Pressor response to mental stress and exercise in hypertension.
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Biomedical subjects
Publications and source records attributed to Y Imamura.
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IABP and well functioning left ventricular assist device for a failing left ventricle have potential for altering the loading condition of the right heart. Depending on the extent of myocardial damage and the pulmonary vascular resistance, IABP and LVAD can have different degree of hemodynamic effect on the right ventricle. We examined 20 clinical cases who required IABP support to wean from cardiopulmonary bypass. In 10 cases (group I), CVP rose up above 20 cmH2O within 12 hrs of post operative period. In another 10 cases (group II), CVP rose less than 20 cm H2O. Then we compared hemodynamic change (m-PAP, PVR, CVP, PAWP, CI and RVSWI) between two groups until 72 hrs of post operative period. No significant differences were noted in PVR and CI between two groups, but CVP, m-PAP, PAWP and RVSWI were markedly higher in I group. Reduction of RV afterload produced with an IABP may probably be due to degree of recovery of failing left ventricular function. It is though that IABP has less favorable effect on right ventricular in the cases whose CVP elevate above 20 mmH2O within 12 hrs after operation than in those with CVP below 20 cmH2O. Clinical studies were made on 4 cases with biventricular failure in our experiences of 8 LVAD cases (LV aneurysmectomy + VSP closure, MVR + AVR + CABG + LV aneurysmectomy, CABG + LV aneurysmectomy and MVR + CABG). LVAD seems to have more beneficial effect on RV afterload, than IABP right ventricular dysfunction, however, is likely to continue in the cases whose CVP elevates above 30 mmH2O even if LVAD is used.
Assessment has been made, using MIC values and coagulase types, of 214 strains of Staphylococcus aureus isolated from the lesions of inpatients at the First Surgical Department, Hiroshima University, from 1983 to 1988. The obtained results are summarized below: 1. Frequency of MRSA among all the strains of S. aureus during a period from 1983 to 1987 was higher than 50%. 2. Highly methicillin-resistant strains (MIC of methicillin greater than 100 micrograms/ml) emerged in 1984 and thereafter, showed a trend of increase through 1987. 3. The highly methicillin-resistant strains are of coagulase II type strain and they are considered to be inhospital epidemic strains. 4. Both ofloxacin and minocycline (MINO) showed good activities against highly methicillin-resistant strains, but many resistant strains were resistant to beta-lactam and aminoglycoside agents. Based on the above basic assessment, chemotherapies mainly using MINO were performed on cases of MRSA infections experienced at the First Surgical Department, Hiroshima University in a period from July, 1987, to November, 1988, and the following results were obtained. 1. Drugs used were: single MINO in 2 cases; MINO+imipenem/cilastatin (IPM/CS) in 4 cases; MINO+IPM/CS+tobramycin in 1 case; MINO+cefmetazole (CMZ) in 1 cases; and MINO+fosfomycin+CMZ (changed to MINO+Amikacin) in 1 case, a total of 9 cases. Clinical result showed remarkable effectiveness of these therapies in 3 cases with some degrees of effectiveness in 6 cases, thus the therapies were all effective or better. 2. No particular abnormality was observed in subjective or objective symptoms or clinical laboratory tests, judged from values obtained before and after administration of MINO. The above results agreed with well those of the basic assessment, suggesting the possibility that the chemotherapies mainly using MINO would exhibit effectiveness on MRSA infections.
We have previously reported that c-myc protein, or protein(s) complexed with c-myc protein, binds to the region upstream of the first exon of the c-myc gene and that this region contains an origin of cellular DNA replication (ori) and also a transcriptional enhancer. Here we show by Southwestern blotting that c-myc protein binds directly to a 7 bp sequence within the above region. Furthermore, we show that the c-myc protein binding sequences are indispensable for both ori and enhancer functions, but that additional sequences are required for maximal ori and enhancer activities. Thus, c-myc protein is a sequence specific factor which is apparently used both in initiation of DNA replication and in regulation of RNA transcription.
