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T Sada

Publications and source records attributed to T Sada.

At least 19 recordsLinked to original sources
PubMed1998

Acute effects of nicotine content in cigarettes on coronary flow velocity and coronary flow reserve in men.

We investigated the acute effects of smoking on coronary flow reserve in terms of the nicotine content of cigarettes in 21 smokers. Coronary flow velocity was measured with a Doppler flow wire. Subjects smoked cigarettes containing >1 mg nicotine (n = 8, group 1) or <1 mg (n = 6, group 2). Subjects in the control group mimicked smoking without a cigarette (n = 7). Coronary flow reserve decreased after smoking in group 1, but not in group 2 or the control group. This reduction may have mediated nicotine or some other unknown substances influenced by smoking.

Adult↗
PubMed1998

[Impaired coronary flow reserve due to long-term smoking recovers after quitting].

Cigarette smoking is a major risk factor for coronary artery disease. The present study examined whether impaired coronary flow reserve by smoking can be recovered by quitting. Coronary flow velocity was measured by Doppler guide wire during coronary angiography and coronary flow reserve was determined by injecting 10 mg intracoronary papaverine in 45 patients who were present or former smokers. Twenty-three patients were smoking more than 800 cigarettes/day x years and 22 patients less than 800, and 13 patients had smoked more than 800 but had quit smoking at least for 5 years. None of the patients had any significant coronary stenosis in the left anterior descending artery where the Doppler probe was positioned, nor any coronary risk factors except smoking. Twenty-six non-smokers served as control subjects. There was no difference in the coronary flow reserve between controls and light smokers (3.3 +/- 0.7 vs 3.3 +/- 1.0), but it was significantly reduced in heavy smokers (2.6 +/- 0.8) compared to controls or light smokers (p < 0.05, p < 0.05, respectively), There was no significant difference in coronary flow reserve between controls, light smokers and ex-smokers (3.3 +/- 1.2). These results suggest that the deteriorating effect on the coronary flow reserve by smoking is corrected after its cessation.

Aged↗
PubMed1997

Effect of time interval between two balloon inflations on ischemic preconditioning during coronary angioplasty.

Ischemic preconditioning, defined as a reduction in myocardial ischemia caused by repeated brief episodes of coronary occlusions, is observed during percutaneous transluminal balloon angioplasty (PTCA). To elucidate the effects of the length of the interval between consecutive balloon inflations on ischemic preconditioning during PTCA, we examined 62 patients with chronic stable angina (48 males and 14 females; mean age 62 +/- 10 yr). PTCA was performed on the left anterior descending artery lacking in collateral vessels. A 2-min balloon inflation was performed twice and the extent of ST segment elevation in the electrocardiogram and the severity of chest pain (scored from 0 to 10) for each inflation were determined and compared. Patients were divided into three groups according to the interval between the two inflations: 1 min, Group 1; 2 min, Group 2; and 5 min, Group 5. In Groups 2 and 5, ST-segment elevation was significantly decreased during the second balloon inflation, as compared with that during the first inflation (P < 0.01, P < 0.001). A significant decrease was also observed in the severity of chest pain (P < 0.05, P < 0.01). However, Group 1 showed no significant decrease in ST-segment elevation or severity of chest pain between the first and second inflations. ST-segment elevation and chest pain were reduced to a greater extent in Group 5 than in Group 2. Results suggest that an interval of more than 2 min between balloon inflations is required to achieve ischemic preconditioning during PTCA.

Aged↗
PubMed1997

PDGF-BB decreases systolic blood pressure through an increase in macrovascular compliance in rats.

The cardiovascular roles of platelet-derived growth factor (PDGF) were examined in anesthetized rats by monitoring blood pressure and in isolated blood vessels and heart preparations. Intravenous injection of PDGF-BB lowered blood pressure. The decrease in systolic pressure was greater than that in diastolic pressure, so the pulse pressure decreased. PDGF-AA and -AB, other isoforms of PDGF, did not have any effect on blood pressure. Pretreatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, shortened duration of the hypotensive effect of PDGF-BB. The administration of L-arginine with L-NAME partially prevented the effect of L-NAME. PDGF-BB relaxed aortic rings precontracted with phenylephrine with a 50% effective concentration of 3 ng/ml. In contrast, in isolated mesenteric vascular preparations, the vasodilating activity of PDGF-BB was observed only at a high concentration (>12.5 ng/ml). In isolated heart preparations, PDGF-BB had no effect on the beat rate or contractile activity. These results suggest a new role of PDGF-BB that may contribute to the regulation in circulation through the increase in macrovascular compliance mediated by NO.

