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Biomedical subjects

S Horio

Publications and source records attributed to S Horio.

At least 19 recordsLinked to original sources
PubMed2003

Inhibition of histamine H1 receptor downregulation by KT5823, a protein kinase G inhibitor.

The role of various protein kinases in the downregulation of histamine H(1) receptors was studied by using their inhibitors and activators. Human histamine H(1) receptors (H(1)Rs) expressed in CHO cells were downregulated by histamine in a dose- and time-dependent manner, and this downregulation continued to increase over a 24-h period. KT5823, an inhibitor of protein kinase G, remarkably but not completely reversed the histamine-induced H(1)R downregulation over 24 h. HA1004, another inhibitor of protein kinase G, showed a similar inhibitory effect. However, both 8-Br-cGMP and 8-pCPT-cGMP, membrane-permeable analogues of cGMP, did not show any effects on H(1)R downregulation in the absence or presence of histamine. Ro 31-8220, an inhibitor of protein kinase C (PKC), did not affect histamine-induced downregulation of H(1)R; nor did phorbol 12-myristate 13-acetate, a PKC-activating phorbol ester. Similarly, histamine-induced downregulation of H(1)R was unaffected by either H-89, an inhibitor of protein kinase A, or 8-Br-cAMP, a membrane-permeable analogue of cAMP.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2003

Direct phosphorylation of histamine H1 receptor by various protein kinases in vitro.

Phosphorylation of G protein-coupled receptors (GPCRs) by various kinases is suggested to be an important step in initiating receptor desensitization. Some reports have indirectly demonstrated the involvement of protein kinase C (PKC)-mediated receptor phosphorylation in the desensitization of the histamine H1 receptor (H1R). In this study, human c-myc-epitope-tagged H1R (hm mcH1R) was expressed in Sf9 cells, and an in vitro approach was taken to obtain direct evidence that H1R could be phosphorylated by various kinases. When hm mcH1R, which had been immunoprecipitated with anti-c-myc antibody from Sf9 cell membranes, was incubated with PKC, cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinase II (CaMKII) or cGMP-dependent protein kinase (PKG), the immunoprecipitated receptor was phosphorylated by these kinases. Membrane-bound hm mcH1R, whose conformation is closer to its physiological state than that of the immunoprecipitated receptor, was also phosphorylated by PKC, PKA, CaMKII and PKG. Phosphorylation of immunoprecipitated and membrane-bound hm mcH1R was inhibited by kinase inhibitors. These data are the first demonstration of the phosphorylation of H1R by four protein kinases, i.e., PKC, PKA, CaMKII and PKG, and provide fundamental information to help us further understand the relationship between H1R phosphorylation and desensitization of this receptor.

Animals↗
PubMed2001

Inhibition of oxotremorine-induced desensitization of guinea-pig ileal longitudinal muscle in Ca2+-free conditions.

The aim of this study was to investigate the differences between oxotremorine-induced and acetylcholine (ACh)-induced desensitization, particularly under Ca2+-free conditions, in guinea-pig ileal longitudinal muscle, and to elucidate the different mechanisms of desensitization that might exist between these two muscarinic agonists. Pretreatment of the tissue with 10(-7)-10(-5) M oxotremorine (desensitizing treatment) in normal Tyrode solution caused desensitization of the responses to ACh, as did the desensitizing treatment with ACh. However, Ca2+-free conditions significantly reduced oxotremorine-induced desensitization, contrary to the previous findings that Ca2+-free conditions enhanced ACh-induced desensitization. The desensitizing treatment with oxotremorine caused suppression of the responses to high K+ (tonic phase), as did the ACh treatment. Ca2+-free conditions removed this suppression, whereasthis condition enhanced ACh-induced suppression of the K+ response. A protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (10(-4) M) had no effect on oxotremorine-induced desensitization of the ACh response. The results suggest that a voltage-gated Ca2+ channel was involved in oxotremorine-induced desensitization, as in ACh-induced desensitization, but that the process of inactivation of Ca2+ channels was different between oxotremorine and ACh, and that oxotremorine-induced desensitization was due not only to Ca2+ channel, but also to other unknown factors. Protein kinase C did not participate in oxotremorine-induced desensitization.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

Enhancement of acetylcholine-induced desensitization of guinea-pig ileal longitudinal muscle in Ca2+-free conditions.

