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Thirty-five patients with typical Prinzmetal's variant angina were studied by coronary cineangiography. There was no demonstrable stenosis of the major coronary arteries in 19 patients. Nine patients with single coronary stenosis underwent aortocoronary bypass and had recurrence of the symptoms postoperatively. Administration of nifedipine effected complete cessation of the symptoms among patients formerly treated medically. Although surgical treatment did not effect permanent relief of pain, all patients initially treated surgically experienced relief of pain when nifedipine was administered. The pathophysiology of variant angina remains obscure. Our results suggest that neurohumoral factors exert more of an effect on the myocardial cell than on the coronary vessels.

One hundred patients undergoing maintenance hemodialysis for chronic renal failure were evaluated by Holter ECG monitoring for a 72-hour period from the day of hemodialysis therapy. Eighteen patients (the frequent group) who had more than 700 premature ventricular contractions (PVCs) per day were found among these 100 patients. In those eighteen, the PVCs were recorded frequently during and for 4 hours after hemodialysis. The values of the serum calcium concentration times those of phosphorus, which are thought to be an index of parathyroid function, were significantly higher in the frequent group than in patients without PVCs (the no arrhythmia group) or in those with fewer PVCs (less than 700 beats per day; sporadic group). Also, in the frequent group, the percent fractional shortening of the left ventricle, as measured by 2-dimensional echocardiography, was significantly lower than those in the no arrhythmia and sporadic groups. From these results, we conclude that the pathogenesis of the PVCs in chronic renal failure resulted partially from impaired cardiac performance and accelerated parathyroid function.

To clarify the mechanical adaptation and interference of coronary vessels, we studied hemodynamics of coronary circulation in control and 4 different pacing rates (80, 100, 120, 150/min) in 5 patients with angina pectoris (AP) and in 5 patients with hypertrophic cardiomyopathy (HCM). Coronary sinus flow (CSF) was measured by a Webster's thermodilution catheter, and we applied ascorbic acid-platinum reaction for the mean transit time measurement in left coronary flow (t0-t2). Coronary vascular bed (CVB) was obtained by multiplying CSF and t0-t2. CSF in AP gradually increased from 104 +/- 21 ml/min at 72/min to 148 +/- 42 ml/min at 120/min, while CSF in HCM changed slightly from 91 +/- 25 ml/min at 64/min to 94 ml/min at 120/min. Average t0-t2 in HCM was 6.0 +/- 1.6 sec in control which was significantly lower than that in AP (7.8 +/- 0.7 sec). Calculated CVB in AP increased at any given heart rate up to 120/min (13.5 +/- 2.4, 15.8 +/- 1.7, 15.0 +/- 4.7, 15.1 +/- 4.3 ml), but CVB in HCM decreased from 9.1 +/- 2.3 ml at 64/min to 8.1 +/- 1.7 ml at 120/min. These data suggest that myocardial compression and suction at different heart rates and with different cardiac muscle structures play an important role for beat to beat adjustment of coronary circulation in cardiac cycle.

Using more than 500 rabbits, we found that the rabbit heart is a good model for the evaluation of drugs which affect acute myocardial infarction (AMI) size. When the ratio of the epicardial coloration area to the long axis length of the left ventricle was controlled immediately after the ligation of the left anterior descending coronary artery and small branches of the left circumflex artery, it was possible to estimate the size of the ischemic region because AMI region in rabbit heart was always transmural. The necrotic region in the left ventricle was determined by phosphorylase histochemistry 24 hours after the operation. The incidence of arrhythmia and death following the operation was negligible. Then, we evaluated several drugs to examine their effects on AMI size. Propranolol (1, 2, and 4 mg/Kg) and verapamil (0.25, 0.5, and 1.0 mg/Kg) reduced AMI size, although the mortality and AMI size increased at higher doses of verapamil. Another Ca2+ antagonist, diltiazem (2 mg/Kg) and an adenosine potentiator, dilazep (2 mg/Kg) also decreased AMI size, while nicardipine, a water soluble, photoresistant nifedipine analogue (0.01, 0.05, and 0.1 mg/Kg) did not show a significant effect. These data suggest that this rabbit model is useful for assessing drug effects on AMI size and that the mechanism(s) of action of nicardipine may differ from other Ca2+ antagonists.

