Streptococcus intermedius-brain abscess in chronic granulomatous disease.
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Adult↗
Biomedical subjects
T Nagatomo
Publications and source records attributed to T Nagatomo.
Identification of binding sites of bopindolol and its two metabolites with beta1-adrenoceptors by molecular modeling: comparison with beta2 adrenoceptors.
This study was designed to examine the importance of interaction in the bindings of nonselective beta-blockers to beta1-adrenoceptors (beta1-ARs) as compared with beta2-ARs, using molecular modeling. The beta-blockers used in this study were bopindolol [4-(benzoyloxy-3-t- butylaminopropyl)-2-methylindol hydrogen malomate], its two metabolites [18-502 - hydrolyzed bopindolol or 4-(3-t-butylamino-2-hydroxypropoxy)-2-methyl indole - and 20-785 - 4-(3-t-butylaminopropoxy)-2-carboxyl indole], and propranolol. Molecular modeling was performed on an Indigo2 workstation (Silicon Graphic) using Discover/Insight II (Molecular Simulations) software. Through molecular modeling, possible binding sites for these drugs were suggested to lie between helices 3, 4, 5, and 6 of the beta1-AR. The amine, benzoic acid, indole methyl, t-butyl, phenyl, and indole functional groups of bopindolol possibly interact with Asp138 (transmembrane - TM - 3), Ser190 (TM 4), Ala343 (TM 6), Val137 (TM 3), Pro339 (TM6), Cys336 (TM 4), Leu237 (TM 5), and Pro236 (TM 5) of beta1-AR, respectively, by either hydrogen bonding or hydrophobic interactions. In addition, 18-502, 20-785, and propranolol also interacted with sites at the same positions as those of beta2-ARs. Thus, the results of the present study suggested that although Ala343 and Val137 of beta1-AR among these amino acids were different from those of beta2-AR, the interactions at the same sites between ligands and amino acids of beta1-AR as those of beta2-ARs may occur because these drugs are nonselective.
Adrenergic beta-Antagonists↗
Sustaining effects of bopindolol on inhibitory chronotropic actions in guinea pig atria.
The dissociating and/or residual inhibitory effects of bopindolol from beta-adrenoceptors (ARs) of atria strips pretreated with this drug and washed out with buffers on isoprenaline-induced chronotropic actions were determined. The effects of this drug were compared with those of its active metabolite 18-502, propranolol, and pindolol. Our results are as follows: (1) Lower concentrations of bopindolol (10(-9) and 10(-8) mol/l) and the active metabolite 18-502 (10(-9) mol/l), propranolol (10(-8) and 10(-6) mol/l) and pindolol (10(-8) mol/l) produced rightward shifts of concentration-response curves of isoprenaline. (2) Higher concentrations of bopindolol (10(-7) mol/l) and 18-502 (10(-8) and 10(-7) mol/l) produced a reduced maximum response by isoprenaline. (3) Bopindolol (10(-9)-10(-7) mol/l), 18-502 (10(-9)-10(-7) mol/l) and propranolol (10(-7) and 10(-6) mol/l) did not recover to control levels at 180 min even after washout with buffers. In conclusion, bopindolol and 18-502 may slowly dissociate and act as noncompetitive beta-antagonists rather than readily reversible beta-AR antagonists. These effects may differ from those of propranolol and pindolol, although propranolol did not recover to control levels after washout with buffer.
Adrenergic beta-Agonists↗
Tamsulosin: assessment of affinityof (3)H-P razosin binding to two alpha-1- adrenoceptor subtypes in the canine aorta.
This study was performed to assess the affinity of tamsulosin to the alpha(1L)- in addition to alpha(1B)-adrenoceptor (alpha(1)-AR) subtypes coexisting in the canine aorta using the radioligand binding assay. The antagonistic effects of this drug on contraction of the rat aorta were also assessed, and the results were compared with those obtained with prazosin, amosulalol, labetalol, ketanserin, clonidine and propranolol. The pKi value of tamsulosin to the alpha(1L)-subtype was lower than those of prazosin and HV-723, but higher than those of amosulalol, ketanserin and labetalol. The pKi value of tamsulosin for the alpha(1B)-subtype in the canine aorta was similar to that of prazosin. However, this drug showed a higher pKi value than amosulalol, HV-723, labetalol and ketanserin. On the other hand, the order of inhibition potencies for contraction of the rat aorta by phenylephrine was as follows: prazosin > tamsulosin > amosulalol > HV-723 > labetalol > ketanserin > clonidine > propranolol. Thus, although the affinity of tamsulosin to the alpha(1B)-AR subtype in the canine aorta was as high as that in the bovine prostate reported in our previous study, the affinity (pKi 7. 87) of this drug to alpha(1L)-AR in the canine aorta was lower than that (pKi 8.99) in the bovine prostate. These observations suggested that the pharmacological potencies of tamsulosin in the aorta and prostate may be different.
