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H Moritoki

Publications and source records attributed to H Moritoki.

At least 19 recordsLinked to original sources
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↗
PubMed1999

Age-related endothelium-dependent vascular relaxation in rat thoracic aorta in response to colforsin.

BACKGROUND: Colforsin, a novel water-soluble forskolin derivative, increases intracellular cyclic AMP by direct stimulation of adenylate cyclase and has strong positive inotropic and vasodilative effects. However, it is not known whether colforsin causes nitric oxide (NO) release and enhances endothelium-dependent vascular relaxation. METHODS: We studied NO production and relaxation on exposure to colforsin in thoracic aorta from rats aged 4, 12 and 60 weeks. RESULTS: When a low concentration of colforsin was added to a solution bathing ring segments of aorta from 12-week-old rats, relaxation was greater in the ring segments with intact endothelium than in those from which the endothelium had been removed. A high concentration of colforsin induced the same degree of relaxation of ring segments with or without endothelium, probably by a direct effect on vascular smooth muscle cells. Production of NO in response to colforsin by cultured endothelial cells from 12-week-old rat aorta was demonstrated by the electron paramagnetic resonance spin trapping method. A low concentration of colforsin relaxed aortic segments with intact endothelium from 4-week-old rats more than those from 12-week-old or 60-week-old rats. Reversal of relaxation by NG-nitro L-arginine, an NO synthesis inhibitor, was most significant in arteries from 4-week-old rats. Production of NO after exposure to colforsin was greater in aortic segments from 4-week-old rats than older rats, as detected by an NO-selective electrode. CONCLUSIONS: Colforsin induces vasodilation in part by releasing NO from the endothelium in rat thoracic aorta. In addition to a direct vasodilative effect on the vascular smooth muscle cells, an endothelium-dependent vasodilative effect is also important in younger arteries.

Aging↗
PubMed1998

Influence of cedar essence on spontaneous activity and sleep of rats and human daytime nap.

We investigated whether exposure to the odor of extracted cedar essence (CE) has (i) an influence on spontaneous activity and sleep-wake states of rats and (ii) a sleep-promoting effect on human daytime nap after taking an ordinary night's sleep. In rats exposed to CE, spontaneous activities and amount of wake were significantly decreased, while the amount of non-rapid eye movement (NREM) sleep was significantly increased. In human daytime nap, NREM sleep stage 2 latency was significantly shortened after exposure to CE.

Animals↗
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↗
PubMed1996

Suppression of inducible nitric oxide synthase mRNA expression by tryptoquinone A.

Triptoquinone A (TQA), which is an anti-inflammatory constituent in plants, was studied for its suppressive effect on nitric oxide production by LPS. TQA significantly suppressed smooth muscle relaxation and increase in cyclic GMP levels by nitric oxide (NO) in an L-arginine-induced relaxation experiment. The mechanistic studies showed that TQA did not directly inhibit NO radicals and inducible nitric oxide synthase (iNOS) enzyme but suppressed IL-1 beta and iNOS mRNA expression by LPS. The suppression level of iNOS gene expression by TQA was comparable to that by dexamethasone. TQA may be a useful candidate for the development of a drug as a potent inhibitor of iNOS gene over-expression.

Animals↗
PubMed1996

Inhibition by triptoquinone-A of LPS- and IL-1 beta-primed induction of NO synthase in rat thoracic aorta.

We investigated the effect of triptoquinone-A (TQA), an active principal of Triptergium wilfordii, on the induction of nitric oxide synthase (NOS) promoted by endotoxin (LPS) and interleukin-1 beta (IL-1 beta). Prophylactic application of TQA selectively prevented LPS-primed initiation of L-arginine (Arg)-induced relaxation, and cGMP formation of rat thoracic aorta, and LPS-stimulated nitrite production by cultured aortic smooth muscle cells, which appear to be mediated by NOS expressed by LPS in vascular smooth muscle. TQA also prevented IL-1 beta-triggered initiation of Arg-induced relaxation and nitrite accumulation. These results suggest that TQA prevents LPS-or IL-1 beta-promoted induction of NOS in vascular smooth muscle, thus inhibiting development of Arg-induced vasorelaxation.