Seventy-four patients with unstable angina are reviewed. A rather high incidence (65%) of a changing pattern syndrome was observed in the study group. A history of prior myocardial infarction was obtained in 22 patients (30%). Fifty-seven patients (77%) were investigated using coronary angiography : 15 did not have any significant occlusive disease but are included in this study ; single vessel disease was present in 20, double in 8 and triple in 14. Ten patients (13.5%) had myocardial infarcts which had occurred between 48 hours and 3 months after admission, and no patients died during this period. Patients who on admission had resting angina of new onset were more likely to have a worse short-term prognosis. Four patients underwent coronary bypass surgery in the first year of the follow-up period because of unsuccessful medical treatment. Six patients died within the first 4 years. Of the 6 deaths, 5 had triple vessel disease and one did not have any significant coronary stenosis. Mortality rate at 2 years was 2.7% and at 4 years 10.3%. This low mortality is probably attributable to a low incidence of 2- or 3-vessel disease.

The antianginal effects of diltiazem and nifedipine alone and in combination were evaluated in a double-blind, randomized, placebo-controlled trial in 11 patients (nine men and two women, 57 +/- 8 years old) with stable effort angina. Each patient received placebo, 30 mg of diltiazem, 10 mg of nifedipine, and 30 mg of diltiazem plus 10 mg of nifedipine four times daily for 1 week each. Antianginal efficacy was assessed by means of a treadmill exercise test. The exercise tolerance time was significantly prolonged from 235.1 +/- 52 (placebo period) to 342.2 +/- 101 sec by diltiazem (p less than .01) and to 325.6 +/- 73 sec by nifedipine (p less than .01). The drug combination further prolonged exercise time to 451.1 +/- 103 sec, which was significantly longer than the interval attained with either diltiazem (p less than .01) or nifedipine (p less than .01) alone. The plasma concentration of diltiazem was unaffected by the addition of nifedipine, whereas the plasma nifedipine concentration was significantly increased from 34.8 +/- 11 to 106.4 +/- 37 ng/ml (p less than .001) by the concomitant administration of diltiazem. These data suggest that exercise tolerance in patients with effort angina is increased by the concomitant administration of diltiazem and nifedipine associated with an increase in the nifedipine plasma concentration.

SUZUKI, M., TERAO, N., ASANO, Y. & HOSODA, S. Adaptive Changes of H+ and/or Bicarbonate Transport in Chronic Metabolic Acidosis: Its Quantitative Evaluation by Using Isolated Perfused Kidney. Tohoku J. exp. Med., 1987, 152 (3), 283-290-We have recently improved the technique of the isolated perfused rat kidney by addition of amino acids to the perfusion solution. Utilizing this improved preparation, we examined to what extent chronic acid-base status can alter H+ and/or bicarbonate transport in the whole kidney and the effect of acetazolamide (10-4M) on this process. Kidneys from rats that had been drinking tap water (control), 1.5% NH4Cl (acidotic), or 1.5% NaHCO3 (alkalotic) were perfused with a solution of identical pH and PCO2. During the control period, the fractional bicarbonate reabsorption was higher in acidotic rats than in control rats by 1.0% and urine pH was lower than those in control. On the other hand, the two parameters were not different between control and alkalotic rats. Acetazolamide increased urine pH and decreased the fractional bicarbonate reabsorption in all, but these parameters in acidotic and alkalotic rats were not different compared with those in control. We conclude that adaptive changes of H+ and/ or bicarbonate transport in chronic metabolic acidosis corresponds to about 1.0% as fractional bicarbonate reabsorption by the isolated perfused kidney and is largely carbonic anhydrase dependent.

