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1.
Effects of the intracellular calcium antagonist, KT-362, on systemic and coronary hemodynamics and the electrocardiogram were evaluated in chronically instrumented, awake dogs during intravenous infusion or bolus administration. Both methods of administration resulted in systemic hypotension, tachycardia and decreases in left ventricular pressure and peak positive left ventricular dP/dt. KT-362 produced a transient increase in mean coronary blood flow velocity only during bolus injection, while subendocardial segment shortening was depressed only by drug infusion. Prolongation of QRS duration and the QT interval (corrected for change in heart rate, QTc) also occurred during drug infusion. The results suggest that the hemodynamic effects of intracellular calcium antagonism by KT-362 are qualitatively similar to those of other calcium channel blocking agents which inhibit extracellular calcium influx. In contrast, the actions of KT-362 on cardiac conduction may be different from those of other slow channel calcium blocking agents.  相似文献   

2.
Summary Electrophysiologic effects of nicorandil, a newly developed coronary vasodilator, on the atrioventricular (AV) node were studied using space-clamped small preparations of the rabbit AV node. At the concentrations of 10–6, 10–5 and 10–4 mol/l, this drug did not cause significant changes in the action potential characteristics including the spontaneous firing frequency, overshoot, maximum diastolic potential, maximum rate of depolarization and action potential duration. When the resting membrane potential of the AV node was obtained by a superfusion with verapamil and then nicorandil was added to the perfusate, no hyperpolarization was observed. This was in sharp contrast to the reported hyperpolarizing action of this drug on the atrial muscle, Purkinje fibres and vascular smooth muscle where the resting potential is much more negative. On the other hand, voltage clamp experiments using double microelectrode techniques revealed that 10–5 to 10–4 mol/l nicorandil increased the steady-state outward current at potentials positive to –40 mV and the steady-state inward current at potentials negative to –40 mV. Such a nicorandil-sensitive component of the steady-state current had an average reversal potential of –41.8 mV (n = 5). This component was considered to reflect changes in the time-independent background current, although, at more negative potential levels, it may partially reflect an increase in the hyperpolarization activated inward current (i h). Nicorandil, at the concentrations of 10–5 and 10–4 mol/l, increased the slow inward current (i si) by 10.8% (n = 5, p < 0.01). As the inactivation kinetics of the i si was not affected after the application of nicorandil, the increase in the may well be attributed to an increase in the fully activated i si (i si). It was also shown that the increase in the i si was not mediated by neurotransmitters, as an increase of a similar degree was again observed in the presence of either propranolol or atropine. The apparent discrepancy between the effects of nicorandil on the action potential configuration and on the membrane currents may have resulted from cancellations between the inward increase in the i si and the outward increase in the background current during the action potential. Possible implications of these nicorandil effects in modifying AV conduction were discussed. Send offprint requests to Y. Watanabe at the above address  相似文献   

3.
The effects of nicorandil [SG-75, 2-nicotinamidoethyl nitrate (ester)] and nifedipine on the recovery of myocardial segment shortening were compared to a vehicle-treated group following a short occlusion (15 min) of the left anterior descending coronary artery (LAD) and reperfusion (5 h). The relationship between myocardial blood flow and myocardial segment shortening was examined by means of the radioactive microsphere technique and sonomicrometry. Nicorandil (100 micrograms/kg followed by 25 micrograms/kg/min, i.v.) or nifedipine (3 micrograms/kg followed by 1 microgram/kg/min, i.v.) was administered 10 min prior to and throughout the occlusion period. Both drugs produced similar decreases in mean arterial pressure (approximately 25 mm Hg) during LAD occlusion. Similar degrees of ischemia (flow deprivation) were produced in the vehicle, nicorandil, and nifedipine groups; however, nicorandil produced a significantly greater decrease in the heart rate-left ventricular systolic pressure product during coronary occlusion. During reperfusion of the LAD there was no difference in the hemodynamics of the vehicle, nicorandil, or nifedipine groups. Neither drug altered myocardial blood flow to the ischemic region during the occlusion or reperfusion period when compared to the vehicle-treated group; however, both nicorandil and nifedipine pretreatment significantly improved recovery of percentage of segment shortening of the ischemic region. Nicorandil improved the recovery of function (percentage of segment shortening) to a greater extent than did nifedipine throughout the reperfusion period, most likely because of the greater decrease in afterload produced by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