The binding of twelve structurally related sulfonamides to serum albumins including human was investigated using a circular dichroic technique. Some differences of circular dichroic spectral characteristics were observed when sulfonamides were bound to the same albumin or when the drug was bound to several albumins. The differences in these circular dichroic characteristics may be due to various asymmetries. The Scatchard plots indicated that only the primary site was capable of inducing ellipticities of the drugs. The interaction with rabbit serum albumin showed significantly large binding constants and apparent anisotropy factors (g' values), in comparison with other albumins. No significant correlation between the g' values of the induced circular dichroic bands and partition coefficients or/and pKa values was observed. The induced ellipticities of the drug-albumin complexes decreased with pH. This pH dependence can be explained by the ionization of drug and albumin as well as the conformational change of the albumin.
A mutant mouse (wriggle mouse sagami, WMS) with neurological disorders was found in a colony of the BALB/c strain. The clinical signs included tremor, dystonia and involuntary movements. The concentrations of the neurotransmitter substances, noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and acetylcholine (ACh), were measured simultaneously with their metabolites in dissected brain regions by high-performance liquid chromatography with electrochemical detection. The turnover of 5-HT was significantly higher in the cerebral cortex, hippocampus, hypothalamus, midbrain and pons-medulla of WMS than of the genetic control, BALB/c. The intrastriatal DA and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid were increased. However, there was no evidence to suggest an increase in turnover rate of this neurotransmitter. An increase in concentration of and decrease in turnover rate of NA were observed in the cerebellum of this mutant. These findings suggest that multiple disturbance of the neurotransmitter system was largely responsible for the manifestation of the clinical signs of WMS.
Reactive change in the number of astrocytes in the stabbed cerebral cortex (layers II-VI) of the hypothyroid mouse was studied quantitatively over a 4-day period after stabbing, by immunohistochemistry for glial fibrillary acidic protein (GFAP) and S-100 protein. The reactive increase in the number of GFAP-positive astrocytes was delayed in the hypothyroid mouse, compared to that in the euthyroid mouse. The number of S-100-positive astrocytes neither increased nor decreased significantly in the hypothyroid and the euthyroid mice. [3H]Thymidine autoradiography showed that the time course and intensity of the reactive proliferation of astrocytes were the same in the hypothyroid mouse as in the euthyroid mouse. These results indicate that hypothyroidism delays the reactive expression of GFAP-antigen and delays the transformation of GFAP-negative astrocytes into GFAP-positive reactive astrocytes.
The interaction of pirprofen with human serum albumin (HSA) was investigated by equilibrium dialysis and spectroscopic (UV absorption, fluorescence, CD, NMR) techniques. It was found that HSA binds pirprofen nonstereospecifically. The binding of pirprofen depends upon the N-B conformational change of albumin. Chloride ions appear to displace the drug from its binding site. The thermodynamic parameters suggest that the interaction may be explained by electrostatic as well as hydrophobic forces. The absorption spectral changes which accompanied the binding of pirprofen to HSA implied that the aromatic portion of drugs was inserted into the hydrophobic crevice in the protein, while the carboxyl group of the drug interacted with a cationic site on the albumin surface. The NMR data indicated that the pyrroline ring and propionic acid parts may be the major binding site for HSA. A specific binding site for pirprofen on the HSA was found to be site II, benzodiazepine site, using fluorescence probes and drug markers. In addition, from the binding data with modified HSA, it seems that Tyr-411 is specifically involved in pirprofen binding.
Urinary kallikrein and potassium were excreted in parallel in not only static but also dynamic sodium states. Oral potassium load stimulated the release of urinary kallikrein in normotensive subjects and WHO stage I essential hypertensive patients. Stage II essential hypertensive patients had the lowest value of basal level of urinary kallikrein and showed no increase in urinary kallikrein by oral potassium load. These results suggest that the functional activity of renal kallikrein-kinin system decreases with the development of essential hypertension.
