Calcium overload-induced myocardial damage caused by isoproterenol and by adriamycin: possible role of taurine in its prevention.
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Biomedical subjects
Publications and source records attributed to H Ohta.
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The immediate haemodynamic effects of the calcium antagonist nilvadipine have been studied in ten patients with established mild essential hypertension. Nilvadipine 4 mg p.o. reduced both the systolic and diastolic blood pressures within 60 min, associated with a fall in total peripheral resistance and an increase in heart rate and cardiac index. The peak of blood pressure and total peripheral resistance reached during a cold pressor test were reduced by nilvadipine, but it did not affect the haemodynamic responsiveness to cold stimulation. Plasma renin activity was unaltered and the plasma noradrenaline concentration was increased only slightly. Thus, nilvadipine lowered blood pressure at rest and during cold stimulation as a result of arteriolar dilatation. The hypotensive effect at rest was associated with a reflex increase in heart rate and cardiac index.
Although the expression of HLA-DR antigens on colonic epithelium in ulcerative colitis has been observed by several groups, the results of the expression in remission have been conflicting and there has been virtually no study concerning the expression in non-inflamed area in active ulcerative colitis. We studied systematically HLA-DR expression on colonic epithelium in 37 patients with ulcerative colitis chronologically, namely in remission as well as in the active stage and inflamed and non-inflamed areas simultaneously in the active stage. HLA-DR antigens were detected by indirect peroxidase staining using anti-HLA-DR monoclonal antibody. We confirmed the previous observation that epithelium from control colon does not express HLA-DR antigens, while epithelium from ulcerative colitis expresses the antigens with high frequency (83.3 percent). In addition, we demonstrated that HLA-DR expression on colonic epithelium in active ulcerative colitis disappeared in remission. Our new finding was that there is no HLA-DR expression on colonic epithelium in non-inflamed mucosa in active ulcerative colitis. Namely HLA-DR antigens were expressed only on inflamed epithelium of ulcerative colitis. These results lead to the conclusion that the expression of HLA-DR antigens on colonic epithelium in ulcerative colitis is closely related to the inflammation of mucosa.
Immunoglobulin (Ig)-containing cells were studied in the lamina propria of the normal human large bowel and around the lymph follicle, including Peyer's patches, in the normal intestine. Ig-containing cells were identified by the indirect immunoperoxidase staining method, using mouse anti-human Ig monoclonal antibodies. In the lamina propria in the large bowel, the mean percentage of IgA+ (IgA1+ cells and IgA2+ cells), IgM+, IgD+, IgG+ and IgE+ cells was 75.9, 8.5, 7.3, 5.8, 2.5, respectively (total 100), namely there was a marked preponderance of IgA+ cells in comparison to IgG+ cells. However, IgG+ cells were observed not only on the epithelial but also in the serosal side of lymph follicles, showing a ring-like pattern. Ig+ cells of the other four classes did not show such a pattern. The ring-like distribution of IgG+ cells around lymph follicles was observed in both the large and small intestine including Peyer's patches. This tendency was observed in 9 out of 14 follicles (64.3 per cent). A large number of IgG+ cells were observed outside lymph follicles, while a small number of IgG+ cells were observed at the most outer rim of lymph follicles which suggested a local maturation of IgG+ cells. The significance and the role of the newly recognized IgG+ cells in the vicinity of lymph follicles remain to be resolved.
In order to elucidate the role of the catecholaminergic system in the cataleptogenic effect of delta 9-tetrahydrocannabinol (THC), the effect of pretreatment with 6-hydroxydopamine (6-OHDA) or with desipramine and 6-OHDA and lesions of the locus coeruleus were investigated in rats. The cataleptogenic effect of THC was significantly reduced in rats treated with 6-OHDA and in rats with lesions of the locus coeruleus but not in rats treated with desipramine and 6-OHDA, as compared with control rats. On the contrary, the cataleptogenic effect of haloperidol was significantly reduced in rats treated with desipramine and 6-OHDA but not in rats treated with 6-OHDA or in rats with lesions of the locus coeruleus. These results indicate that noradrenergic neurons have an important role in the manifestation of catalepsy induced by THC, whereas dopaminergic neurons are important in catalepsy induced by haloperidol.