Animals↗
PubMed1996

Endothelium-dependent relaxation of rat thoracic aorta by amrinone-induced nitric oxide release.

To determine whether amrinone and its induced increase of cyclic AMP releases nitric oxide and enhances endothelium-dependent vascular relaxation, we studied nitric oxide production and vascular relaxation of rat thoracic aorta on treatment with amrinone and forskolin, an activator of adenylate cyclase. When 20 microM amrinone was applied to ring segments of aorta previously contracted with phenylephrine, relaxation was greater in segments with endothelium than in those without (% relaxation 94 +/- 4 vs 37 +/- 7%, P < 0.01). However, a higher concentration of amrinone (> 50 microM) induced the same degree of relaxation in ring segments with or without endothelium, probably due to its direct effect on vascular smooth muscle. The maximal relaxant concentration (100 microM) of amrinone induced an increase (2.5 fold) in cyclic GMP in ring segments. Forskolin also induced concentration-dependent relaxation, but removal of the endothelium attenuated the relaxation induced by forskolin about seven-fold. NG-nitro L-arginine reversed the relaxation induced by amrinone or forskolin in ring segments with, but not without, endothelium. Nitric oxide production in ring segments of aorta, following application of amrinone or forskolin, was detected by nitric oxide-selective electrode and electron paramagnetic resonance spin trapping methods. Pre-treatment with NG-nitro L-arginine or removal of the endothelium suppressed nitric oxide production by amrinone or forskolin. These data showed that amrinone enhances the release of nitric oxide from rat aortic endothelial cells, and induces endothelium-derived relaxing factor/nitric oxide-mediated vasodilation.

Amrinone↗
PubMed1996

Inhibition by SK&F96365 of NO-mediated relaxation induced by Ca2(+) -ATPase inhibitors in rat thoracic aorta.

1. We investigated the effect of SK&F96365, a putative inhibitor of receptor-operated Ca2+ entry, on the endothelium-dependent, NO-mediated relaxation and cyclic GMP formation induced by Ca2(+)-ATPase inhibitors in rat thoracic aorta. 2. SK&F96365 inhibited cyclopiazonic acid or thapsigargin-induced relaxation and cyclic GMP formation mediated by a constitutive NO synthase, which is known to be activated by the Ca2+ that enters into the endothelial cells via plasma membrane Ca2+ channels subsequent to depletion of stored Ca2+ by Ca2(+)-ATPase inhibitors. 3. SK&F96365 also inhibited relaxation and cyclic GMP formation induced by acetylcholine, without affecting those induced by nitroprusside and A23187. 4. Ni2+ attenuated relaxation and cyclic GMP formation induced by cyclopiazonic acid and acetylcholine. 5. In contrast, the voltage-dependent Ca2+ channel blocker, nifedipine, did not affect the relaxation caused by Ca2(+)-ATPase inhibitors. 6. These results suggest that endothelium-dependent, NO-mediated relaxation of the arteries induced by Ca2(+)-ATPase inhibitors is triggered by the Ca2+ that enters into endothelial cells via receptor-operated channels (SK&F96365-sensitive channels) subsequent to depletion of stored Ca2+ as a result of inhibition of the Ca2(+)-ATPase (Ca2+ pump) of the stores.

Animals↗
PubMed1995

Possible involvement of tyrosine kinase in the LPS-promoted initiation of L-arginine-induced relaxation of rat aorta mediated by induction of no synthase.