1. To determine the role of cellular Ca2+ in desensitization, acetylcholine(ACh)-induced desensitization was studied under Ca2+-free condition in guinea-pig ileal longitudinal muscle. 2. Pretreatment of the tissue with 10(-4) M ACh (desensitizing treatment) in normal Tyrode solution caused desensitization of the responses both to ACh and histamine. The desensitizing treatment performed in Ca2+-free solution enhanced desensitization of the responses to ACh and histamine significantly. 3. The desensitizing treatment with ACh caused suppression of the responses to high K+ (tonic component) and Bay K 8644. The desensitizing treatment performed in Ca2+-free solution potentiated the suppression of the responses to high K+ and Bay K 8644 significantly. 4. ACh-induced desensitization was enhanced significantly in the presence of a protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine(H-7, 10(-4) M) to a similar extent as desensitization obtained under Ca2+-free condition, but not in the presence of a non-specific and less potent kinase inhibitor, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride (HA1004, 10(-4) M). 5. These results suggested that voltage-gated Ca2+ channels were involved in ACh-induced desensitization and that intracellular Ca2+, which was increased during the stimulation with ACh, inhibited desensitization through the activation of protein kinase C. This kinase could have activated or protected Ca2+ channels during the desensitization process to reduce desensitization.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Local health care system utilizing the LPG (liquid propane gas) network.

JAC's LPG monitoring network system is mainly provided in mountain villages. However, by using this system, it will be possible to start a Digital Network Program for the Elderly while maintaining superior economic feasibility and public benefit using existing information infrastructures. This project also has the capabilities for the creation of a fire/disaster monitoring system, as well as a health care system by using conventional LPG monitoring systems. Telemedicine is an option for the future, as well, by connecting medical equipment and a tele-conferencing system.

Aged↗
PubMed1998

Effects of local anesthetics on acetylcholine-induced desensitization of guinea pig ileal longitudinal muscle.

We investigated which of the major actions of local anesthetics (i.e., inhibition of phospholipase A2, interaction with Ca++ channels or blockade of receptor) was responsible for the inhibition of acetylcholine-induced desensitization in guinea pig ileal longitudinal muscle. Desensitization was inhibited by amine local anesthetics and related compounds in the order of potency quinacrine > chloroquine > tetracaine > procaine. Potent phospholipase A2 inhibitors, manoalide (1 microM) and p-bromophenacyl bromide (5 microM) had no effect on desensitization. The rank order of interaction of local anesthetics with Ca++ channels did not agree with the potency order of inhibition of desensitization. These data indicated that local anesthetics did not inhibit desensitization through their inhibition of phospholipase A2 or their interaction with Ca++ channels. Quinacrine, chloroquine, tetracaine and procaine inhibited [3H]N-methylscopolamine binding to solubilized membrane with pKi values of 7.03 +/- 0.10, 6.59 +/- 0.02, 5.40 +/- 0.10 and 5.03 +/- 0.04 and reduced receptor occupancy by agonist from 99.0% (without inhibitor) to 96.8%, 95.1%, 89.4% and 49.8%, respectively, under the conditions where each drug induced half-maximum inhibition of desensitization, indicating that they (except for procaine) did not effectively block muscarinic receptors. However, the combined dose-ratio test showed that some of these drugs (quinacrine and chloroquine) interacted noncompetitively at muscarinic receptors. Therefore, these drugs could have bound to an allosteric site on the receptor, modified agonist-receptor interaction and thus inhibited the pathway specific to the desensitization process.

Acetylcholine↗
PubMed1997

Interaction of local anaesthetics with histamine H1 receptors in guinea-pig ileum.

The interaction of amine local anaesthetics and related compounds with histamine H1 receptors was investigated in guinea-pig ileal longitudinal muscle. Quinacrine, chloroquine, tetracaine and procaine inhibited [3H]mepyramine binding to solubilized membrane from ileal muscle with pKi values of 5.27 +/- 0.11, 5.66 +/- 0.01, 4.28 +/- 0.08 and 3.97 +/- 0.11, respectively. The pKB values obtained from the initial parallel shift of the dose-response curves for histamine in the presence of these drugs were 5.49 +/- 0.11, 6.14 +/- 0.09, 4.86 +/- 0.06 and 4.58 +/- 0.06, respectively, in reasonable agreement with the pKi values. The combined dose-ratio test with both local anaesthetics and antagonist (mepyramine) present showed that tetracaine and procaine were competitive and chloroquine was partially competitive, but that quinacrine was not competitive at histamine H1 receptors. These local anaesthetics inhibited histamine-induced desensitization in guinea-pig ileum. Receptor occupancy (%) by agonist decreased from 95.2 (without inhibitor) to 73.9, 42.8, 35.9 and 33.9 in the presence of quinacrine, chloroquine, tetracaine or procaine, respectively, under the conditions where each inhibitor drug induced half maximum inhibition of desensitization. The results suggested that most of these local anaesthetics interacted competitively at histamine H1 receptors and inhibited desensitization through their antagonizing actions, whereas quinacrine interacted allosterically and inhibited desensitization through a separate action.

Anesthetics, Local↗
PubMed1997

Role of cellular Na+ accumulation in acetylcholine-induced desensitization of guinea pig ileal longitudinal muscle.