The acute haemodynamic effects of taurine were studied in normal and in beta blocker (propranolol) or calcium antagonist (diltiazem) treated rabbits and in rabbits with experimentally produced chronic aortic regurgitation. The administration of taurine (25 mg.kg-1) did not affect heart rate and left ventricular end diastolic pressure but produced significant increases in left ventricular dP/dtmax, cardiac output, and left ventricular systolic pressure in control hearts, indicating that intravascularly administered taurine substantially increased cardiac performance. In propranolol (1 mg.kg-1) treated rabbits taurine significantly improved left ventricular dP/dtmax and cardiac output, which were previously depressed by propranolol. Taurine had the same effect on diltiazem (1 mg.kg-1) treated rabbits. In rabbits with aortic regurgitation a bolus injection of taurine improved cardiac performance. Continuous infusion of taurine (100 mg.h-1) also produced a significant increase in left ventricular dP/dtmax. These results suggest that taurine has a unique action as an inotropic agent and that it may be useful in the treatment of patients with congestive heart failure.
Leukotoxic activity in Actinobacillus (Haemophilus) actinomycetemcomitans isolated from patients with rapidly progressive periodontitis (RP), gingivitis (G), and juvenile periodontitis (JP), and several oral bacteria, was determined by observation of morphological changes in polymorphonuclear leukocytes (PMNs). Many A. actinomycetemcomitans isolates yielded both rough-surfaced and umbonate-shaped colonies (A-type), and smooth-surfaced and convex-shaped colonies (B-type), when stock cultures were streaked on agar medium. Both types of cells were identical in terms of Gram stain, cell morphology, sugar fermentation profile, nitrate reduction and cellular fatty acid composition. Sonic extracts were prepared from 32 A. actinomycetemcomitans strains isolated from patients and from 3 American Type Culture Collection (ATCC) strains. Sonic extracts from 8 isolates and 2 ATCC strains induced sphering of PMNs during a 45-50 min period of incubation at 37 C. Extracts from the other oral bacteria had no effects on PMN morphology. The sphered PMNs were found by their fluorochromatic-negative reactions to be damaged cells. The leukotoxic substance was heat-sensitive (56 C, 30 min), trypsin-sensitive and did not induce sphering of PMNs at 4 C. There was no clear correlation between colony type and leukotoxicity. Among 8 leukotoxic strains, 5 were isolates from an RP patient.
1 In atrial preparations of the young guinea-pig (body weight 150-250 g), five proteolytic enzymes (trypsin, chymotrypsin, bacterial-Al-proteinase (nagarse), bromelain and kallikrein) produced concentration-dependent positive inotropic and chronotropic effects, while they exerted only minimal effects on the papillary muscle preparations. 2 To characterize the effects, further experiments were conducted in atrial preparations using trypsin. There was a strong tendency for tachyphylaxis: a second exposure to the same concentration of trypsin resulted in considerably smaller positive inotropic and chronotropic effects. The positive inotropic and chronotropic effects of this substance were not affected by propranolol (5 X 10(-7)M). However, an accumulation of cyclic AMP was observed and the positive inotropic and chronotropic effects were potentiated by aminophylline (10(-4)M) in association with an augmentation of the accumulation of cyclic AMP. In preparations partially depolarized with high K+ (22mM) medium (contractions ceased under this condition) trypsin 100 micrograms ml-1 reinstated the contraction. Treatment of the preparation with aprotinin (200 u ml-1) resulted in a strong inhibition of the positive inotropic and chronotropic effects. 3 Islet activating protein (IAP), a specific inhibitor of the 'inhibition specific' guanine nucleotide binding regulatory protein of the adenylate cyclase system, did not produce significant inhibition of the positive inotropic and chronotropic effects of trypsin, whereas it produced a complete inhibition of the negative inotropic and chronotropic effects of carbachol. 4. These results suggest that the positive inotropic and chronotropic effects ofproteolytic enzymes are intimately connected with the proteolytic activities through which adenylate cyclase is activated to produce an accumulation of cyclic AMP within the myocardium. The destruction of the 'inhibition specific' guanine nucleotide regulatory protein of the adenylate cyclase was not substantiated as a mechanism of activation of the adenylate cyclase.