The development and reversal of tolerance to the hemodynamic and anti-anginal effects of isosorbide dinitrate in a sustained release form (ISDN-SR) were investigated in 11 male patients (mean age 58.9 y.o.) with stable effort angina. Treadmill exercise test, evaluation of hemodynamic parameters and measurement of plasma ISDN concentrations were performed during the control period, on the 1st, 7th and 14th days of therapy with 40 mg of ISDN-SR orally every 8 h and, subsequently, on the day when ISDN-SR was re-administered after a 72 h placebo period (17th day). Initially, exercise tolerance time (ETT) was prolonged significantly (p less than 0.001) by ISDN-SR from 257 +/- 50 sec in the control period to 434 +/- 55 sec on day 1. This prolongation was significantly reduced with sustained therapy and ETT was shortened to 332 +/- 69 sec on the 7th day (p less than 0.01 vs day 1) and 326 +/- 73 sec on the 14th day (p less than 0.01 vs day 1). The effects of ISDN-SR initially observed were restored after a 72 h placebo period and ETT was prolonged to 432 +/- 57 sec on the 17th day. The resting heart rate was increased significantly (p less than 0.01 vs control) and systolic blood pressure was decreased (p less than 0.001 vs control) by ISDN-SR on day 1. These changes were also diminished significantly (p less than 0.01 vs day 1) with sustained therapy and were restored after a 72 h nitrate-free interval.(ABSTRACT TRUNCATED AT 250 WORDS)

The direct and secondary effects of tachycardia on the coronary circulation were analyzed in the dog's heart with atrioventricular block, pacing the heart at rates of 60, 120, 180 and 240 per minute from ventricular automatism (heart rate 45 on an average). The effect of bradycardia was also studied by turning off the pacemaker from various heart rates. 1. In the initial phase of marked tachycardia, a decrease in coronary blood flow and an increase in coronary vascular resistance were observed, presumably due to direct mechanical effect of tachycardia on the coronary vasculature. Increases in coronary vascular resistance were 4.9%, 8.5%, 26.7% and 38.8% at ventricular rates of 60, 120, 180 and 240, respectively. 2. The coronary blood flow increased in the late phase of marked ventricular tachycardia. This suggested the effect of metabolic and humoral factors. The coronary vascular resistance decreased by 1.0%, 12.5%, 30.5% and 32.2% at the pacemaker rates of 60, 120, 180 and 240, respectively. 3. Changes in heart rate from ventricular tachycardia to the ventricular automatism were considered to reveal the effect of bradycardia. The coronary vascular resistance remained unchanged in bradycardia starting from ventricular rates of 60 and 120, but it decreased in bradycardia from ventricular rates of 180 and 240, and averaged -15.3% and -24.6%, respectively.

Summary 21 cases of bulboventricular inversion type corrected transposition of the great arteries were analyzed electro- and vectorcardiographically with 15 cases uncomplicated by intracardiac anomalies collected from the literature. Frontal QRS axes were divided according to the extent of right-sided ventricular overloading (RVO) as follows: group I, right axis deviation from +90° to +140°, consisted of 12 cases with severe RVO, such as pulmonary stenosis (PS) with ventricular septal defect (VSD) or VSD with severe pulmonary hypertension; group II, left axis deviation from +10° to −75°, consisted of 19 cases with no associated anomalies or with mild to moderate RVO, such as VSD with left-to-right shunt or mild PS. In the precordial leads, reversal of the normal precordial Q wave pattern was observed. Moreover, in cases with no associated anomalies, characteristics QS or rS patterns in III, aVF and right precordial leads were found. These patterns were found in 50% of the cases with no associated anomalies. In most cases, with or without associated anomalies, the direction of the frontal plane initial QRS vectors was to the left and superior. However, in the horizontal plane, the initial vectors were divided into two directions, left anterior and left posterior. Therefore, it is the author's opinion that on interpreting electrocardiograms with the initial QRS vector oriented in the left posterior or anterior direction, it is necessary to consider corrected transposition of the great arteries as a possible cause, in addition to the usual considerations of antero-septal myocardial infarction. WPW syndrome, left bundle branch block and myocardial disease.

The nervous control of the cardiac output was studied in the anesthetized and hemithoracotomized dogs. 1) The stimulation of the left sympathetic cardiac nerve usually caused biphasic increase in cardiac output as well as biphasic elevation of the systemic blood pressure. Initial marked increase in cardiac output was accompanied with the first elevation of blood pressure during the stimulation. After the stimulation, however, the late elevation of blood pressure was usually accompanied with only a slight increase in cardiac output and marked increase in coronary blood flow. 2) The stimulation of the right sympathetic cardiac nerve caused marked tachycardia with less increase in cardiac output compared with these changes on the left side. 3) The stimulation of the proximal end of the cut cervical vagal nerve caused pressor and/or depressor effect. In the pressor response, cardiac output increased slightly almost in parallel with the systemic blood pressure, while in the depressor response, cardiac output increased with the depression of the blood pressure. 4) The carotid sinus nerves influence particularly the biphasic elevation of the blood pressure by stimulation of the left sympathetic cardiac nerve. 5) The changes of the coronary blood flow were parallel with the blood pressure than with the cardiac output.