Tyrosine kinase inhibitors herbimycin A, genistein and erbstatin analog prevented endotoxin (LPS)-promoted initiation of L-arginine (Arg)-induced relaxations and cGMP formation in rat thoracic aorta, which appear to be mediated by nitric oxide synthase expressed by LPS in the vascular smooth muscle. Similarly, interleukin-1 beta (IL-1 beta) triggered initiation of Arg-induced relaxation of the arteries. In addition, in the aortic smooth muscle cells cultured in the presence of Arg, LPS- or IL-1 beta-triggered accumulation of nitrite was suppressed by the tyrosine kinase inhibitors. These results suggest that tyrosine kinase is involved in the LPS- and IL-1 beta-promoted induction of nitric oxide synthase in the vascular smooth muscle, which in turn mediates production of NO from added Arg, thus stimulating formation of cGMP and causing relaxation. Alternatively, it is possible that LPS acts indirectly through cytokines such as IL-1 beta.

Amino Acid Oxidoreductases↗
PubMed1995

Synthesis and enantioselectivity of optically active 1- and 3-substituted 4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols and related compounds as norepinephrine potentiators.

Optically active 1,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols (1R,4R-3a and 1S,4S-3b, 1S,4R-4a, and 1R,4S-4b) and 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolines (4S-5a and 4R-5b) were prepared in order to examine the effects of the 1-, 3-, and 4-substituents of 2-methyl-4-phenyl- 1,2,3,4-tetrahydroisoquinolin-4-ol (PI-OH) (1) on the enantioselectivity for norepinephrine (NE) potentiating activity. The conformations and absolute configurations of 3-5 were determined from their 1H-NMR and circular dichroism (CD) spectra and by single-crystal X-ray diffractometric analysis. The NE potentiating activity of the optically active 3-5 and previously prepared 3-methyl derivatives (3R,4R-6a and 3S,4S-6b) of PI-OH were tested. The results show that compounds 3, 4, and 6 had high enantioselectivity for NE potentiation: the 4R series of the enantiomers exhibited activity but not the 4S-enantiomers. The activity of the 4-desoxy compound 5 also resided exclusively in the 4S-enantiomer. These findings suggest the presence of a specific receptor for NE uptake, and the enantiomers 3a, 4a, 5a, and 6a may be antagonistic at this NE uptake receptor.

Adrenergic Uptake Inhibitors↗
PubMed1995

Tyrosine kinase may participate in Ca2+ entry for endothelial nitric oxide production.

We have suggested that cyclopiazonic acid (CPA), a Ca(2+)-ATPase inhibitor, produces nitric oxide (NO) by triggering a Ca(2+)-influx resulting from Ca(2+)-depletion in the endoplasmic reticulum of endothelial cells. The tyrosine kinase inhibitor methyl 2,5-dihydroxycinnamate, while having no effect on relaxations induced by A23187 or Na nitroprusside, did inhibit the CPA-induced relaxation and cyclic GMP formation in rat aorta. Tyrosine kinase may participate in endothelial NO synthesis through activation of a Ca2+ entry mechanism.

Animals↗
PubMed1994

Nonendothelial-derived nitric oxide activates the ATP-sensitive K+ channel of vascular smooth muscle cells.

To determine whether endogenous nitric oxide (NO) opens the ATP-sensitive K+ channel (KATP channel), we investigated the effect of nonendothelial-derived NO on this channel in cultured smooth muscle cells of the porcine coronary artery by the patch-clamp technique. In the cells pretreated with endotoxin, the addition of 10(-4) M L-arginine generated NO and activated the KATP channel. Activation of this channel was suppressed by pretreatment with 10(-3) M NG-methyl-L-arginine or 10(-3) M Nx-nitro-L-arginine methyl ester, each of which is a specific antagonist of the L-arginine-NO pathway, and by 10(-6) M Methylene blue, which blocks guanylate cyclase. The activation of the KATP channel by L-arginine-NO pathway is expected to produce hyperpolarization of the cell membrane and relaxation of vascular smooth muscle cells.

Adenosine Triphosphate↗
PubMed1994

Thapsigargin, a Ca(2+)-ATPase inhibitor, relaxes rat aorta via nitric oxide formation.