YM-09151-2, a novel benzamide derivative, significantly increased the concentrations of dopamine (DA) metabolites, both 3,4-dihydroxyphenylacetic acid and 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid). The maximum increase in such metabolites was about 4-fold the concentration in control animals, and was observed at 2 hr after oral administration. 3-Methoxy-4-hydroxyphenylethylene glycol, a metabolite of noradrenaline, was slightly increased in its concentration exhibiting a transient effect, but 5-hydroxyindoleacetic acid was not. YM-09151-2 antagonized the decreasing effects of apomorphine, a nonselective DA agonist, and LY-171555, a selective D2 DA receptor agonist, on the concentrations of DA metabolites in the brain. In contrast, SCH-23390, a selective D1 DA receptor antagonist, did not antagonize the effects of DA agonist. These results strongly suggest that YM-09151-2 is a selective antagonist of D2 DA receptor and a candidate as a new antipsychotic agent for clinical use.
The interactions of acidic and basic drugs with alpha 1-acid glycoprotein (alpha 1-AGP) were investigated using circular dichroism (CD) measurements. Extrinsic Cotton effects were generated by the binding of drugs to alpha 1-AGP. The CD data suggested the presence of a single binding site on the alpha 1-AGP molecule. The induced ellipticities of the acidic drug-alpha 1-AGP system decreased with increasing pH, while the ellipticities for the basic drugs increased with pH. The ellipticities for all drugs were reduced by the addition of fatty acids. Furthermore, the induced ellipticities decreased in the presence of cesium chloride for basic drugs bound to alpha 1-AGP. The extrinsic Cotton effects therefore appear to result from hydrophobic interaction with alpha 1-AGP for the acidic drugs and from hydrophobic and electrostatic interactions for the basic drugs.
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Sarcoplasmic reticulum membranes were treated with trypsin, and samples enriched with A1a, A1b, and C fragments (Saito, K. et al. (1984) J. Biochem. 95, 1297-1304), respectively, were prepared. A1b and C fragments were purified to apparent homogeneity, and an approximately equimolar mixture of A1(Met1-Arg198), A1a, and A1b fragments free from other contaminants was also obtained through gel permeation and hydroxylapatite chromatography in the presence of sodium dodecyl sulfate. N- and C-terminal amino acid sequence analyses of these peptides were carried out in order to identify the tryptic cleavage sites responsible for the formation of these fragments. Both A1a and A1b fragments had the same C-terminal sequence as A1 fragment. Single cleavage of A1 at T3a (Lys218-Ala219) yielded A1a, while a cleavage between either Lys234-Ile235 or Arg236-Asp237 (collectively designated as T3b) resulted in A1b fragment. Thus, A1a and A1b fragments differed from A1 fragment only by their loss of short stretches corresponding to the N-terminal region of the latter. On the other hand, C fragment represented the C-terminal half of B fragment (Ala506-Gly994). It had the same C-terminal sequence as B fragment and was produced by cleavage at T4 (Lys728-Thr729). Cleavages at T3a and T3b profoundly affected the catalytic properties of SR-ATPase (Imamura, Y. and Kawakita, M. (1986) J. Biochem. 100, 133-141), and it was suggested that the segment of the ATPase molecule including the region between Ala199 and Arg236 is important in mediating the coupling between ATP splitting and Ca2+-transport.
Adenosinetriphosphopyridoxal (AP3PL) specifically modifies Lys684 of Ca2(+)-ATPase of sarcoplasmic reticulum (SR-ATPase) in the presence of Ca2+, leading to its inactivation (Yamamoto, H. et al. (1988) J. Biochem. 103, 452-457). We have now investigated the effects of AP3PL on SR-ATPase in the absence of Ca2+. Similarly to its action in the presence of Ca2+, AP3PL inhibited the Ca2(+)-transporting activity in a dose-dependent manner in the absence of Ca2+ as well. ATP and ADP protected SR-ATPase against inactivation by this reagent. One mole of AP3PL was bound per mol of SR-ATPase with concomitant loss of the Ca2(+)-transporting activity. Binding of AP3PL to SR-ATPase was prevented by ATP. AP3PL-labeled SR membranes were digested with thermolysin and labeled thermolytic peptides were purified through C18 reversed-phase HPLC. Two major AP3PL-labeled peptides were obtained in approximately 1:1 ratio; one was an octapeptide corresponding to 679-ValGluProSerHisLys*SerLys-686, and the other, a nonapeptide corresponding to 487-PheSerArgAspSerLys*ArgMetSer-495 (Lys* indicates a labeled Lys residue) of SR-ATPase. Lys684 in the former turned out to be the same as the highly specific target of AP3PL in the presence of Ca2+ which was identified previously. The target site specificity of AP3PL thus changed significantly but not entirely on binding of Ca2+ to SR-ATPase. This indicates that the spatial arrangement around the gamma-phosphoryl group of the bound ATP is affected by Ca2+ ions bound at the transport site. It is also likely that Lys492 and Lys684 are situated close together in the ATP binding site of SR-ATPase.