The role of cellular Na+ accumulation in acetylcholine-induced desensitization was investigated in guinea pig ileal longitudinal muscle. Desensitization was induced by the pretreatment with acetylcholine (10(-4) M, 30 min) and was expressed by the rightward shift in the concentration-response curve for acetylcholine after the treatment. The same treatment with acetylcholine caused accumulation of cellular Na+ that amounted to about 3.5-fold of the control level. To study the relationship between the gain of cellular Na+ and the development of desensitization, we treated the muscle strips with acetylcholine under the condition in which the external Na+ concentration ranged from zero to 149.2 mM. The result showed that cellular Na+ content is closely related to the extent of desensitization; that is, desensitization was at the lowest level when acetylcholine induced no increase in cellular Na+, while desensitization developed in proportion to the increase in cellular Na+ content. However, when cellular Na+ was increased by another method (by the treatment with ouabain), the inhibition of the acetylcholine response was far less than that observed in the case of desensitization. We concluded that both muscarinic stimulation and the accompanying accumulation of cellular Na+ are required for desensitization to occur in full. This desensitization could be the result of a muscarinic stimulated and cellular Na+-dependent mechanism.

Acetylcholine↗
PubMed1990

Alterations in histamine receptors of guinea-pig ileal smooth muscle produced during agonist-induced desensitization.

1. The effects of prolonged treatment with histamine (10(-4) M, 30 min) on desensitization at histamine H1-receptors of guinea-pig ileal longitudinal muscle were investigated. 2. This treatment did not change either the maximum amount or dissociation constant (Kd) of [3H]-mepyramine binding to membranes of guinea-pig ileal muscle. 3. In contrast, this treatment shifted the histamine inhibition curves of [3H]-mepyramine binding to the right both in the presence and absence of 0.5 mM guanosine-5'-triphosphate (GTP). This rightward shift of the curves occurred rapidly in the first 10 min of exposure to histamine. 4. The histamine inhibition curves were analyzed with a two binding sites model. It was shown that the histamine-induced affinity change of the receptor for the agonist occurred with the high affinity binding component (which comprise about 80% of the total), whereas no significant change occurred with the low affinity component. The GTP-dependent decrease in the affinity of the receptor for the agonist also occurred with the high affinity component both in control and histamine-treated preparations. 5. These studies suggest that histamine-induced desensitization was caused by alteration in the affinity of the receptor for the agonist rather than reduction in the number of the receptors and that the interaction of the receptor with a guanine nucleotide regulatory protein was retained in the desensitized state.

Animals↗
PubMed1990

Temperature-dependence of desensitization induced by acetylcholine and histamine in guinea-pig ileal longitudinal muscle.

1. The effects of temperature on the time course of desensitization induced by acetylcholine and histamine, and on the recovery from desensitization were studied in the longitudinal muscle of the guinea-pig ileum. 2. Self- and cross-desensitization produced by acetylcholine (10(-5) M) occurred rapidly in the first 10 min of exposure to the agonist, with the same time course and the same degree of desensitization over the temperature range of 11 degrees C to 31 degrees C. 3. Self-desensitization produced by histamine (10(-5) M) also occurred rapidly in the first 10 min of exposure to the agonist, and showed great temperature-dependence, especially at 11 degrees C and 21 degrees C, but scarcely occurred at 6 degrees C. 4. Cross-desensitization produced by histamine developed gradually with time and showed a moderate temperature-dependence between 11 degrees C and 31 degrees C, but scarcely occurred at 6 degrees C. 5. The recovery processes from desensitization showed marked temperature-dependence. Recovery was halted completely at 11 degrees C. 6. These studies suggest that acetylcholine-induced desensitization may be attributed to a single non-specific mechanism. Histamine-induced desensitization may be due to at least two mechanisms: it occurs in both a specific and non-specific manner. Each of these desensitizations can be characterized by its unique temperature-dependence.

Acetylcholine↗
PubMed1987

A new method of inhalation challenge with propranolol: comparison with methacholine-induced bronchoconstriction and role of vagal nerve activity.

To establish a safe procedure for examining propranolol-induced bronchoconstriction, we have developed a new method for performing inhalation challenge with propranolol. Monitoring respiratory resistance during tidal breathing with continuous inhalation of propranolol in 1.5-fold increasing concentrations from 0.78 to 30 mg/ml for 1 minute at each concentration, we tested 43 subjects with stable asthma and 10 normal subjects. We also compared bronchial responsiveness with responsiveness to inhaled methacholine on separate days. In addition, to determine the role of vagal nerve activity in propranolol-induced bronchoconstriction, we studied the effect of atropine. Inhaled propranolol caused dose-related bronchoconstriction in all subjects with asthma but not in normal subjects. None of the subjects suffered severe asthmatic attack during the test, which was performed in 15 minutes or less. The minimum cumulative dose of methacholine and of propranolol, at the point where respiratory conductance began to decrease, was not significantly correlated. Increased respiratory resistance was reversed by atropine in 70% of the subjects with asthma with marked individual differences. These data suggest that, although in most subjects with asthma, vagal nerve activity contributes in varying degree to bronchoconstriction, other constricting factors may contribute in the remaining subjects. It is also suggested that the mechanism of bronchial response to propranolol differs from that of the nonspecific airway reactivity estimated by methacholine challenge.

Adolescent↗