Biomedical subjects
Publications and source records attributed to I Matsubara.
Fortimicins C, D, and KE are new aminocyclitol antibiotics produced by a mutant of fortimicin-producing organisms. Their structures have been determined by 1H and 13C NMR and mass spectra and chemical degradations. Fortimicin C is 4-N-hydantoylfortimicin B, fortimicin KE is 6'-demethylfortimicin B, and fortimicin D is 4-N-glycylfortimicin KE. The last two antibiotics have purpurosamine C instead of 6-epi-purpurosamine B.
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1. A position sensitive X-ray counter was connected to a data-collection system which registered the outputs of the counter as a function of time. This enabled us to study time-dependent changes in the intensities of the equatorial reflexions from frog sartorius muscle during an isometric twitch. 2. The intensity ratio of the 1.0 and 1.1 equatorial reflexions (I1,0/I1,1) decreased during a twitch. The time at which the intensity ratio started to decrease coinsided approximately with the onset of tension development. No detectable change in the intensity ratio occurred during the latency relaxation. 3. The intensity ratio reached a minimum level approximately 90 msec before the peak of tension, and stayed at that level until the peak tension. 4. The intensity ratio returned to the 'resting' value 0.7--1.1 sec after the twitch tension had fallen to zero. 5. The observed decrease in the intensity ratio was interpreted as being caused by radial movements of the myosin projections from the vicinity of thick filaments to that of thin filaments. This leads us to conclude that, early in the rising phase of twitch tension, the number of myosin projections in the vicinity of thin filaments reaches the value obtained during a maximum isometric tetanus.
Antiarrhythmic effects of oxprenolol, a beta-blocker, were studied quantitatively on arhythmias produced by epinephrine during halothane anesthesia and by two-stage coronary ligation, and were compared to those of other beta-blockers, propranolol and Kö 1400, which have been already reported. Though oxprenolol has potent beta-blocking activity, the antiarrhythmic effect on halothane-epinephrine arrhythmia was significantly weaker than those of propranolol and Kö 1400. The effective dose of oxprenolol was 60 +/- 18 microgram/kg (mean +/- S.E., N = 6), which is in the range of the so-called beta-adrenergic blocking dose. The weaker antiarrhythmic effect of oxprenolol as compared to propranolol and Kö 1400 is probably due to the intrinsic positive chronotropic effect, which is most clearly observed in oxprenolol as compared to the other two drugs. As for two-stage coronary ligation arrhythmia, oxprenolol suppressed only that observed 48 hours after coronary ligation using higher doses (5 to 10 mg/kg). Other beta-blockers also showed similar effects. Because of the high doses necessary for the antiarrhythmic effects on the coronary ligation arrhythmia, the mechanism for suppressing the arrhythmia is probably due to the local anesthetic action of the beta-blockers.
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The equatorial X-ray reflections were recorded from contracting muscle after a slow stretch. The intensity ratio of the 1,0 to the 1,1 reflections (I10/I11) after the stretch was not significantly different from that during an isometric tetanus at the same sarcomere length, although the tension after the stretch was considerably greater than isometric. This suggests that an almost identical number of cross-bridges produce a greater tension after a slow stretch than during an isometric tetanus.
The heads of myosin molecules, which move to the vicinity of the thin filaments to react with actin during muscle contraction, return to the thick filaments after contraction. The return occurs in two stages; a rapid return of the majority of the myosin heads is followed by a slow return of the rest.
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1. The equatorial X-ray diffraction pattern was recorded from a papillary muscle of a cross-circulated canine heart at different phases of the cardiac cycle. The intensity ratio of the 1, 0 and the 1, 1 reflexions (I1, o/I1,1) was 0-79 in the systolic phase and 1-19 in the diastolic phase. 2. Using the intensity ratio obtained, the approximate proportion of the myosin projections present in the vicinity of the thin filaments was calculated. This was 70-71% in the systolic phase and 51-52% in the diastolic phase of the total myosin projections. 3. The peak systolic tension was roughly proportional to the proportion of the projections present in the vicinity of the thin filaments during systole. 4. The projections which stayed in the vicinity of the thin filaments during diastole did not produce significant contractile force.
beta-Blocking actions of orally administered Kö 1400 and tiprenolol, new beta-blocking agents, were studied in unanesthetized rats and dogs, using a fall of blood pressure and an increase in heart rate produced by isoproterenol as a measure of beta-receptor activation. Blood pressure was recorded from the aorta of the dog and the caudal artery of rat via indwelling catheter, and heart rate of the dog was recorded by a cardiotachometer triggered by R waves of the lead II electrocardiogram. Mean resting blood pressure was 116 mmHg in rats and 93 mmHg in dogs, and heart rate was 99 beats/min in dogs. Isoproterenol (0.5 microgram/kg) was injected via indwelling venous catheter. Kö 1400, tiprenolol and propranolol inhibited the hypotension and tachycardia induced by isoproterenol at an oral dose level of 2 mg/kg or more. beta-blocking action in these preparations was found to be tiprenolol greater than Kö 1400 greater than propranolol. Pharmacological half life of tiprenolol was longer than that of propranolol, whereas that of Kö 1400 was shorter. No selectivity of beta-blocking actions was observed with all three beta-blockers. These findings are in agreement with the results obtained in isolated atrial and tracheal preparations of the guinea pig.
