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T Sada

Publications and source records attributed to T Sada.

At least 19 recordsLinked to original sources
PubMed1992

Electrophysiologic effects of RS-2135, a new antiarrhythmic compound, on canine Purkinje fibers.

RS-2135 is the (+) isomer of a novel, fused carbazol derivative. The agent, when administered orally, shows long-lasting antiarrhythmic effects in several models of arrhythmia. We used standard microelectrode techniques to characterize the electrophysiological effects of the agent on canine Purkinje fibers. RS-2135 reduced the maximum upstroke velocity of the action potential (Vmax) and shortened the action potential duration (APD) in a concentration-related manner (0.3-3 microM). RS-2135 decreased Vmax at lower concentrations than disopyramide, flecainide, and mexiletine. RS-2135 shortened the effective refractory period (ERP), but significantly increased the ratio of ERP to APD90. Additionally, the effects of the (-) optical isomer of RS-2135 were compared with those of RS-2135, the (+) enantiomer. The (-) isomer was much less potent than RS-2135 in decreasing Vmax. These data suggest that RS-2135 belongs to the class I or "local anesthetic" type of antiarrhythmic agent and that the stereochemistry of the drug molecule is an important determinant of Na channel blocking activity.

Action Potentials↗
PubMed1991

The effects of R-75,317 on antiglomerular basement membrane glomerulonephritis in rats.

Platelet-activating factor (PAF) is a potent inflammatory mediator which is released by various inflammatory cells and produced by certain tissues, including the kidney. PAF has been shown to increase glomerular permeability to protein and to decrease glomerular filtration rate (GFR) by contracting mesangium. On the basis of these observations, it has been suspected that PAF may play a role as mediator of glomerular damage in glomerular nephritis. To examine this possibility, we studied the effects of a specific PAF antagonist, R-75,317, on the development of an experimental model of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Glomerulonephritis was initiated by injecting rabbit anti-rat GBM serum into rats. Proteinuria gradually developed after serum injection, plateaued at week 2, and remained at the high level of week 2 throughout the experimental period (6 wk). Chronic treatment with R-75,317 (10 mg/kg/day i.p.) tended to delay the onset of proteinuria and significantly accelerated the recovery phase. Creatinine clearance (Ccr) fell to 40% at week 3. R-75,317 treatment completely prevented this decline of Ccr. Histological changes in this model (glomerular hypertrophy, proliferation of mesangial matrix and interstitial fibrosis) were also ameliorated by the R-75,317 treatment. The results suggest that PAF may play a role in the development of glomerulonephritis and that PAF antagonists could be used in the treatment of human renal disease.

Acetylglucosaminidase↗
PubMed1990

Cytosolic free calcium of aorta in hypertensive rats. Chronic inhibition of angiotensin converting enzyme.

Cytosolic free calcium concentration ([Ca2+]i) and muscle tension were simultaneously measured in aortic tissue isolated from spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) rats, and SHR chronically treated with a novel angiotensin converting enzyme inhibitor, CS-622. In the presence of 2.5 mM Ca2+ in the bathing solution, aortic [Ca2+]i measured with fura-2 was higher in SHR than in WKY rats, and it was almost the same in CS-622-treated SHR and untreated WKY rats. Increase of external Ca2+ concentration from zero to 2.5 mM elicited a contraction in SHR aortas but not in aortas from both CS-622-treated SHR and untreated WKY rats. When the aortas were contracted by 60 mM K+, however, [Ca2+]i as well as developed tension was similar in the three groups. CGP-28392 (10(-6) M), a Ca2+ channel activator, induced a rhythmic activity superimposed on a gradual increase of [Ca2+]i and tension in SHR aortas but not in the aortas of CS-622-treated SHR or untreated WKY rats. Nicardipine (10(-7) M) decreased the resting [Ca2+]i and the resting tone in SHR aortas, but not in WKY rat aortas. These results suggest that SHR aortas have a higher myogenic tone due to increased [Ca2+]i than WKY rat aortas and that the increased [Ca2+]i is attributed to alterations of dihydropyridine-sensitive Ca2+ channels in SHR aortas. Further, the decrease of the vascular tone induced by long-term administration of the angiotensin converting enzyme inhibitor may be due to a reduction of increased [Ca2+]i in SHR.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Hemodynamic changes following long-term administration of CS-905, a novel dihydropyridine calcium blocker, in conscious SHR.

