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K Shigenobu

Publications and source records attributed to K Shigenobu.

At least 37 records · Page 2Linked to original sources
PubMed2001

Effects of endothelin-1 on the myogenic contraction of canine cerebral artery in response to quick stretch.

The present study was performed to investigate the effects of endothelin-1 (ET-1) on the myogenic contraction in response to mechanical stimulation in cerebral artery. Quick stretch at a rate of 10 cm/sec with the amount of 10 - 40% of the initial muscle length (=100%) produced a myogenic contraction in canine cerebral artery. ET-1 at 30 pM, which itself produces a small contraction corresponding to about 15% of the maximal response, potentiated stretch-induced contraction. By contrast, ET-1 at concentrations over 100 pM suppressed the stretch-induced tone. The potentiated component of stretch-induced tone in the presence of 30 pM ET-1 was largely attenuated by Ca2+ channel blockers, nimodipine (1 microM) or diltiazem (1 microM). These findings suggest that lower concentrations (pM range) of ET- 1 potentiates myogenic tension development of cerebral artery in response to mechanical stretch possibly via an increased Ca2+ influx through voltage-gated Ca2+ channel.

Animals↗
PubMed2001

[Pharmaceutical agents for calcium-induced cell damage (T-type calcium channel antagonist)].

T-type Ca(2+) channels have properties distinct from the L-type and are involved in cardiac pacemaking and blood flow. Novel drugs with action on both L-type and T-type Ca(2+) channels, such as efonidipine, has been shown to optimize blood pressure and heart rate with minimum effect on myocardial contraction. Further studies on their organ-protective effects are now in progress.

English Abstract↗
PubMed2000

Frequency-dependent blockade of T-type Ca2+ current by efonidipine in cardiomyocytes.

Efonidipine is a dihydropyridine Ca2+ antagonist with inhibitory effects on both L-type and T-type Ca2+ channels and potent bradycardiac activity especially in patients with high heart rate. In the present study, we examined the frequency dependence of efonidipine action on the T-type Ca2+ channel in isolated guinea-pig ventricular myocytes. The potency of efonidipine to inhibit the T-type Ca2+ current was higher under higher stimulation frequencies. The IC50 values were 1.3 x 10(-8), 2.0 x 10(-6) and 6.3 x 10(-6) M under stimulation frequencies of 1, 0.2 and 0.05 Hz, respectively. The reduction of T-type Ca2+ current amplitude was not accompanied by change in the time course of current decay. Efonidipine (10 microM) inhibited T-type Ca2+ current elicited by depolarization from holding potentials ranging from -90 to -30 mV by about 30%; the voltage-dependence of steady-state inactivation was not changed by the drug. Efonidipine slowed the recovery from inactivation following an inactivating prepulse. In conclusion, efonidipine was shown to have frequency-dependent inhibitory effects on the T-type Ca2+ channel, which could be explained by slow dissociation of the drug from the inactivated state of the channel.

Animals↗
PubMed2000

Involvement of K(+) channel in procainamide-induced relaxation of bovine tracheal smooth muscle.

The relaxant effect of procainamide, a class Ia antiarrhythmic agent, was examined in bovine tracheal smooth muscle. Procainamide produced concentration-dependent decreases in tension and full relaxation in the preparations contracted with methacholine (0.3 microM). By comparison, in preparations contracted with 40 mM K(+), procainamide had only slight relaxant effects. The relaxant effects of cromakalim and salbutamol on 40 mM K(+)-contracted preparations were significantly (P<0.01) smaller than those on 0.3 microM methacholine-contracted ones. On the other hand, the concentration-response relationships for quinidine, lidocaine, mexiletine and propafenone were not so dramatically different between 0.3 microM methacholine- and 40 mM K(+)-contracted preparations. Tetraethylammonium (300 microM), iberiotoxin (30 nM) and Ba(2+) (1 mM) significantly (P<0.05) attenuated the relaxant effects of procainamide on methacholine-induced contractions, whereas apamin (100 nM), 4-aminopyridine (300 microM), and glibenclamide (10 microM) did not affect them. The inhibitory effect of a combination of iberiotoxin and Ba(2+) was greater than that of iberiotoxin or Ba(2+) alone (P<0.01). These results suggest that the activation of at least two types of K(+) (maxi-K(+) and inward rectifier K(+)) channels contributes to the procainamide-induced relaxation of bovine tracheal smooth muscle.