Using the canine heart-lung preparation supported by a donor, effects of a new adrenergic beta-blocking agent, dl-1-(tert. butylamino)-3-[ (2-propinyloxy) phenoxy]-2-propanol hydrochloride (Kö 1400), on cardiac function, myocardial metabolism, and coronary circulation were studied and compared with those of propranolol. Effects of this substance on the peripheral vascular bed were also studied in the perfused hindlimb preparation of the dog. Kö 1400 produced a positive inotropic and chronotropic effect. Mechanical efficiency of the heart improved after Kö 1400, while it lessened after propranolol. A decrease in the coronary flow was observed in association with a slight increase in myocardial O2 consumption, indicating that the substance exerted a direct constrictive effect on the coronary vasculature. As a beta-blocker, Kö 1400 was found to be 2-3 times more effective than propranolol. The uptake of the free fatty acid (FFA) by the heart was increased by Kö 1400 and the myocardial redox potential improved. In the perfused hindlimb preparation, intraarterial injection of Kö 1400 resulted in a transient increase of the femoral blood flow for a decrease in the flow followed by a sustained decrease. With repeated administration a marked tachyphylaxis was observed.
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Pharmacological effects of o-chloro-alpha-[(tert.-butylamino)methyl]benzylalcohol hydrochloride (C-78) on the nervous systems and miscellaneous organs were studied. 1. Through a low dosage of C-78 had little influence on the central nervous system, a high dosage of C-78 had a little slow-waving effect on the spontaneous EEG in rabbits, inhibitory action of the convulsion caused by pentetrazol or electroshock in mice and anti-pyrogenic action in rabbits. C-78 also dose-dependently inhibited the increase of motility caused by amphetamine in mice. 2. Only high concentrations of C78 had a local anesthetic action on the cornea and the skin of the back in guinea pigs. 3. C-78 significantly increased non-esterified fatty acids (NEFA) and glucose contents of blood in rabbits, but these actions were inhibited by propranolol. Another, high dosage of C-78 had anti-ulcer and anti-inflammatory action. From the results of the previous experiments and this study, it was concluded that C-78 is a new beta 2-receptor stimulating drug where beta 2-receptor selectivity is greater than that of isoproterenol, salbutamol and clorprenaline.
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The new antibiotic, XK-90, produced by Streptomyces sp. is active against Gram-positive and Gram-negative bacteria. The structure has been determined as N-acetyl-N'-(3-formyl-4-hydroxyphenyl)hydrazine (1) and is the second example of a naturally occurring antibiotic having the phenylhydrazine skeleton.
Antiarrhythmic property of a new adrenergic beta-blocking agent, dl-1-(tert.butylamino)-3[(2-propinyloxy) phenoxy]-2-propanol hydrochloride (Kö 1400-Cl) was studied, using 1) ouabain-induced arrhythmia in the guinea pig, 2) aconitine-induced arrhythmia in the rat, 3) arrhythmia induced by two-step ligation of coronary artery (Harris's method) in the dog and 4) halothane-adrenaline arrhythmia in the dog and was compared with those of propranolol, oxprenolol, procainamide and ajmaline. Procainamide and ajmaline produced a marked protective effect against aconitine-induced ventricular extrasystole, but were not so effective against aconitine-induced ventricular fibrillation, while oxprenolol and, to a lesser degree, propranolol were effective against the latter type of aconitine arrhythmias. Kö 1400-Cl proved to be ineffective. All the compounds tested produced a marked protective action against ouabain-arrhythmia. Whereas procainamide was most effective in abolishing the ventricular arrhythmia due to coronary-ligation even on the first postoperative day, Kö 1400-Cl and propranolol were almost ineffective on the first day. Even on the second postoperative day, the antiarrhythmic effects of these two beta-blockers were not remarkable, effective only in 2/4 animals in the case of Kö 1400-Cl and in 2/3 animals in the case of propranolol. On the contrary, all the beta-blockers tested produced a protective action against halothane-adrenaline arrhythmia at much lower doses than against coronary ligation arrhythmia. The potency ratio of Kö 1400-Cl and propranolol was 3 : 1, which paralleled with beta-blocking activity of these compounds.