4.
The purpose of this study was to compare the effects of nicorandil [SG-75; 2-nicotinamidoethyl nitrate (ester)] and nitroglycerin on the distribution of blood flow between subendocardium and subepicardium [endocardial/epicardial blood flow ration (endo/epi)] distal to a proximal flow-limiting coronary artery stenosis in anesthetized dogs. Myocardial blood flow distribution was determined by use of 15-micron radioactive microspheres. Various indices of reactive hyperemia (peak flow, duration, volume) and poststenotic coronary pressures were used to assess the severity of ischemia in the area distal to the stenosis. Partial ischemia was produced by a 10-s total left circumflex coronary occlusion followed by 110 s of reflow to 50-60% of the control flow. Microspheres were injected during steady-state conditions during the partial reflow period. In the absence of drug, coronary artery stenosis produced marked underperfusion of the subendocardium (endo/epi, 0.55 +/- 0.05). Following administration of nicorandil (60 micrograms/kg i.v.) or nitroglycerin (15 micrograms/kg i.v.), the endo-epi during a subsequent partial reflow (stenosis present) period was significantly increased (0.67 +/- 0.06). The duration of reactive hyperemia and reactive hyperemic flow were also decreased by both compounds following release of the stenosis. These results suggest that nicorandil and nitroglycerin reduce subendocardial ischemia distal to a flow-limiting coronary artery stenosis. This beneficial effect may partially explain the efficacy of these two compounds in the therapy of angina pectoris.  相似文献   

5.
The results obtained by a study of acute and chronic toxicity of nonachlazine--a new original coronary-active agent endowed with antianginal properties are reported. Nonachlazine has been found to have a sufficiently wide range of therapeutic action. With its repeated (for 36 days) oral introduction to rats in an effective dose of 10 mg/kg the drug does not produce any adverse effect on the general condition of the animals, reduces but insignificantly their weight gain, fails to exert any damaging effect on the blood system, does not change biochemical characteristics featuring the function of the liver, nor evokes any pathohistological changes of the internal organs. Nonachlazine has no locally irritating effect on the gastro-intestinal tract and is a compound producing but a slight stress action.  相似文献   

6.
In anesthetized rats, intra-carotid injections of arachidonate . Na (20 mg/kg) elicited a marked pressor response, producing death within 10 min in untreated rats. The antianginal agents (nicorandil, nitroglycerin and diltiazem) and cyclooxygenase inhibitors (indomethacin and aspirin), applied i.v. or p.o., effectively protected the rats from death. In the surviving rats, these drugs significantly prevented intravascular thrombosis in cerebral vessels and the marked pressor response to arachidonate . Na. The protective mechanism of the antianginal agents tested seems to be different from that of cyclooxygenase inhibitors.  相似文献   

7.
The effects of nicorandil, N-(2-hydroxyethyl)nicotinamide nitrate (ester), in reducing systemic blood pressure (SBP) in rats were studied in comparison with isosorbide dinitrate and nitroglycerin. The drugs were administered to pentobarbitone-anaesthetized rats by jugular vein (i.v.), portal vein (p.v.), intrajejunal (i.j.), intraperitoneal (i.p.) and subcutaneous (s.c.) routes.Nicorandil was absorbed rapidly through all routes, and caused marked hypotension dose-dependently. With isosorbide dinitrate and nitroglycerin, unlike nicorandil, the p.v. dose required to induce a vasodepressor response was significantly greater than that required to cause a comparable response after i.v. administration. In non-recirculating rat liver perfusion experiments, nicorandil was reduced only 5-10% during a single passage through the liver, while nitroglycerin was reduced over 95%. In recirculating liver perfusion experiments, the progressive decrease of nicorandil in the blood recirculated was accompanied by a corresponding increase of SG-86, a dinitrate compound of nicorandil (its main metabolite). Sixty min after dosing, nicorandil was decreased by approximately 73% of the initial nicorandil blood concentration and SG-86 was increased by approximately 70%. The extent of degradation of nicorandil in liver homogenates, examined by thin-layer chromatography, was in the following order: rat = guinea-pig greater than dog = monkey greater than pig. In these species a close inverse relationship is apparent between the rate of liver nicorandil degradation and hypotensive effects of nicorandil.  相似文献   