Albuterol↗
PubMed2000

Validity of the Short-Memory Questionnaire in vascular dementia.

PURPOSE: To determine whether the Short-Memory Questionnaire (SMQ) being administered by caregivers to patients with Alzheimer's disease (AD) is also valid when given to patients with vascular dementia (VaD). METHODS: Subjects were 58 patients with VaD, 26 patients with cerebrovascular disorders free of cognitive deficit (CVD) and 62 healthy controls. All subjects received the Mini-Mental State Examination (MMSE), and their primary caregivers (or family members with same household) received the SMQ. RESULTS: In the VaD patients, the SMQ score was highly correlated with the MMSE score. When 39/40 was defined as a cutoff point based on the results of previous study, the SMQ properly classified 55 of the 58 VaD patients and 61 of the 62 controls, but only about half of the 26 CVD patients, as cases. CONCLUSION: The SMQ, a simple quantitative rating test for memory disturbance, is useful for the assessment and screening of VaD patients as well as AD patients, although careful attention should be paid to the assessment of CVD patients.

Aged↗
PubMed2000

Comparison of the Ca2+ entry channels responsible for mechanical responses of guinea-pig aorta to noradrenaline and thapsigargin using SK&F 96365 and LOE 908.

Noradrenaline (NA) produces sustained contractions in conduit arteries such as aorta isolated from various animal species. In guinea-pig aorta, NA-produced sustained contraction is largely dependent upon the influx of extracellular Ca2+, but is refractory to the treatment with organic Ca2+ entry blockers. In the present study, we attempted to characterize pharmacologically the Ca2+ entry channel responsible for NA-produced sustained contraction of guinea-pig aorta using SK&F 96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl]-1H-imi dazole) and LOE 908 ((R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2- (2,3,4-trimethoxyphenyl)ethyl]-acetamide), both of which block voltage-independent Ca2+ channels. The effects of SK&F 96365 and LOE 908 on NA-produced contraction were compared with those on extracellular Ca2+-dependent contractile and endothelium-dependent relaxant responses to thapsigargin (TSG), an inhibitor of Ca2+-pump Ca2+-ATPase. NA (3x10(-6) M)-produced sustained contraction of guinea-pig aorta without endothelium exhibited a strong dependency on the extracellular Ca2+. Nicardipine (10(-7) M), diltiazem (10(-5) M) and verapamil (10(-5) M) did not show any appreciable inhibitory effects on NA-produced sustained contraction. SK&F 96365 concentration-dependently (10(-6)-10(-4) M) attenuated the NA-produced sustained contraction whereas LOE 908 did not affect it at concentrations up to 10(-4) M. Similarly, extracellular Ca2+-dependent contraction of guinea-pig aorta without endothelium in response to TSG was also diminished by SK&F 96365 but was unaffected by LOE 908. In fura-PE3-loaded vascular preparations, SK&F 96365 decreased both cytoplasmic Ca2+ level ([Ca2+]i) and muscle tension elevated by NA and TSG. Both SK&F 96365 and LOE 908 did not affect an endothelium-dependent relaxation of guinea-pig aorta in response to TSG. These findings suggest that in guinea-pig aortic smooth muscle cells, NA activates Ca2+ influx across the plasma-membrane through the Ca2+-permeable channel which is identical with or has similar properties to the store-operated Ca2+ channel (SOCC) stimulated by TSG, but is distinct from endothelial cell SOCC.

Acetamides↗
PubMed2000

Potentiation of stretch-induced tone in the rabbit facial vein by an isoquinoline derivative, LOE 908.