Adrenergic alpha-Antagonists↗
[Modeling study of three-dimensional structure of human beta adrenoceptors and receptor-antagonists interactions].
We deduced the three dimensional structures of transmembrane regions in human beta adrenoceptors by computer simulating using the 2D electron density maps of bacteriorhodopsin and frog rhodopsin as templates. The deduced membrane-spanning helical regions, their arrangements and axes to the membrane plain were different between two models. Typical beta adrenergic antagonist, propranolol, and long-lasting beta antagonist, bopindolol, were docked in these models. The receptor-antagonist interactions were different between both models, in which the 3, 4, 5 and 6th transmembrane domains might participate in the antagonists-binding in both models, however, the amino acid residues in the domains contributing to the binding might be different between models. Propranolol and bopindolol have high affinity to beta 1 and beta 2 subtypes, but low affinity to beta 3 subtype. The simulated receptor-antagonist relationships could account, in part, for the selectivity of the antagonists to the beta subtypes.
Adrenergic beta-Antagonists↗
External doses of residents near Semipalatinsk nuclear test site.
Accumulated external radiation doses of residents near the Semipalatinsk nuclear test site of the former USSR are presented as a results of study by the thermoluminescence technique for bricks sampled at several settlements in 1995 and 1996. The external doses that we evaluated from exposed bricks were up to about 100 cGy for resident. The external doses at several points in the center of Semipalatinsk City ranged from a background level to 60 cGy, which was remarkably high compared with the previously reported values based on military data.
Environmental Exposure↗
Relationship between hydrophobicity and beta-blocking potencies, affinities or dissociation of beta-blockers from beta-adrenoceptors.
The present study was performed to assess the relationship between the hydrophobicity of drugs and (1) inhibitory strength (pA2) on chronotropic or inotropic actions, (2) displacemental potencies of 3H-CGP12177 or 125I-iodocyanopindolol binding to beta-adrenoceptors (beta-ARs) (pKi) or (3) dissociating potencies of these drugs from beta-ARs of atria strips pretreated with drugs. The beta-blockers used in the present study were bopindolol, active metabolite of bopindolol (18-502), atenolol, propranolol, pindolol, nadolol, alprenolol, oxprenolol, metoprolol, labetalol and acebutolol. The value of the partition coefficient of propranolol was the highest, and that of the beta1-selective blocker atenolol was the lowest. Although low correlation coefficients between hydrophobicity and inhibitory beta-blocking potencies determined by pharmacological experiments or displacemental potencies by the radioligand binding assay using 3H-CGP12177 and 125I-iodocyanopindolol were observed, significant relationships between hydrophobicities of these drugs and dissociating potencies from beta-ARs were observed. These results suggest that the hydrophobicity of drugs may be important for the slow dissociation from beta-ARs, but not for the beta-blocking action.
Adrenergic beta-Antagonists↗
Studies on relationships between chemical structure and beta-blocking potency of bopindolol and its two metabolites.
The structure-activity relationships of bopindolol and its two metabolites (18-502 and 20-785) and their beta-blocking potencies in the human beta2-adrenoceptor (AR) were assessed using molecular modeling on an INDIGO2 workstation (SGI Co., Ltd.) and DISCOVER/INSIGHT II (Biosym Co., Ltd.). Through modeling, possible binding sites for these agents were hypothesized to involve the 3rd, 4th, 5th and 6th helices of the beta2-AR, and these shared a common interaction site at Asp113 in helix 3. The different chemical structure of these three agents, however, showed binding to different binding sites (amino acids). This study therefore suggests that different beta-blocking potencies of these agents may be due to different chemical structure.
Adrenergic beta-Antagonists↗
Tamsulosin: assessment of affinity of 3H-prazosin bindings to two alpha1-adrenoceptor subtypes (alpha1H and alpha1L) in bovine prostate and rat heart and brain.