To investigate the central and regional hemodynamics after long-term administration of CS-905, a novel calcium blocker, we administered the agent (1 and 3 mg/kg/day) for 15 weeks in spontaneously hypertensive rats. At the end of the dosing period, hemodynamic changes were examined using the radioactive microsphere technique. CS-905 produced a sustained dose-dependent antihypertensive effect without inducing tolerance during the 15-week dosing period and prevented cardiac hypertrophy. The agent increased cardiac output, decreased blood pressure and thus decreased total peripheral resistance in a dose-related manner. Regional blood flows measured by the microsphere technique were increased in the kidney and brain despite the lowered blood pressure. There was no organ where regional blood flow was decreased. These changes after chronic treatment with CS-905 would be beneficial in the long-term therapy of hypertension.

Animals↗
PubMed1989

Chronic inhibition of angiotensin converting enzyme decreases Ca2+-dependent tone of aorta in hypertensive rats.

Long-term effects of a novel angiotensin converting enzyme (ACE) inhibitor, CS-622, on Ca2+-dependent tone in aortic smooth muscles of spontaneously hypertensive rats (SHR) were examined. CS-622 (3 or 10 mg/kg/day), when orally administered to SHR for 21 weeks, exhibited a dose-dependent antihypertensive action. In Krebs-Henseleit solution, removal of Ca2+ caused much greater relaxation in aortas excised from control SHR than those from SHR treated with CS-622. Restoration of Ca2+ from zero to 2.5 mM elicited a marked contraction in aortas from control SHR but only a small contraction in aortas from both CS-622-treated SHR and normotensive Wistar-Kyoto rats. These findings suggested that myogenic tone that resulted from increased Ca2+ permeability in aortas of SHR was suppressed by long-term treatment with CS-622. The aortic tone from the individual rats correlated well with systolic blood pressure in both CS-622-treated and control SHR. The exaggerated myogenic tone in aortas of SHR was attenuated in the medium containing nicardipine but was not altered in the presence of CS-622 diacid (active form of CS-622) at a concentration high enough to fully inhibit aortic ACE. The myogenic tone in normal Ca2+ concentration was not decreased in aortas excised from SHR treated with hydralazine (5 mg/kg/day) for 21 weeks. We conclude that after prolonged administration CS-622 reduced the high vascular tension resulting from increased Ca2+ permeability of vascular smooth muscle membrane in SHR and that the restoration of normal Ca2+ permeability of vascular smooth muscles may underlie long-term antihypertensive action of ACE inhibitors.

Administration, Oral↗
PubMed1989

Long-term inhibition of angiotensin converting enzyme suppresses calcium channel agonist-induced contraction of aorta in hypertensive rats.

To elucidate functional changes in the vascular smooth muscle of spontaneously hypertensive rats (SHR) after chronic inhibition of angiotensin converting enzyme, we examined the contractile responses to different pharmacological interventions in the isolated aortas from SHR treated with a novel angiotensin converting enzyme inhibitor, CS-622 (10 mg/kg/day) for 20 weeks. In normal K+ medium, a marked contraction was elicited by increasing Ca2+ concentration from 0 to 3 mM in aortas from a control group of SHR, but not in aortas from SHR treated with CS-622. In 60 mM K+ medium, however, the sensitivity of aorta to Ca2+ was almost the same in the two groups. A calcium channel activator, CGP-28392 (10(-7) to 10(-6) M), induced a marked contraction in the aortas from control SHR, but not in the aortas from CS-622-treated SHR. When slightly depolarized in 10 or 12 mM K+ solution, the aortas from CS-622-treated SHR contracted in response to CGP-28392. The aortic sensitivity to KCl contraction was much lower in CS-622-treated SHR than in untreated SHR, whereas the sensitivity to phenylephrine contraction was little different in the two groups. These contractile profiles of aortas from CS-622-treated SHR were very similar to those from normotensive Wistar-Kyoto rats but not to those from hydralazine-treated SHR. These data suggest that contractions due to Ca2+ through voltage-dependent calcium channels are exaggerated in SHR aorta and that long-term treatment with angiotensin converting enzyme inhibitor suppresses the abnormal contractility of SHR vascular smooth muscle, probably through alterations of voltage-related functions of calcium channels.

Animals↗
PubMed1989

Lactone and cyclic ether analogues of platelet-activating factor. Synthesis and biological activities.