Animals↗
PubMed1997

Effects of angiotensin AT1 receptor antagonist on volume overload-induced cardiac gene expression in rats.

The present study was undertaken to examine the effects of volume overload on cardiac gene expression and the possible role of angiotensin AT1 receptor in such expression. Cardiac volume overload was prepared by abdominal aortocaval shunt in rats. Rats with aortocaval shunt were treated with 1) vehicle, 2) an angiotensin AT1 receptor antagonist, CS-866 (10 mg/kg/d), or 3) an angiotensin-converting enzyme inhibitor, temocapril (10 mg/kg/d), for 7 days. Cardiac tissue mRNA was measured by Northern blot analysis with specific probes. Aortocaval shunt not only caused cardiac hypertrophy but also upregulated the gene expression of atrial natriuretic polypeptide, collagen III, and downregulated Ca(2+)-ATPase expression in the left ventricle. These changes were prevented by treatment with CS-866, while temocapril failed to normalize left ventricular Ca(2+)-ATPase expression. Unlike the left ventricle, the significant downregulation of alpha-myosin heavy chain and transforming growth factor-beta 3 by aortocaval shunt was observed in the right ventricle, and CS-866 normalized this decreased expression of transforming growth factor-beta 3. The left and right atria showed increased expression of collagen type I as well as of collagen type III and atrial natriuretic polypeptide, and these increases were more effectively prevented by CS-866 than by temocapril. Thus, the effects of cardiac volume overload on cardiac performance-related gene expression differ between the ventricles and atria. Our results suggest that AT1 receptor partially contributed to volume overload-induced changes in cardiac gene expression and that AT1 receptor antagonists and angiotensin-converting enzyme inhibitors have different effects in this model of cardiac hypertrophy.

Actins↗
PubMed1996

Nonpeptide angiotensin II receptor antagonists: synthesis, biological activities, and structure-activity relationships of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds.

A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)-methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2'-1H-tetrazol-5- ylbiphenyl-4-yl)-methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken.

Acetylation↗
PubMed1996

[Effects of the time interval between the first and second balloon inflations on ischemic preconditioning during percutaneous transluminal coronary angioplasty].

Ischemic preconditioning is an attenuation of myocardial ischemia by repeated brief coronary occlusions observed during percutaneous transluminal coronary angioplasty (PTCA). The effects of the time delay between balloon inflations during PTCA on ischemic preconditioning were investigated in 48 patients with chronic stable angina but no rich collateral vessels. After successful predilatation, two 2-min balloon inflations were performed and the ST segment elevation in the electrocardiogram and chest pain were measured during each balloon inflation and compared. Patients were divided into three groups according to the interval between balloon inflations; 1 min (I1), 2 min (I2) and 5 min (I5). There were no significant differences in ST elevation (3.4, 3.2 and 3.7 mm) and chest pain during the first balloon inflation between these three groups. ST elevation and chest pain were decreased in groups I2 and I5 (2.6 and 2.8 mm) during the second balloon inflation compared with those during the first balloon inflation. However, there was no significant difference in ST elevation and chest pain during the first and second (3.7 mm) balloon inflations in group I1. ST elevation and chest pain were reduced more in group I5 than in I2. These results suggest that an interval of more than 2 min between balloon inflations is necessary to obtain the effect of ischemic preconditioning during PTCA.

Aged↗
PubMed1995

Pharmacology of CS-866, a novel nonpeptide angiotensin II receptor antagonist.