8.
Although blood pressure effects have been reported for adrenomedullin 5 (AM-5), a newly identified member of the calcitonin gene-related peptide superfamily, little is known about other biological actions. We report the integrated hemodynamic, hormonal, and renal actions of AM-5 (10 and 100 ng·kg·min each for 90 minutes) in normal conscious sheep. AM-5 reduced the mean arterial pressure by 12 mm Hg at the end of the high dose (P < 0.001) in association with dose-dependent increments in the heart rate (40 beats/min--high dose, P < 0.001) and cardiac output (50%-high dose, P < 0.001) and dose-dependent falls in calculated total peripheral resistance (P < 0.001). Plasma renin activity (4-fold increment, P < 0.001), aldosterone (2-fold increment, P = 0.014), and cyclic adenosine monophosphate (50% increment, P < 0.001) all rose in response to high dose AM-5. Urine volume and sodium excretion were unchanged. In conclusion, it is observed that intravenous infusions of AM-5 administered to normal conscious sheep induced significant hemodynamic actions including reduced mean arterial pressure and calculated total peripheral resistance and increased heart rate and cardiac output. Concurrently, AM-5 activated plasma cyclic adenosine monophosphate, plasma renin activity, and aldosterone. These actions are similar to those previously reported for AM and AM-2. Thus, AM-5 may be an another important regulator of volume and pressure homeostasis and may play a role in the pathophysiology of heart disease.  相似文献   

9.
The effects of nicorandil, a new antianginal drug, on size of myocardial infarction were studied in anesthetized, open-chest dogs after left anterior descending coronary artery occlusion. To quantify the extent of the hypoperfused zone, 99mTc-albumin microspheres were injected into the left atrium 1 min after occlusion. Fifteen minutes after occlusion, dogs were randomly assigned to a control group or a nicorandil-treated group that received immediately after assignments 100 micrograms/kg of nicorandil followed by a continuous infusion of 30 micrograms/kg/min for 6 h. Six hours after occlusion, the left ventricle was cut into 3 mm thick slices for triphenyltetrazolium chloride staining and autoradiography. The extent of the hypoperfused zone (26.1% +/- 3.1% of the left ventricle in the control vs. 23.2% +/- 3.7% in the treated group, mean +/- SEM) was not different between the two groups. The ratio of the extent of myocardial necrosis to the extent of the hypoperfused zone was significantly smaller in the treated group (64.3% +/- 7.2%, n = 7, p less than 0.05) than in the control group (92.6% +/- 9.2%, n = 7). Thus, nicorandil administered early after coronary artery occlusion reduced the size of myocardial infarction by 31%.  相似文献   

10.
The cardiac and hemodynamic effects of increasing doses (0.1-3 mg/kg i.v.) of the novel cardiotonic agent, DPI 201-106 (DPI), were investigated over a 60 min period in conscious dogs chronically instrumented for the measurement of arterial pressure, heart rate, left ventricular pressure (LVP), LV (+) dP/dtmax and cardiac output. LV (+) dP/dtmax, cardiac output and stroke volume were significantly increased by DPI whereas the total peripheral resistance was significantly decreased. These effects were dose-dependent in intensity and in duration. The mean arterial pressure and heart rate remained unaffected, except by the 3 mg/kg dose, which increased them slightly. Autonomic blockade with hexamethonium, atropine and propranolol did not alter the positive inotropic properties of DPI but unmasked its intrinsic bradycardic effect. At equipotent positive inotropic doses, DPI (0.3 mg/kg), milrinone (40 micrograms/kg) and dobutamine (5 micrograms/kg per min) induced similar increases in cardiac output and similar decreases in total peripheral resistance, but only dobutamine and milrinone accelerated the heart rate, whereas ouabain (17.5 micrograms/kg) induced a strong rise in the total peripheral resistance and markedly lowered the heart rate and cardiac output. After coadministration of DPI and ouabain, LV (+) dP/dtmax was further increased whereas the ouabain-induced bradycardia, the rise in the total peripheral resistance and the decrease in cardiac output were reinforced, halved and unaltered, respectively. We conclude that (a) DPI exhibits potent and direct positive inotropic properties, associated with a peripheral vasodilating action, and almost no positive chronotropic effects, and (b) coadministration of DPI and ouabain results in synergistic positive inotropic effects.  相似文献   