Six-membered lactone and tetrahydropyran analogues of platelet-activating factor (PAF), 4-11, and related antagonistic derivatives 41-46 were synthesized. None of the delta-lactones 4-7 showed PAF-like activities, while the corresponding cyclic ethers 8, 9 and 11 were slightly active. Some of the cyclic antagonists showed more potent inhibitory activities than the open chain antagonist CV-3988 against platelet aggregation (rabbit platelet-rich plasma, IC50) and hypotension (rat, ID50) induced by C16-PAF: e.g. dl-3-[6-[O-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2- yl)methyl]phosphonoxy]hexylthiazolium (inner salt) (41d) (IC50 5.5 x 10(-7) M, ID50 0.046 mg/kg, i.v.); dl-3-[5-[O-(cis-3-heptadecylcarbamoylthiotetrahydropyran-2- yl)methyl]phosphonoxy]pentylthiazolium (inner salt) (43c) (IC50 5.7 x 10(-7) M, ID50 0.076 mg/kg, i.v.).

Animals↗
PubMed1989

Synthesis and antagonistic activities of enantiomers of cyclic platelet-activating factor analogues.

Enantiomers of platelet-activating factor (PAF) antagonists, 3-(6-[O-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2-yl)methyl ] phosphonoxy)hexylthiazolium (inner salt) (3), 3-[5-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2-yl) methoxycarbonylamino]pentylthiazolium bromide (4) and 3-(5-[O-(cis-3-heptadecylcarbamoylthiotetrahydropyran-2-yl) methyl]phosphonoxy)pentylthiazolium (inner salt) (5), were synthesized, starting from (2R,2R)- and (2S,2S)-tartaric acid. Antagonistic activities of these compounds against C16-PAF were measured in vitro (rabbit platelet aggregation, IC50) and in vivo (hypotension in rats, ID50). In these three enantiomeric pairs, the (3S)-(tetrahydropyran numbering) enantiomers were one order more potent than the (3R)-isomers: (2R,3S)-3a (R-74,654), IC50 0.59 microM and ID50 0.054 mg/kg, i.v.; (2S,3R)-3b, IC50 4.7 microM and ID50 0.30 mg/kg, i.v.; (2R,3S)-4a, IC50 0.20 microM and ID50 0.032 mg/kg, i.v.; (2S,3R)-4b, IC50 2.2 microM and IC40 0.21 mg/kg, i.v.; (2R,3R)-5a, IC50 1.1 microM and ID50 0.92 mg/kg, i.v.; (2S,3S)-5b (R-74,717), IC50 0.27 microM and ID50 0.064 mg/kg, i.v.

Chemical Phenomena↗
PubMed1989

Antihypertensive effects of CS-905, a novel dihydropyridine Ca++ channel blocker.

CS-905 is a novel dihydropyridine calcium blocker. A single oral administration of CS-905 or nicardipine at doses of 0.3-3.0 mg/kg produced a dose-dependent reduction of blood pressure in conscious SHR. CS-905, when administered orally in conscious SHR, was more than 3 times as potent as nicardipine. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in heart rate. An intravenous administration of CS-905 also produced a hypotension with a slow onset and long duration in SHR, but CS-905 was 3 times less potent than nicardipine by intravenous administration. This difference may be attributed to the first pass effect, which was associated with nicardipine but not with CS-905. The blood pressure lowering effects of CS-905 was most potent in DOCA-salt hypertensive rats, followed by SHR, RHR and normotensive rats, in this order. CS-905 is expected to be an antihypertensive agent that is effective on a once a day regimen in clinical settings.

Anesthesia↗
PubMed1989

Effects of RS-1893, a novel cardiotonic agent, on central and peripheral hemodynamics in anesthetized rats.

After the use of two radionuclides in the tracer microspheres technique in the rat was verified, we examined the central and peripheral hemodynamic effects of RS-1893, an orally active cardiotonic agent. An intravenous infusion of RS-1893 at a dose of 3 micrograms/kg/min gradually decreased blood pressure and increased heart rate and cardiac output. Blood flows in the kidney and stomach were increased. There was no organ in which blood flow was decreased despite the fall in blood pressure. These data suggest that RS-1893 dilates blood vessels in the whole body, especially in the kidney and stomach.

Anesthesia↗
PubMed1989

Risk factors for the complication of cerebral infarction in Japanese patients with acute myocardial infarction.

The incidence and risk factors for cerebral infarction in Japanese patients with acute myocardial infarction were evaluated. Seven (5.0%) of 140 patients with acute myocardial infarction suffered from cerebral infarction during their initial hospitalization. The incidence was slightly higher than those reported in Western countries. Anterior wall myocardial infarction and a past history of cerebrovascular disease were considered to be probable risk factors for the complication. A beneficial effect of anticoagulant therapy in preventing cerebral infarction in cases of acute myocardial infarction with those risk factors is suggested.

Aged↗
PubMed1988

Effects of chronic treatment with a novel angiotensin converting enzyme inhibitor, CS622, and a vasodilator, hydralazine, on atrial natriuretic factor (ANF) in spontaneously hypertensive rats (SHR).