The rabbit facial vein exhibits extracellular Ca2+- and temperature-dependent spontaneous myogenic tone in response to stretch. The present study aimed to elucidate pharmacological characteristics of Ca2+ entry mechanisms responsible for the stretch-induced tension development of the rabbit facial vein. Ca2+- and temperature-sensitive vascular tone in response to stretch was refractory to L-type Ca2+ channel blockers such as nifedipine and diltiazem but was abolished by papaverine or SK&F 96365 which blocks both receptor- and store-operated Ca2+ channels. Interestingly, LOE 908, another type of voltage-independent Ca2+-permeable channel blocker, showed augmentation of the stretch-induced vascular tone instead of inhibition. Potentiation by LOE 908 of stretch-induced vascular tone was also extracellular Ca2+-dependent and counteracted by SK&F 96365. Membrane stretch-activated Ca2+ channels in the rabbit facial vein smooth muscle cells may have a unique characteristic that their opening is stimulated by LOE 908 and thus is distinguishable from other voltage-independent Ca2+-permeable channels.

Acetamides↗
PubMed2000

Possible requirement of phosphonate moiety for efonidipine effects on the sino-atrial node action potential.

The effects of efonidipine, a 1,4-dihydropyridine phosphonate, and structurally related compounds on rabbit sino-atrial node action potential were examined with microelectrodes. 3NIC5NZ has a phosphonate moiety identical to that of efonidipine at the C5 position of the dihydropyridine ring and a side chain identical to nicardipine at C3, while 3NZ5NIC has C5 and C3 side chains identical to nicardipine and efonidipine, respectively. All four compounds decreased the slope and prolonged the early and late phases of pacemaker depolarization. The selectivity for the late phase against the early phase was in the order of efonidipine > 3NIC5NZ >> nicardipine > 3NZ5NIC. Thus, the phosphonate moiety at C5 position of the may be important for the characteristic prolongation of the late phase pacemaker depolarization by efonidipine.

Action Potentials↗
PubMed2000

Positive and negative inotropic effects of muscarinic receptor stimulation in mouse left atria.

In isolated mouse left atria, acetylcholine (ACh) produced a biphasic inotropic response; a transient decrease in developed tension was followed by an increase. Both negative and positive responses were concentration dependent and were inhibited by atropine. The negative and positive inotropic responses were also observed with a nonselective muscarinic stimulant, oxotremorine-M, but not with an M1-receptor selective stimulant, McN-A343. Pirenzepine, an M1-receptor antagonist, inhibited both negative and positive inotropic responses at high concentrations. Gallamine, an M2-receptor antagonist, inhibited the negative response. Hexahydro-siladifenidol hydrochloride, p-fluoro analog (p-F-HHSiD), an M3-receptor antagonist, inhibited the positive response with no effect on the negative phase. In pertussis toxin (PTX) treated preparations, negative inotropic response to ACh was not observed. These results suggest that the negative and positive inotropic responses to acetylcholine in mouse atria are mediated by M2 and M3 receptors, respectively. The negative phase, but not the positive phase, was mediated by a PTX-sensitive G protein.

Acetylcholine↗
PubMed2000

NO-mediated MaxiK(Ca) channel activation produces relaxation of guinea pig aorta independently of voltage-dependent L-type Ca(2+) channels.

The role of L-type Ca(2+) channels in the relaxation to nitric oxide (NO)-mediated MaxiK(Ca) channel activation was examined in guinea pig aorta. Acetylcholine (ACh) produced an endothelium-dependent relaxation of guinea pig aorta precontracted with noradrenaline (NA), which was abolished by an NO synthase inhibitor, N(G)-nitro-L-arginine (L-NNA). Both endothelium-dependent relaxation by ACh and endothelium-independent relaxation by an NO donor, (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (NOR3), were strongly suppressed by a soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), suggesting that increased intracellular cGMP plays the key role in both responses. ACh- and NOR3-induced relaxations were significantly suppressed by iberiotoxin (IbTX), a selective blocker of MaxiK(Ca) channels. ACh- and NOR3-induced relaxations were greatly attenuated when arteries were precontracted with high KCl instead of NA, supporting the idea that K(+) channel activation mediates the relaxant responses. (6) NOR3-induced relaxations were not affected by a L-type Ca(2+) channel blocker, diltiazem. Furthermore, endothelium-independent relaxation by a K(ATP) channel opener, (+)-7,8-dihydro-6, 6-dimethyl-7-hydroxy-8-(2-oxo-1-piperidinyl)-6H-pyrano[2,3-f] benz-2,1, 3-oxadiazole (NIP-121) was not affected by diltiazem and nicardipine. These findings suggest that blockade of L-type Ca(2+) channels is not a major mechanism responsible for the vascular relaxation due to NO-mediated MaxiK(Ca) channel activation in guinea pig aorta.