Long-term changes in regional wall motion (RWM) following acute myocardial infarction (AMI) in 42 patients with uncomplicated single-vessel disease were examined retrospectively by repeat cardiac catheterizations. The first and second cardiac catheterizations were performed at an average of 28 days and 6.6 years after the onset of AMI, respectively. All 42 patients underwent first and second cardiac catheterizations without undergoing coronary artery bypass surgery or coronary angioplasty. Regional left ventricular functions were analyzed by the centerline method using a right anterior oblique left ventriculogram. The wall motion abnormality score (WMAS) was defined as [# chord below -2SD] x [mean SD chord below -2SD]. The improvement in the WMAS was more prominent in cases with an occluded infarct-related artery. Thus, we concluded that 1) RWM improves significantly with medical treatment in long-term follow-up in cases of uncomplicated AMI with single-vessel disease, and 2) the improvement of RWM is completed within the first few weeks after AMI in cases with a patent infarct-related artery.

Pharmacological protection of acute ischemic myocardial injury was studied using diltiazem, bunazosin, coenzyme-Q10 (Co-Q), and nicorandil, in dogs of which the left anterior descending coronary artery was ligated for 60 min. Drugs were given intravenously prior to and/or during coronary ligation. Co-Q, bunazosin and diltiazem suppressed degradation of sarcoplasmic reticulum (SR) expressed as inhibitions of reduction in Ca++-dependent ATPase activity and degradation of major ATPase protein. Fine structures of ischemic myocardial cells were simultaneously retained as well. On the contrary, the effects of nicorandil on ischemic myocardial injury were few. It is likely that protection of ischemic myocardial injury could be expected with drugs which react with ischemic myocardium directly and inhibit excess inflow of extracellular Ca++ in ischemic myocardium.

Bei 9 von 23 Kaninchen mit beiderseitiger Nierenarteriendrosselung und auch bei 4 von 12 Kaninchen mit einseitiger Nierenarteriendrosselung wurde nach 1–5 Wochen eine Verlangerung der Silicon-Gerinnungszeit festgestellt. Bei 10 Kaninchen mit Scheinoperation und bei 6 Kaninchen mit einseitiger Nephrektomie wurde keine Gerinnungsstorung bemerkt. Nach einem Mischversuch scheint die Gerinnungsstorung auf einem Hemmkorper zu beruhen. Es bestand keine Beziehung zum Auftreten von Hypertonie oder Uramie.

E6010 is a novel modified t-PA, in which cysteine 84 in the epidermal growth factor domain has been replaced by serine. This is the first modified t-PA to be effective by i.v. bolus injection, and it has a prolonged half-life (Tα1/2 g 20 min) compared to native t-PA. A randomized, double-blind multicenter trial of i.v. bolus injection of E601 0, 27,500 EU/kg, compared with native t-PA (cell culture), 14,400,000 IU has been performed in the treatment of AMI of ≤ 6 hr duration and total occlusion of the infarct-related arteries. Angiograms were used to evaluate the patency of infarct-related arteries at 15, 30, 45, and 60 minutes after the administration. Result % Recanalization Rate (TIMI grade 2 or 3) 15 min. 30 min. 45 min 60 min. E6010 n = 97 36.5 61.9 73.7 79.4 native t-PA n = 102 13.7 32.4 49.5 64.7 The time to reperfusion with E601 0 was shorter than that with native t-PA. Coronary recanalization at 30 and 60 minutes after administration was obtained in 61.9% and 79.4% of the case with E6010 and in 32.4% and 64.7% of the case with native t-PA, and the difference between both were statistically significant. No fatal bleeding complications were observed in E601 0.4 patients (3.8%) in E6010 and 3 patients (2.8%) in native t-PA died during 48 days post treatment hospitalization. Discussion and Conclusion Native t-PA is required to be administered over period of 1 hr with 10% of the total dose administered as an i.v. bolus and the remainder infused i.v. over 1 hr. Our present results indicate that E601 0 can be easily administered by i.v. bolus injection taking 2–3 minutes and it exerts a valuable thrombolytic effects, namely a high rate and early recanalization of infarct-related arteries