1. The present study was designed to assess the displacement potencies of tamsulosin to 3H-prazosin bindings in two alpha1-adrenoceptor (AR) subtypes (alpha1H and alpha1L) in bovine prostate, rat heart and brain compared with those of amosulalol, labetalol, ketanserin, clonidine and propranolol. 2. The pKi values of tamsulosin to alpha1H and alpha1L subtypes in bovine prostate were 9.13 and 8.99 and these values were almost the same as those of prazosin. On the other hand, low pKi binding values of amosulalol, labetalol, ketanserin, clonidine and propranolol to these subtypes were observed. 3. Low pKi values of tamsulosin to alpha2- and beta-ARs and muscarinic and 5HT2 receptors in the rat brain were observed. 4. These results suggest that tamsulosin has high affinities to alpha1L-AR subtypes in bovine prostate and rat hearts as well as alpha1H-AR subtypes, implying an inhibitory effect of this drug on the contraction of the prostate.
Adrenergic alpha-Antagonists↗
Treatment of malignant neurocardiogenic vasovagal syncope with a rate drop algorithm in dual chamber cardiac pacing.
A 29-year-old man with malignant vasovagal syncope presented with episodes of abrupt loss of consciousness associated with an aura, totaling more than 10 episodes over 3 months. Holter monitoring showed cardiac arrest with a duration of 15 seconds. Oral propranolol and disopyramide therapy failed to prevent the syncope. A dual chamber pacemaker with a rate drop response algorithm successfully prevented the syncope but not the aura. There may be multifactors involved in the mechanism of this syndrome. The patient has returned to a normal active life. This rate drop algorithm is an effective therapy for the prevention of syncope in malignant vasovagal syncope.
Adult↗
Temperature dependence of early and late currents in human cardiac wild-type and long Q-T DeltaKPQ Na+ channels.
Na+ current (INa) through wild-type human heart Na+ channels (hH1) is important for normal cardiac excitability and conduction, and it participates in the control of repolarization and refractoriness. INa kinetics depend strongly on temperature, but INa for hH1 has been studied previously only at room temperature. We characterized early INa (the peak and initial decay) and late INa of the wild-type hH1 channel and a mutant channel (DeltaKPQ) associated with congenital long Q-T syndrome. Channels were stably transfected in HEK-293 cells and studied at 23 and 33 degreesC using whole cell patch clamp. Activation and inactivation kinetics for early INa were twofold faster at higher temperature for both channels and shifted activation and steady-state inactivation in the positive direction, especially for DeltaKPQ. For early INa (<24 ms), DeltaKPQ decayed faster than the wild type for voltages negative to -20 mV but slower for more positive voltages, suggesting a reduced voltage dependence of fast inactivation. Late INa at 240 ms was significantly greater for DeltaKPQ than for the wild type at both temperatures. The majority of late INa for DeltaKPQ was not persistent; rather, it decayed slowly, and this late component exhibited slower recovery from inactivation compared with peak INa. Additional kinetic changes for early and peak INa for DeltaKPQ compared with the wild type at both temperatures were 1) reduced voltage dependence of steady-state inactivation with no difference in midpoint, 2) positive shift for activation kinetics, and 3) more rapid recovery from inactivation. This study represents the first description of human Na+ channel kinetics near physiological temperature and also demonstrates complex gating changes in the DeltaKPQ that are present at 33 degreesC and that may underlie the electrophysiological and clinical phenotype of congenital long Q-T Na+ channel syndromes.
Cell Line↗
Discrimination of alpha1-adrenoceptor subtypes in rat aorta and prostate.
This study was designed to further discriminate alpha1-adrenoceptor subtypes in rat aorta and prostate using functional experiments. Responses induced by phenylephrine were equilibrated in both tissues. The pA2 values and slope factors of several alpha1-antagonists were assessed using concentration-response curves. The antagonists used were prazosin, WB-4101, 5-methylurapidil (5-MU), HV-723, and tamsulosin. In addition, the effects of chloroethylclonidine (CEC) and nifedipine on phenylephrine-induced contractions were investigated. A high pA2 value for prazosin was observed in both tissues (aorta 9.84, prostate 9.19) and the ranking of each drug's pA2 value is as follows: tamsulosin > prazosin > WB-4101 > HV-723 > 5-MU in the aorta, and tamsulosin > prazosin > 5-MU > WB-4101 = HV-723 in the prostate. A significant difference between the pA2 value of each drug except for tamsulosin in the aorta and in prostate was observed (p < 0.01). Inhibition of contraction by pretreatment with CEC was 83.9 +/- 2.42% in the aorta, and 6.17 +/- 0.94% in the prostate. On the other hand, inhibition of maximal response by pretreatment with nifedipine (1 micromol/l) was 35.1 +/- 2.2% in the aorta and 24.5 +/- 3.1% in the prostate. A good correlation between these pA2 values and pKi values for recombinant human alpha1b-adrenoceptor expressed in CHO cells (aorta) and alpha1a-subtypes of CEC pretreated rat hippocampus (prostate) were observed. In conclusion, these results suggest that: (1) the contraction of these two tissues is mediated by alpha1H-adrenoceptor with a high affinity for prazosin; (2) alpha1H-adrenoceptors correspond to alpha1b-(aorta) and alpha1a-subtypes (prostate), and (3) each alpha1-adrenoceptor subtype in the aorta and prostate may be alpha1b-(aorta) and alpha1a-subtypes (prostate), respectively.