Acetylcholine↗
PubMed2000

Possible involvement of endothelium-derived hyperpolarizing factor (EDHF) in the depressor responses to platelet activating factor (PAF) in rats.

1. In anaesthetized rats, platelet activating factor (PAF; 1 microg kg(-1)) decreased mean arterial blood pressure by around 60 mmHg (n=18). This depressor response was completely blocked by the PAF antagonist, CV-6209 (1 mg kg(-1)), indicating the role of PAF-specific receptor in the response. 2. N(G)-nitro-L-arginine methyl ester (L-NAME; 50 mg kg(-1)), an NO synthase inhibitor, profoundly elevated systemic blood pressure (n=19), indicating an important role of NO in the basal blood pressure regulation. The depressor response to PAF (1 microg kg(-1)) normalized against that to sodium nitroprusside (SNP) (10 microg kg(-1)) was not substantially different between rats treated without and with L-NAME (n=4). In contrast, the depressor effect of acetylcholine (0.03 - 1.0 microg kg(-1)) normalized against that of SNP (10 microg kg(-1)) was significantly attenuated by L-NAME (n=5). 3. Charybdotoxin (0.4 mg kg(-1)) plus apamin (0.2 mg kg(-1)) significantly attenuated the depressor response to PAF (1 microg kg(-1)) (n=5) without affecting the blood pressure change due to SNP (1 mg kg(-1)) (n=3). Charybdotoxin (0.4 mg kg(-1)) (n=4) or apamin (0.2 mg kg(-1)) (n=4) alone did not affect the PAF-induced depressor response. 4. These findings suggest that EDHF may make a significant contribution to the depressor response to PAF in rats. Although NO plays the determinant role in the basal blood pressure regulation, its contribution to PAF-produced depressor response seems to be less as compared with that to the depressor response to acetylcholine.

Animals↗
PubMed2000

Inhibition of T-type and L-type Ca(2+) currents by aranidipine, a novel dihydropyridine Ca(2+) antagonist.

The effects of aranidipine, a novel dihydropyridine Ca(2+) channel antagonist, on membrane currents in guinea pig ventricular myocytes and on action potentials in rabbit sinoatrial node tissue were examined. In myocytes, aranidipine (10 nmol/l to 1 micromol/l) concentration-dependently decreased T-type and L-type Ca(2+) currents. Aranidipine (1 micromol/l) had little effect on K(+) currents. In the sinoatrial node, 0.1 micromol/l aranidipine increased cycle length, and decreased +V(max) and the slope of the phase 4 depolarization. Thus, inhibition of both T-type and L-type Ca(2+) currents by aranidipine may partly explain its potent negative chronotropic activity.

Action Potentials↗
PubMed2000

The therapeutic efficacy of VP-343, a selective vasopressin V2 receptor antagonist, in the experimental SIADH rat model.

The aim of this work is to investigate the therapeutic efficacy of VP-343 ((N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-a]qunoxalin-5(1H)-yl]phenyl]-4'-methyl[1,1'-biphenyl]-2-carboxamide), a selective vasopressin V2 receptor antagonist, using the experimental SIADH (syndrome of inappropriate secretion of antidiuretic hormone) rat model. In the model, which was accomplished by administering continuously 1-desamino-8-D-arginine vasopressin (DDAVP), serum sodium levels (S(Na)) and serum osmolarity levels (S(Osm)) significantly and remarkably decreased, which was accompanied with hyper-osmolarity of urine and oliguria. VP-343 increased rapidly and dose-dependently S(Na) and S(Osm). VP-343 exhibited marked diuretic action and decreased urine osmolarity dose-dependently. In the SIADH rat model, all serum levels of chloride, calcium, creatinine, total cholesterol, and uric acid decreased when compared with normal levels. VP-343 increased all serum levels of chloride, calcium, and total cholesterol. These results indicate that VP-343 has efficacy to normalize the abnormalities in DDAVP-induced SIADH.