11.
Hemodynamic effects of labetalol, an alpha- and beta-adrenoceptor blocking drug, were investigated in the conscious dog and in the anesthetized open-chest dog. In the conscious dog, intravenous injection of labetalol, in a dose of 0.5 mg/kg, decreased the total peripheral resistance by approximately 20% (P less than 0.01) in association with falls in blood pressure and heart rate. The total peripheral resistance of the anesthetized open-chest dog was not affected by labetalol in the presence of the same extent of blood pressure fall as results of the conscious dog. In contrast, agents which have beta-adrenoceptor blocking effect alone provided substantial elevation of the total peripheral resistance in the anesthetized dog. These results indicate that the different responses of the resistance to labetalol probably result from the vascular alpha-adrenoceptor blocking action, and also show that in the conscious state alpha-adrenoceptor blocking action of labetalol is enhanced in comparison with the effect in the anesthetized open-chest dog.  相似文献   

12.
The hemodynamic effects of quipazine, a serotonergic agent, were determined in pentobarbital-anesthetized, open-chest dogs administering the drug IV, either by bolus injection or by continuous infusion. Bolus injections of 0.1 and 1 mg/kg elicited transient increases in blood pressure, peripheral resistance, aortic flow, and stroke volume. Administration of 10 mg/kg decreased blood pressure, aortic flow, heart rate, cardiac contractility, and venous pressure, and increased stroke volume. Infusion of quipazine at a rate of 0.5 mg/kg/min for 30 min initially increased blood pressure and peripheral resistance and subsequently produced hypotension and decreased cardiac function. From the beginning of infusion, heart rate and venous pressure decreased, while stroke volume increased. Pretreatment with methysergide antagonized the hypotension and bradycardia, as well as the changes in venous pressure and stroke volume. It was concluded that quipazine elicits complex, dose-related cardiovascular effects, some of which (hypotension, venodilatation, bradycardia) are mediated through methysergide-sensitive central serotonin receptors. The arterial vasoconstriction produced by low doses of the drug was not mediated through these receptors and was probably the result of activation of a cardiogenic reflex.  相似文献   

13.
1. FK336 (10(-6)-10(-4) M) inhibited contractile responses to norepinephrine (NE), KCl and Ca2+ in isolated rabbit aortas. 2. Relaxing effect of FK336 on KCl-response was inhibited by nitroglycerin (NG), but not by nifedipine or verapamil. 3. FK336 inhibited residual NE response and a subsequent Ca2+ response in Ca(2+)-free medium. FK336 did not affect the inositol monophosphate level. 4. Relaxing effect of FK336 on NE response was inhibited by methylene blue, NG, K(+)-channel inhibitors and acetylcholine (ACh), and potentiated by M&B 22,948 and theophylline. 8-Br cGMP and dibutyl cAMP had no effect. 5. FK336 increased cGMP level in rat aorta. 6. Potentiation of isoproterenol-relaxation by FK336 was inhibited by methylene blue. 7. The inhibitory effect of ACh on FK336-relaxation was eliminated by endothelium removal, nordihydroquaiaretic acid and guinacrine, but not by indomethacin. These treatments themselves did not affect FK336-relaxation. 8. The mode of vasorelaxing action of FK336 is discussed.  相似文献   

14.
The aim of this study was to investigate the cellular electrophysiological effects of ranolazine on action potential characteristics. The experiments were carried out in dog and human cardiac preparations using the conventional microelectrode technique. In dog Purkinje fibres ranolazine produced a concentration- and frequency-dependent depression of the maximum rate of depolarization (V(max)) while action potential duration (APD) was shortened. In dog and human right ventricular papillary muscle ranolazine exerted no significant effect on APD, while it produced, like mexiletine, use-dependent depression of V(max) with relatively fast onset and offset kinetics. In dog midmyocardial preparations the drug did not exert statistically significant effect on repolarization at 10 μM, although a tendency toward prolongation was observed at 20 μM. A moderate lengthening of APD(90) by ranolazine was noticed in canine atrial preparations obtained from dogs in sinus rhythm and in tachypacing induced remodelled preparations. Use-dependent depression of V(max) was more pronounced in atria from dogs in sinus rhythm than those in remodelled atria or in the ventricle. These findings indicate that ranolazine, in addition to its known late sodium current blocking effect, also depresses peak I(Na) with class I/B antiarrhythmic characteristics. Although peak I(Na) inhibition by ranolazine is stronger in the atria, it is also substantial (at fast stimulation frequencies) in ventricular preparations. Ranolazine also decreased the dispersion of ventricular repolarization (the difference in APD(90) values between Purkinje fibres and papillary muscles), which can contribute to the antiarrhythmic property of the drug.  相似文献   