Acetonitriles↗
Bopindolol: a slowly dissociating antagonist from the beta-adrenoceptors in guinea pig atria.
The dissociating and/or residual inhibitory effects of bopindolol from beta-adrenoceptors of atria strips pretreated with this drug which was then washed out with buffers on the responses to isoprenaline were determined and compared with those of propranolol, pindolol, atenolol, and the two active metabolites of bopindolol: 18-502 and 20-785. Low concentrations of bopindolol (10(-9) to 10(-8) mol/l) and the active metabolite 18-502 (10(-9) mol/l) produced rightward shifts of the concentration-response curves. On the other hand, high concentrations of bopindolol (10(-7) mol/l) and metabolite 18-502 (10(-8) and 10(-7) mol/l) produced a reduced maximum response by isoprenaline, suggesting that these nonparallel rightward shifts have pD2 values of 7.57 (bopindolol) and 7.67 (18-502), respectively, at 0 min after washout with buffers. Pindolol (10(-7) mol/l) and propranolol (10(-7) and 10(-8) mol/l) also produced a rightward shift of isoprenaline response curves, and these concentration-response curves in guinea pig atria strips pretreated with pindolol (10(-7) mol/l) and propranolol (10(-6) mol/l) recovered to control levels. Neither of these drugs, however, reduced the maximum response by isoprenaline. A high concentration (10(-5) mol/l) of atenolol was required for a rightward shift of the isoprenaline concentration-response curve, and this drug also did not reduce the maximum response. Thus, we conclude that bopindolol and metabolite 18-502 slowly dissociate and act as noncompetitive beta-antagonists rather than easily reversible beta-adrenoceptor antagonists.
Adrenergic beta-Agonists↗
Hypertrophic cardiomyopathy with type I CD36 deficiency.
CD36 is a multifunctional membrane-type receptor glycoprotein that reacts with oxidized low-density lipoprotein and long-chain fatty acid (LCFA). A patient presented with hereditary hypertrophic cardiomyopathy (HCM) and type I CD36 deficiency (neither platelets nor monocytes expressed CD36) but showed no myocardial LCFA accumulation. CD36 was expressed in the capillary endothelial cells of the cardiac muscle of a control subject, while the patient's myocardial capillary endothelial cells were completely CD36-negative. These results suggest that type I CD36 deficiency is closely related to hereditary HCM and lack of myocardial LCFA accumulation.
CD36 Antigens↗
Comparison of binding affinities of omega-conotoxin and amlodipine to N-type Ca2+ channels in rat brain.
AIM: To compare the binding affinities of omega-conotoxin (CTX) and amlodipine to N-type Ca2+ channels in rat brains. METHODS: Whole rat brains were homogenized in HEPES buffer 50 mmol.L-1 (pH 7.4) and centrifuged at 40,000 x g to obtain the membrane-entriched fraction. 125I-omega-conotoxin (125I-omega-CTX) was used as a radioligand. Using radioligand binding assay Kd and Bmax values of the radioligand were determined by Scatchard analysis. The IC50 value for each drug was obtained from displacement experiments. RESULTS: No differences in Bmax values of 125I-omega-CTX binding sites between frozen and fresh tissues were observed. Values of Kd and Bmax of N-type Ca2+ channels were 0.02 +/- 0.01 nmol.L-1 and 1029 +/- 108 pmol/g protein, respectively. The pKi values of omega-CTX and amlodipine were 9.57 and less than 4, respectively. The pKi values of propranolol, prazosin, atropine, and histamine were very low. CONCLUSION: The binding affinity of the L-type Ca(2+)-antagonist amlodipine to N-type Ca2+ channels in the rat brain was very low.
Amlodipine↗
Beta3-adrenoceptors mediate relaxation of guinea pig taenia caecum by BRL37344A and BRL35135A.