Animals↗
PubMed2000

Pharmacological profile of VP-343, a novel selective vasopressin V2 receptor antagonist, in rats.

The pharmacological profile of a novel selective vasopressin V2 receptor antagonist, VP-343(N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[ 1,2-a]quinoxalin-5(1H)-yl]carbonyl]phenyl]-4'-methyl[1,1'-biphenyl ]-2-carboxamide) was characterized in several in vitro and in vivo rat models. The IC50 values of VP-343 for vasopressin V1A and V2 receptors were 110 and 0.77 nM, respectively. VP-343 inhibited dose-dependently the pressor response to exogenous arginine vasopressin (AVP; 30 mU/kg, i.v.) in pithed rats, with an ID50 value of 0.57 mg/kg (i.v.). VP-343 induced strong aquaresis in normal saline-loaded conscious rats. Antidiuretic activities of VP-343 have not been detected in AVP deficient Brattleboro rats, showing its lack AVP V2 agonistic activity. During repeated administration for 21 d (3 mg/kg, p.o.) and after recovery, the aquaretic action of VP-343 still remained. In the aged (17 month) saline-loaded conscious rats study, VP-343 (3 mg/kg, p.o.) exhibited remarkable diuretic action. In a single dose oral toxicity study in mice, VP-343 did not produce any clinical signs and mortality at any of the tested doses. The results indicate that VP-343 is a potent, orally active, selective V2 receptor antagonist, suggesting that it can be expected to be useful as an aquaretic drug.

Animals↗
PubMed2000

Cerebral artery selective inhibition of protein kinase c-mediated contraction by hns-32, a novel azulene-1-carboxamidine derivative.

The vasorelaxant actions of a novel azulene-1-carboxamidine derivative, HNS-32, were investigated on the tension development evoked by phorbol 12, 13 dibutyrate (PDBu) in cerebral and femoral arteries isolated from the dogs. In basilar artery, HNS-32 inhibited almost completely PDBu-induced contraction in a concentration-dependent manner with potency about 10 times stronger than that of fasudil, a protein kinase inhibitor. In contrast, in femoral artery, HNS-32 failed to suppress the tension development in response to PDBu whereas fasudil inhibited it with a similar potency as in basilar artery. These findings indicate that HNS-32 selectively suppresses cerebral artery contraction mediated via an activation of protein kinase C.

Animals↗
PubMed1999

Role of P-glycoprotein in human natural killer-like cell line-mediated cytotoxicity.

Natural killer (NK) cells express the highest amount of P-glycoprotein (Pgp), a product of the multidrug resistance (MDR) 1 gene, among lymphoid cells, and our previous studies demonstrated that Pgp is required for NK cell-mediated cytotoxicity. In this study we examined the role of Pgp in NK cell-mediated cytotoxicity using a human NK-like cell line, i.e., YTN cells and two MDR reversing agents, nicardipine and its structural analog, AHC-93. These two agents inhibited the Pgp function (rhodamine-123 excretion) as well as cell-mediated cytotoxicity, confirming that Pgp is critical for NK cell-mediated cytotoxicity. As revealed by video-rate ultraviolet laser-scanning confocal microscopy, AHC-93 did not inhibit the increase in the intracellular calcium concentration upon binding to target cells, whereas nicardipine did, as reported previously. These two reagents relocated acridine orange dye from lysosomes to the cytoplasm at concentrations similar to those required for the inhibition of cell-mediated cytotoxicity. These results suggest that Pgp is directly or indirectly involved in pH regulation in lysosomes, but not in calcium homeostasis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