15.
新型抗心绞痛药雷诺嗪的合成研究   总被引:4,自引:0,他引:4  
目的 合成新型抗心绞痛药雷诺嗪。方法 以邻甲氧基苯酚、环氧氯丙烷、2,6-二甲基苯胺、哌嗪为原料,采用常规的化学合成法。结果 通过优化条件以较高的收率合成雷诺嗪二盐酸盐。结论 用元素分析、质谱、氢谱、碳谱等鉴定了目标物的结构。优化了反应条件,简化了后处理过程,为进一步工业生产和临床应用打下基础。  相似文献   

16.
The metabolism of denopamine, (R)-(-)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol, a new, orally active, selectively inotropic cardiotonic agent, was studied in the rat and dog. Animals were given single oral doses of 5 mg/kg of denopamine labeled with 14C. Denopamine was metabolized in the rat and dog by several pathways including conjugation, side chain oxidation, and ring hydroxylation followed by O-methylation. Rats excreted the drug in the urine almost entirely as unchanged drug and its phenolic O-glucuronide whereas in the dog, the major metabolites were the phenolic O-glucuronide, the alcoholic O-glucuronide, and the phenolic O-sulfate of denopamine and the phenolic O-glucuronide of 3-methoxydenopamine. Demethylation, which has been shown to be a major metabolic pathway in man, and side chain oxidation were minor pathways in the rat and dog. Furthermore, a high degree of stereoselective resistance of the alcoholic O-glucuronide of denopamine to hydrolysis by beta-glucuronidase was observed.  相似文献   

17.
18.
Nicorandil, nitroglycerin and diltiazem effects on normoxic and anoxic contractile responses to 5-hydroxytryptamine (5-HT) and norepinephrine (NE) were compared in isolated miniature pig coronary artery strips. Anoxia augmented contractile responses of the strips to 5-HT and NE. Nicorandil and nitroglycerin inhibited the normoxic contractile responses to 5-HT and NE and the further contraction induced by subsequently imposed anoxia. Diltiazem inhibited only the responses to 5-HT and to subsequently imposed anoxia. Whereas nicorandil and nitroglycerin produced relaxation of both potassium- and lanthanum-induced contractions, diltiazem was an effective relaxant of the potassium-induced contraction. The present experiments demonstrate that anoxia can augment the contractions of isolated large coronary arteries to 5-HT and NE. Nicorandil as well as nitroglycerin attenuate normoxic and anoxic contractions to 5-HT and NE. This is probably accomplished by inhibition of intracellular Ca2+ mobilization.  相似文献   

19.
目的:对抗心绞痛药雷诺嗪现有合成工艺进行改进.方法:以2,6-二甲基苯胺为起始原料,经过酰化、缩合、环加成、成盐等4步反应合成产品雷诺嗪.结果:产品总收率为51.9%,其化学结构经1H NMR、MS、IR确证,HPLC法检测纯度达到99.2%.结论:该工艺反应条件温和,收率较高,操作简便,易于工业化生产.  相似文献   

20.
雷诺嗪(ranolazine)于2006年1月美国FDA批准上市,用于治疗慢性心绞痛.它是一种脂肪酸部分氧化抑制剂,通过改变葡萄糖和脂肪酸的代谢而发挥作用.临床研究表明,雷诺嗪单独使用或者与其他药物联合应用,可以安全有效地治疗慢性心绞痛.雷诺嗪常见的不良反应是眩晕、头痛、便秘、恶心.文中对雷诺嗪的药理作用、药动学、临床研究、药物相互作用、安全性评价等进行综述.  相似文献   

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