Thapsigargin induced endothelium-dependent relaxation and cGMP production in rat thoracic aorta, and these effects were inhibited by nitric oxide (NO) pathway inhibitors, a calmodulin inhibitor and removal of Ca2+, suggesting that NO is involved in the thapsigargin-induced relaxation. Thapsigargin may deplete Ca2+ stores in the endothelial cells by inhibiting the Ca(2+)-ATPase, a Ca2+ pump, which in turn triggers influx of extracellular Ca2+, leading to activation of constitutive NO synthase and resultant NO generation. The NO thus formed may activate soluble guanylate cyclase to produce cGMP in the vascular smooth muscle.

Aminoquinolines↗
PubMed1994

Relaxation of rat thoracic aorta induced by the Ca(2+)-ATPase inhibitor, cyclopiazonic acid, possibly through nitric oxide formation.

1 The effect of the Ca(2+)-ATPase inhibitor, cyclopiazonic acid (CPA), was studied on rat thoracic aortic ring preparations. 2 At concentrations above 0.3 microM, CPA induced relaxation in the arteries precontracted with phenylephrine. Removal of the endothelium abolished CPA-induced relaxation. 3 The nitric oxide (NO) synthase inhibitor NG-nitro L-arginine (3-300 microM), the free radical scavenger haemoglobin (0.1-3 microM), the soluble guanylate cyclase inhibitor, LY83583 (0.1-10 microM), each inhibited the endothelium-dependent relaxation to CPA. The potassium channel blocker, glibenclamide (10 microM) and cyclo-oxygenase inhibitor, indomethacin (100 microM for 60 min and then washed out) did not alter the action of CPA. 4 The calmodulin inhibitors calmidazolium (3-10 microM) and W-7 (100 microM) also abolished CPA-induced relaxation. 5 CPA (10 microM) increased guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels in arteries with an intact endothelium, without affecting adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 6 The inhibitors of NO synthesis and actions, the calmodulin inhibitor and removal of the endothelium abolished the CPA-stimulated increase in the levels of cyclic GMP. 7 In Ca(2+)-free solution, CPA failed to induce relaxation or to stimulate cyclic GMP production. Relaxation to nitroprusside was not affected under these conditions. 8 These results suggest that CPA can stimulate NO synthesis, possibly by inhibiting a Ca(2+)-ATPase, which replenishes Ca2+ in the intracellular storage sites in endothelial cells. Depletion of the Ca2+ store in the endothelium may then trigger influx of extracellular Ca2+, contributing to an increase in free Ca2+ in the endothelial cells, which activates NO synthase and NO formation.

Amino Acid Oxidoreductases↗
PubMed1994

New norepinephrine potentiators: synthesis and structure-activity relationships of a series of 4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols.

A variety of 1,2,3,4-tetrahydroisoquinolin-4-ols (1-6) were prepared as part of our search for new norepinephrine (NE) potentiators and to clarify the structure-activity relationships. These compounds and some previously prepared compounds were compared with 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (PI-OH) (1a) for ability to potentiate NE. The potency, for 2-substitution, was found to be in the order: Me > Et > iso-Pr > H. The compounds substituted by a halogen atom at the para position in the 4-phenyl group of PI-OH showed greater activities than did PI-OH, and the observed order of potency for the substitution was Cl > Br > F > H. The compound (4) methylated at the hydroxy group in PI-OH had greatly diminished activity. Although the desoxy compound (6) of PI-OH potentiated the response to NE at low concentrations, the potentiation was progressively masked by an inhibitory activity as the concentration of 6 was increased. In addition, the 4-cyclohexyl analogue (5) failed to potentiate NE. These results show the importance of the beta-phenylethanolamine skeleton of PI-OH for producing NE potentiation without accompanying inhibitory action. The racemic 4-chlorophenyl analogue (2a) was resolved by HPLC to (R)-(+)-2a and (S)-(-)-2a. The NE-potentiating activity was found to reside exclusively in (R)-(+)-2a, which had the highest activity among compounds tested in this study; the activity ratio was 25 at 3 x 10(-6) M. The antidepressant activity of racemic 2a was evaluated by a forced swimming test.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