CS-866, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy-4-(1-hydroxy-1- methylethyl)-2-propyl-1-(4-[2-(tetrazol-5-yl)-phenyl]phenyl)met hylimidazol- 5-carboxylate, a prodrug type angiotensin receptor antagonist, is deesterified to the active acid, RNH-6270. RNH-6270 inhibited [125I]angiotensin II binding to bovine adrenal cortical membranes (angiotensin AT1 receptors) with an IC50 value of 7.7 nM, but not [125I]angiotensin II binding to bovine cerebellar membranes (angiotensin AT2 receptors), indicating the selectivity of the compound for angiotensin AT1 receptors. In guinea pig aortas, RNH-6270 reduced the maximal response of the concentration-contractile curve for angiotensin II (pD'2 = 9.9), but had no effect on the contractile response induced by phenylephrine or KCl. In conscious rats, intravenously injected RNH-6270 inhibited angiotensin II-induced pressor responses in a dose-dependent manner, and orally administered CS-866 produced a long-lasting inhibition of angiotensin II pressor responses. SK&F-525A, a P-450 inhibitor, suppressed the angiotensin II inhibitory effect of losartan, but not that of CS-866. These results demonstrate that RNH-6270 is a potent and AT1-selective angiotensin receptor antagonist and that, after oral administration, CS-866 has a long-lasting angiotensin II inhibitory action which is not affected by drug metabolizing enzymes in the liver.

Adrenal Cortex↗
PubMed1995

Negative chronotropic effect of endothelin 1 mediated through ETA receptors in guinea pig atria.

Endothelins exert potent excitatory cardiac effects by acting on specific receptors on myocytes. In this study, we have examined the signal transduction mechanism for the chronotropic effect of endothelins in guinea pig atria. A competition binding of [125I]endothelin 1 ([125I]ET-1) using the recently developed ETA receptor-selective antagonist BQ123 showed the presence of almost equal populations of ETA (44%) and ETB (56%) receptors in the guinea pig right atria. In a concentration-response study, endothelin 3 (ET-3), an agonist with higher affinity to ETB receptors than to ETA receptors, and sarafotoxin S6c (STXS6c), an ETB receptor-selective agonist, increased the rate of spontaneous beating at all concentrations tested (10 pmol/L to 100 nmol/L). In contrast, ET-1, a nonselective agonist, increased the heart rate at lower concentrations (10 pmol/L to 10 nmol/L) but decreased it at higher concentrations (30 to 100 nmol/L). When ET-1 (100 nmol/L) was applied in a single amount, heart rate was strongly increased; however, this increase was followed by a rapid decline in the response. ET-1 (100 nmol/L) but not ET-3 or STXS6c significantly reduced the heart rate when it was raised by isoproterenol (ISO, 300 nmol/L) either in the absence or presence of a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). Correspondingly, ET-1 significantly reduced the ISO-induced elevation of cAMP accumulation (19.1 +/- 1.7 pmol/mg protein [n = 8] and 12.6 +/- 1.2 pmol/mg protein [n = 7] in the absence and presence of ET-1, respectively; P < .01), which was also observed even in the presence of IBMX.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of RS-2135, a new antiarrhythmic agent, on the kinetics of use-dependent decrease in maximum upstroke velocity in guinea pig ventricular myocardium.

The use-dependent decrease in maximum upstroke velocity (Vmax) caused by RS-2135, a new antiarrhythmic compound was analyzed in isolated papillary muscles of guinea pigs. RS-2135 3 and 10 microM decreased Vmax of action potential (AP) in a concentration-related manner without affecting resting membrane potential (RMP). Vmax decay in the presence of RS-2135 was exponential at stimulation rates > 0.5 Hz. This use-dependent block of Vmax was enhanced at higher stimulation frequencies. The time constants and onset rates per action potential of the use-dependent block were 10.7-26.9 s and 0.021-0.041 AP-1, respectively. The time constants of recovery from use-dependent block were 57.9 and 63.6 s, respectively, in the presence of 3 and 10 microM RS-2135. The predicted half-time of the recovery process calculated by physicochemical parameters of RS-2135 agreed well with the observed values. These results suggest that RS-2135 is a sodium channel blocking agent with slow kinetics and that the physicochemical properties underlie these characteristics.

Action Potentials↗
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↗