Aerotolerance in the growth of Streptococcus mutans and related streptococci was examined under glucose-limited conditions. The growth rate of all strains tested was more or less retarded when they were transferred from anaerobic to aerobic conditions. As for growth yield, however, some strains (group 1) showed reduced values for the increment of cellular dry weight change (in grams per mole of glucose), whereas others showed either unaltered (group 2) or increased (group 3) yields. The characteristic feature of strains in groups 2 and 3 was their high activity of both glucose- and pyruvate-dependent oxygen uptake when strains were grown under aerobic conditions. By contrast, the activity of pyruvate-dependent oxygen uptake by group 1 strains was negligibly low, whether grown under aerobic or anaerobic conditions. Some strains (group 1a) consumed oxygen in the presence of glucose at a much faster rate than others did (group 1b). There seems to be a good correspondence of these aerotolerance groupings to those based on serotypes of S. mutans. Thus, the groups 1a, 1b, 2, and 3 correspond to serotypes g, a+d, c+f, and b, respectively.
The response to angiotensin II analog infusion during sodium deletion and the effects of a one-month captopril treatment were compared between 15 renovascular hypertensive patients with unilateral and 6 with bilateral renal artery stenosis. Plasma renin activity, its response to sodium depletion, and the renal vein renin ratio during sodium depletion were greater in unilateral than in bilateral stenosis. A fall in diastolic blood pressure induced by analog infusion during sodium depletion was correlated with the preinfusion plasma renin activity and with the renal vein renin ratio. Treatment with captopril showed a comparable hypotensive effect in unilateral and bilateral stenosis. The reduction in blood pressure was not correlated with the pretreatment renin levels or changes in blood pressure observed during analog infusion. Plasma renin activity rose and plasma aldosterone level fell in all patients. These results indicate that the mechanism maintaining high blood pressure is more renin dependent in unilateral than in bilateral stenosis and that the long-term effect of captopril does not depend solely on the suppression of the renin-angiotensin-aldosterone system.
We studied the acute hemodynamic effects of dopamine, dobutamine, and isoproterenol in infants and young children with large ventricular septal defect (VSD). Dopamine (5 micrograms/kg/min) had no significant hemodynamic effects. Dobutamine (5 micrograms/kg/min) administration resulted in modest increases in heart rate and systemic arterial pressure and a decrease in left atrial pressure. This drug decreased the pulmonary blood flow, and the pulmonary-to-systemic blood flow (Qp/Qs) ratio, although these changes were not statistically significant. Isoproterenol, infused at doses of 0.03 and 0.06 micrograms/kg/min, increased the heart rate and lowered left atrial pressure. Only the high dose of isoproterenol lowered systemic and pulmonary arterial pressure. The low dose infusion of this drug increased the pulmonary blood flow as well as the systemic flow, whereas the high dose infusion resulted in a decrease of the Qp/Qs ratio without an increase in the pulmonary blood flow. Right atrial pressure was lowered by dobutamine and the high dose of isoproterenol, but the mean change was only 1 to 2 mmHg. The difference of the effects among these catecholamines is due to their relative strength of action on the vascular bed and the myocardium. Although the doses and durations of the drug infusions were limited, these acute hemodynamic effects should be taken into account when they are to be given to congested infants and young children with large VSD.
Electroencephalographic (EEG) effect of quinupramine was investigated in unanesthetized rabbits with chronic electrode implants, and it was compared with those of imipramine and amitriptyline. Quinupramine (0.56-3.2 mg/kg) induced a marked drowsy pattern of spontaneous EEG: high voltage slow waves increased in the cortex, while the hippocampal theta rhythm was desynchronized. Imipramine (1.0-5.6 mg/kg) and amitriptyline (0.56-3.2 mg/kg) also elicited similar EEG effects. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus was markedly suppressed by quinupramine, imipramine and amitriptyline. The EEG arousal response induced by i.v. injection of physostigmine was markedly suppressed by quinupramine, amitriptyline and imipramine. Quinupramine showed no significant effect on the photic driving response and recruiting response. Quinupramine slightly enhanced the limbic afterdischarges elicited by either hippocampal or amygdaloid stimulation, while amitriptyline and imipramine caused an initial suppression followed by a quick recovery. The EEG effects of quinupramine were similar to those of amitriptyline in both qualitative and quantitative aspects.