We studied the effects of chronic treatment with a novel angiotensin converting enzyme inhibitor, alpha-[(2S,6R)-6-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino-5-oxo-2- (2-thienyl)perhydro-1,4-thiazepin-4-yl]acetic acid.HCl (CS622), and a vasodilator, hydralazine, on plasma atrial natriuretic factor (ANF) levels and kidney ANF receptors in spontaneously hypertensive rats (SHR). Plasma ANF level was decreased and cardiac hypertrophy reduced in CS622 treated SHR, but not in hydralazine treated SHR, although blood pressure was lowered similarly in both SHR groups. The binding capacity of kidney ANF receptors increased and the affinity decreased in CS622 treated SHR compared to untreated SHR. These results suggest that decrease of plasma ANF results from decreased cardiac load but not from lowered blood pressure, and that changes in ANF receptors result from increased plasma ANF.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Pharmacological profiles of CS-622, a novel angiotensin converting enzyme inhibitor.

CS-622 is a prodrug type ACE inhibitor with a thiazepin ring. Its active form, CS-622 diacid, was slightly more potent than enalaprilat in inhibiting ACE isolated from rabbit lung. The inhibitory potency of CS-622 diacid on isolated rat aorta was 3 times that of enalaprilat. The inhibitory action of enalaprilat was abolished quickly by washing the aortic strip with drug-free solution, whereas that of CS-622 diacid was abolished only slowly. This difference suggests that CS-622 diacid binds to vascular ACE more firmly than enalaprilat. By oral administration, CS-622 was 3 times more potent than enalapril, and its onset of action was faster than that of enalapril, suggesting that the conversion of CS-622 to its active diacid occurs faster than the conversion of enalapril. Although CS-622 diacid was only slightly more potent than enalaprilat by intravenous administration, it had a longer duration than enalaprilat. Elimination of renal excretory function potentiated the action of captopril but not that of CS-622, suggesting that unlike captopril, only a small portion of CS-622 is excreted through the kidney.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

Ambulatory electrocardiograms obtained by Holter monitoring system in patients with permanent demand pacemakers.

Ventricular inhibited demand pacemakers (VVI) were implanted in 27 patients with complete A-V block and pacemaker arrhythmias were analyzed by Holter system ambulatory electrocardiograms and conventional electrocardiograms. With Holter ECG, 13 patients showed myopotential inhibition, 5 patients had sensing failure and premature ventricular contractions (PVC) were observed in all patients. On the contrary, myopotential inhibition and sensing failure were not detected by conventional ECG and the detection rate of PVC was only 30%. The transient recovery of A-V conduction was observed in 14 of 27 patients with Holter ECG, but was not detected by conventional ECG. The Holter system ambulatory electrocardiogram clearly demonstrated the complex cardiac arrhythmias. Therefore, it is useful for monitoring arrhythmias caused by VVI pacemakers.

Adult↗
PubMed1979

Halothane solubility in blood during cardiopulmonary bypass: the effect of haemodilution and hypothermia.

The influence of haemodilution and cooling on the solubility of halothane in blood during cardiopulmonary bypass was studied in six normothermic and six hypothermic patients undergoing open-heart operations. The solubility of halothane in blood was 2.17 at 30 degrees C and 1.34 at 37 degrees C. There was also an increase in the blood/gas partition coefficient of about 8.7 per cent for each degree celsius of temperature fall. These changes in haemodiluted blood explain the different anaesthetic requirements observed in patients undergoing cardiopulmonary bypass, either at normal temperature or at moderate hypothermia.

Cardiopulmonary Bypass↗
PubMed1979

Some observations on serum concentrations of digitoxin and digoxin.

Serum concentrations of digitoxin and digoxin were measured in 145 cases with various heart diseases receiving maintenance doses of digitalis. Digitalis toxicity was seen in only 2 cases (1.4%). Day-to-day variation of serum concentration while taking the same daily dose was small in digitoxin therapy (13.8%), but a considerable variation was seen in digoxin therapy (24.4%). Serum concentrations of both digitoxin and digoxin were measured in the patients receiving digitoxin, and there was a positive correlation between the two (r = 0.66, p less than 0.001). This fact suggested that the effect of digitoxin was the sum of the effects of digitoxin and its metabolite, digoxin. In the patients taking digoxin, digitoxin was not detected in the serum. Serum digitoxin level had a significantly positive correlation to serum albumin level, presumably because digitoxin was retained in serum in the bound form to albumin. Minimal effective level, 10 ng/ml, was however obtained with higher daily dose of digitoxin in patients with lower serum albumin.

Adolescent↗