Beta-adrenoceptor-mediated relaxation of guinea pig taenia caecum was investigated by studying the effects of the beta3-adrenoceptor agonists, BRL37344A [(R*,R*)-(+/-)-4-[2'-[2-hydroxy-2-(3-chlorophenyl) ethylamino] propyl] phenoxyacetic acid sodium salt sesquihydrate] and BRL35135A [(R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl) ethylamine] propyl] phenoxyacetate hydrobromide]. BRL37344A and BRL35135A caused dose-dependent relaxation of the guinea pig taenia caecum. The concentration-response curves for BRL37344A and BRL35135A were unaffected by propranolol, ICI118551 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-but an-2-ol], atenolol, butoxamine, prazosin, yohimbine and phentolamine. Bupranolol produced shifts of the concentration-response curves for BRL37344A and BRL35135A. Schild regression analyses carried out for bupranolol against BRL37344A and BRL35135A gave pA2 values of 5.79 and 5.84, respectively. These results suggest that the relaxant response to BRL37344A and BRL35135A of the guinea pig taenia caecum is mediated by beta3-adrenoceptors.
Adrenergic beta-Agonists↗
Alpha-1 adrenoceptor subtypes (high, low) in human benign prostatic hypertrophy tissue according to the affinities for prazosin.
BACKGROUND: A novel classification of alpha-1 adrenoceptor subtypes (High, Low) was applied to human benign prostatic hypertrophy (BPH) tissue. METHODS: Human BPH specimens were examined by a radioligand binding assay method using 3H-prazosin, and those data were compared with preoperative therapies. RESULTS: (1) Scatchard analysis showed a high-affinity site (Kd:27.18 +/- 6.41 pM; Bmax:9.29 +/- 0.98 fM/mg protein; mean +/- SE) as alpha 1H, and a low-affinity site (Kd: 4088.0 +/- 744.34 pM, Bmax: 140.81 +/- 19.98 fM/mg protein) as alpha 1L subtype, for prazosin. (2) The Kd and Bmax were not different in the nontreated group (n = 5), alpha 1 blocker group (n = 5), and antiandrogen group (n = 5), in either alpha 1-high affinity or alpha 1-low affinity subtype. (3) Phenoxybenzamine had different pKi values for the above two adrenoceptor subtypes. Scatchard analysis showed that alpha 1-high affinity binding site disappeared in the presence of 1 microM of phenoxybenzamine, and the Kd and Bmax values in the presence of 1 microM of phenoxybenzamine were almost identical to the alpha 1-low affinity site of the two subtypes. CONCLUSIONS: Human BPH tissue possesses both alpha 1H- and alpha 1L-adrenoceptor subtypes according to the affinities for prazosin, and only the alpha 1H subtype can be completely inhibited by some concentration of phenoxybenzamine. Treatment by alpha 1 blocker may not change the conditions of alpha 1-adrenoceptors in prostatic tissue.
Adrenergic alpha-Antagonists↗
Osmotic modulation in glutamatergic excitatory synaptic inputs to neurons in the supraoptic nucleus of rat hypothalamus in vitro.
To clarify influence of osmotic stimulation on the excitatory synaptic inputs to the neurosecretory cells of the supraoptic nucleus (SON), the blind patch technique was used in rat hypothalamic slice preparations. Stable whole-cell recordings were made from 22 neurons in the SON. To observe spontaneous excitatory postsynaptic currents (sEPSCs) in the SON neurons, membrane potentials were clamped between -50 and -90mV. The effects of hypertonic stimulation on the frequency of the sEPSCs were tested in 18 SON neurons. Bath application of mannitol 30 or 60 mM increased the frequency of the sEPSCs. During the application of mannitol (60 mM), the frequency of the sEPSCs increased in 12 of 15 neurons without a change in amplitude. Hypertonic stimulation with NaCl (30 mM) had similar effects to that of mannitol. The increased frequency of miniature EPSCs (mEPSCs) during mannitol application persisted in the presence of TTX in all 8 SON neurons tested with no change in amplitude. Both the non-NMDA antagonist CNQX at 10-30 microM (n = 6) and the non-selective glutamate antagonist kynurenic acid at 1 mM (n = 3) almost completely blocked the EPSCs while the NMDA antagonist AP-5 at 10 microM had no effect on the frequency of the EPSCs in the 4 neurons tested. During application of CNQX, mannitol (60 mM) was added to the perfusion medium in 3 SON neurons. Under these conditions, mannitol had no effect on the frequency of EPSCs. We conclude that hypertonic stimulation directly influences glutamatergic inputs to the neurosecretory cells of the SON by an action on the presynaptic terminals and enhances the excitatory synaptic events.
6-Cyano-7-nitroquinoxaline-2,3-dione↗