Effects of condensed tannins isolated from Rhei Rhizoma on the activities of angiotensin converting enzyme (ACE) and various proteases were examined in vitro. Among the various condensed tannins tested, procyanidin B-5 3,3'-di-O-gallate and procyanidin C-1 3,3',3"-tri-O-gallate strongly inhibited the activity of ACE. The concentration of procyanidin B-5 3,3'-di-O-gallate required for 50% inhibition of ACE was 1.3 X 10(-6) M. The inhibition of ACE by condensed tannins was reversible and non-competitive, according to dialysis and to Dixon plots. However, over one hundred times the concentration was required to inhibit activities of other proteases such as trypsin, chymotrypsin, leucine aminopeptidase, carboxypeptidase A and urinary kallikrein. These results suggest that the inhibitory effects of condensed tannins on the activities of ACE are specific.
Behavioral effects of zopiclone were investigated in mice and rats and compared with the data on diazepam, nitrazepam and flurazepam. The electroencephalographic effect of the drug was also examined in unanesthetized rabbits with chronic electrode implants and compared with that of diazepam. The present results indicate that zopiclone possesses pharmacological properties qualitatively similar to benzodiazepines, which are characterized by potent anticonflict and antiaggressive effects and much weaker anticonvulsant, muscle relaxant, ataxiogenic, sedative and anesthesia potentiating effects; the properties of this drug were compared with those of diazepam, nitrazepam and flurazepam. Zopiclone suppressed the EEG arousal responses and inhibited afterdischarges induced by electrical stimulation of the hippocampus and amygdala. The effects of zopiclone on EEG and afterdischarges were approximately 1/10 those of diazepam.
To assess the importance of anti-adrenergic and anti-serotonergic activities of bunitrolol for its efficacy as an antihypertensive and antianginal agent, effects of this substance on the binding of adrenergic and serotonergic agents to the respective receptors of the rat brain, rat heart, dog brain, and/or dog aorta were examined using the radioligand binding assay methods. In addition, the pA2 values of bunitrolol as an antagonist against the positive chronotropic and inotropic actions (beta 1-adrenoceptor) of isoproterenol were also determined by pharmacological methods using the isolated guinea pig atria. To assess the specificity, pA2 values were also obtained in the isolated trachea (beta 2-adrenoceptor) using isoproterenol as an agonist and in the isolated aorta from the guinea pig and the rat using phenylephrine as an agonist (alpha 1-adrenoceptor). A strong inhibition by bunitrolol of 3H-dihydroalprenolol (3H-DHA) binding to beta-adrenoceptors was observed, while the inhibition of 3H-prazosin binding to alpha 1-adrenoceptors, 3H-serotonin binding to 5HT1-receptors. 3H-p-aminoclonidine binding to alpha 2-adrenoceptors, and 3H-ketanserin binding to 5HT2-receptors were found to be very weak. The rank order of antagonistic potencies of bunitrolol against the adrenergic receptors as assessed with pA2 values were beta 1 greater than beta 2 much greater than alpha 1. From these two different types of experiments, it is clear that the antihypertensive and antianginal effects of bunitrolol are mainly due to its beta-blocking actions, with the alpha 1-blocking action of this drug playing a minor role.
Three cases of Crohn's disease (CD) which showed an elevation of creatine phosphokinase (CPK) during the course were reported. In two cases, elevations of serum myoglobin and aldolase were also observed which indicated rhabdomyolysis. Rhabdomyolysis occurred unrelated to the activity of CD and it was asymptomatic. It was unable to identify an apparent known cause for rhabdomyolysis. All three cases were under elemental diet (ED) but the causality of ED for rhabdomyolysis was uncertain. So far as we know, there is no report on rhabdomyolysis during ED treatment and there are only two reports in which rhabdomyolysis was documented in CD. The latter was rhabdomyolysis due to electrolyte depletion secondary to malabsorption in CD which was not encountered in our cases. Our department dealt only three cases of CD and all of them had an elevation of CPK which had been measured as one of routine blood chemistry in our hospital. These observations led to a following conclusion that subclinical rhabdomyolysis may be one of extra-intestinal complications of CD.
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