In this study, the authors evaluated the effects of spine manipulations, similar to those used in scoliosis surgery, on the compound muscle action potential (CMAP) and spinal evoked potential (SEP) in 25 cats: a distraction maneuver was performed in ten, a rotation in five, and a combined (distraction and rotation) procedure in ten cats. Compound muscle action potential was only minimally changed by the rotation maneuver alone in all five cats. Distraction resulted in earlier deterioration of CMAP than SEP; when CMAP was no longer elicitable in ten cats, seven still showed measurable SEP. All ten cats became paraplegic. With the combined procedure, both CMAP and SEP were abolished earlier than with distraction alone. This was observed in all ten cats becoming paraplegic. The authors further extended the study to ten rabbits having experimentally induced scoliosis. Following corrective surgery with distraction and derotation, eight rabbits lost both CMAP and SEP. Two lost CMAP with still recordable SEP. All ten rabbits became paraplegic. These findings suggest that monitoring CMAP is a more sensitive measure than SEP, and that the spinal cord is more vulnerable to a combined distraction and derotation maneuver than to either one alone.
Streptozocin-induced diabetes significantly decreased acetohexamide reductase activity of 10,000 g supernatant of liver homogenates from both male and female rats. However, the decrease in activity from female rats was smaller than that from male rats, thereby eliminating the sex difference in the activity of the 10,000 g supernatant. In male rats, the diabetes markedly decreased acetohexamide reductase activity only in the microsomal fraction of liver homogenate, whereas in female rats, it decreased the activity only in the cytosolic fraction. These results indicate that the mechanism for the decreasing effect of the diabetes on reductive metabolism of acetohexamide in 10,000 g supernatant differs between male and female rats.
The effect of phenylbutazone (PBZ) on the in vitro binding of sulfadimethoxine (SDM) to serum or albumin was compared among rabbits, dogs and rats. In rabbits, a major metabolite of SDM, N4-acetylsulfadimethoxine (N4-AcSDM), markedly reduced the in vitro binding of SDM, and PBZ significantly increased the serum concentration of N4-AcSDM after SDM administration. PBZ did not affect the in vitro binding of SDM. These findings indicate that in rabbits, PBZ indirectly reduces the in vivo binding of SDM through the interaction of PBZ with N4-AcSDM. In dogs, both PBZ and N4-AcSDM caused the reduction in the in vitro binding of SDM. However, unlike rabbits, the contribution of N4-AcSDM to the in vivo binding of SDM appeared to be negligible in dogs. In rats, PBZ or N4-AcSDM had little effect on the in vitro binding of SDM. The co-administration of PBZ significantly increased the total body clearance and steady-state volume of distribution of SDM in rabbits. Such changes in pharmacokinetic behavior were not observed in dogs and rats.
The in vivo and in vitro bindings of (-)-hydroxyhexamide, a major metabolite of acetohexamide, to rabbit serum were examined by using an ultrafiltration method. The in vivo serum protein binding of (-)-hydroxyhexamide was much lower than the in vitro serum protein binding. The in vitro serum protein binding of (-)-hydroxyhexamide was strongly displaced by the addition of acetohexamide. Furthermore, the in vitro serum protein binding of (-)-hydroxyhexamide in the presence of acetohexamide and (-)-hydroxyhexamide at the same concentrations as those found 1.0 h after acetohexamide administration was approximately similar to the in vivo serum protein binding of (-)-hydroxyhexamide. These results lead us to conclude that acetohexamide, the parent drug of (-)-hydroxyhexamide, plays an important role in the in vivo serum protein binding of (-)-hydroxyhexamide.