastimulus technique) were performed to induce reciprocating tachycardia and to measure antegrade and retrograde effective refractory periods (A-ERP and R-ERP) of the accessory pathway (AP) and the A-V node (AVN). Atrial extrastimulus technique was performed at 2 or more basic cycle lengths and repeated after an intravenous administration of procainamide (600 mg). Prior to the procainamide administration reciprocating tachycardias were induced in 10 of the 31 patients. After procainamide, induction of the tachycardia became impossible in 2 of these 10 patients. In 3 patients, procainamide decreased the tachycardia zone, while procainamide widened the tachycardia zone in the other 4 patients. In the remaining one, procainamide had no significant effect on the tachycardia was induced in 21 of the 31 patients. In 15 of these 21, no tachycardia was induced after procainamide. However, in 6 of the 21 patients, sustained reciprocating tachycardias were induced after procainamide. All reciprocating tachycardias that occurred in these patients were characterized by narrow QRS complexes, and demonstrated circus movement with antegrade conduction via the normal pathway and retrograde conduction via the accessory pathway. In 10 of the 31 patients (32%), induction of the tachycardia by an atrial premature beat after procainamide was shown while prior to its administration no tachycardia could be initiated, or the tachycardia zone was widened on procainamide administration. In these patients, procainamide could not block retrograde conduction over the AP and altered the relationship between the A-ERP_AP and the A-ERP_AVN by lengthening the A-ERP_AP with shortening the A-ERP_AVN, i.e., after procainamide the A-ERP_AP became longer than the A-ERP_AVN, and, by shortening the A-ERP_AVN, procainamide did augment the differences in length of the ERP of the 2 A-V pathways, so that sustained reciprocating tachycardia could be induced by atrial stimulation. In conclusion, we consider that in some patients with WPW syndrome procainamide may facilitate the induction of sustained reciprocating tachycardia by prolonging the A-ERP_AP and, at the same time, by shortening the A-ERP_AVN but by only minimally increasing the R-ERP_AP.

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Although subjective symptoms and brief recording of ECG have been used for an efficacy evaluation of new antiarrhythmics on ventricular premature contraction (VPC), incidence of subjective complaints in VPC was under 25% and number of VPC for 3 min did not correlate enough to those for 24 hours, indicating these parameters are not appropriate for such a trial. Number of VPC automatically counted by DECG (continous ECG recording for 24 hours) showed high accuracy, while day to day variation of VPC arose as the next problem. While cases of more than about 7, 000/day showed very little day to day variation, cases of less than about 1, 000/day had poor reproducibility, indicating that the former group can be used for the trials of new antiarrhythmics, but not the latter group. For cases with medium magnitude of VPC variation, DECG should be recorded twice during the period without drug administration and application of the paired t-test for number of VPC in each corresponding hour may bring a good evaluation.

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Using Holter monitoring tachycardia was found in 145 out of 2058 patients suffering from various underlying diseases. Three thousand seven hundred and forty monitorings were performed. The mean age of patients was 54.5 years with a range of 19 to 83 years. The observed tachycardia was classified into three types : tachycardia with short duration, tachycardia with long duration and tachycardia with complex form. The attacks of tachycardia were more frequently observed during periods of physical activity than during sleeping periods. The relationship of the number of tachycardia with short duration between 24-hour Holter monitorings was examined in order to establish day to day variability of the attacks. The 95% confidence interval about the resultant regression line was calculated and the percent reduction required for the evaluation of drug efficacy to avoid the chances of interference of spontaneous variation was found to be about 44.0, 55.0 and 82% when the total number of attacks during a 24-hour period were 50, 100 and 1, 000, respectively. Holter monitoring showed higher positive results as compared to exercise testing for detection of tachycardia. Higher correlation coefficients between numbers of premature ventricular contractions (PVCs) and the plasma concentrations of procainamide or N-acetylprocainamide were observed in 3 or more successive PVCs than in individually occurring PVCs. Using repeated 24-hour Holter monitorings a significant reduction in the number of tachycardia was observed when the therapeutic concentration was reached after the combined or single administration of the drug. These results suggest that repeated Holter monitorings, exercise testing and determination of plasma level of the drug may be useful for the evaluation of antiarrhythmic drug efficacy for tachycardia.

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Cases with tachyarrhythmias are presented, in which the limitations of antiarrhythmic drugs are implicated. Discussions are made on when and how the drug in question is considered to be ineffective in a given patient.

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