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Shigetoshi Chiba - One of the best experts on this subject based on the ideXlab platform.
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effects of verapamil Zatebradine and e 4031 on the pacemaker location and rate in response to sympathetic stimulation in dog hearts
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Yasuyuki Furukawa, Masamichi Hirose, Yusuke Miyashita, Koichi Nakajima, Fumio Kurogouchi, Shigetoshi ChibaAbstract:To investigate whether slow inward Ca2+ current (ICa), hyperpolarization-activated inward current (If), and a rapid type of delayed rectifier K+ current (IKr) similarly act on the pacemaker location, sinoatrial node region, and subsidiary superior and inferior pacemaker regions, we studied the effects of verapamil, Zatebradine, and E-4031 on the atrial rate and the 3-ms earliest activation region (EAR) determined from the isochronal activation sequence map in the autonomically decentralized heart of the anesthetized dog. Three blockers decreased atrial rate similarly. Verapamil shifted the EAR from the SA node region to the inferior pacemaker region. The EAR induced by Zatebradine was variable, but the EAR induced by E-4031 tended to shift to the inferior pacemaker region. Sympathetic nerve stimulation increased atrial rate and shifted the EAR to the superior pacemaker region. Verapamil attenuated the increased atrial rate by 28%, and it shifted the EAR to the lower pacemaker regions consistently. Zatebradine also attenuated the increased rate by 53% and shifted the EAR from the anterior to the posterior-superior right atrium. On the other hand, E-4031 affected neither the rate nor the EAR in response to sympathetic stimulation. These results suggest that ICa, If, and IKr inhibitors differentially influence the pacemaker activity among three pacemaker regions when sympathetic tone is absent or present and that the role of ICa, If, and IKr of the pacemaker cells distributed in the atrial pacemaker complex is different in the dog heart in situ.
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effects of low temperature on the chronotropic and inotropic responses to Zatebradine e 4031 and verapamil in isolated perfused dog atria
Japanese Journal of Pharmacology, 1998Co-Authors: Miho Kasama, Yasuyuki Furukawa, Takeshi Oguchi, Yuji Hoyano, Shigetoshi ChibaAbstract:: We investigated the effects of hypothermia (25 degrees C) on the chronotropic and inotropic effects of Zatebradine (a blocker of hyperpolarization-activated inward current, I(f)), E-4031 (a blocker of the rapid type of the delayed rectifier K+ current, I(Kr)) and verapamil, and on the positive cardiac responses to isoproterenol after treatment with Zatebradine and E-4031 in isolated, blood-perfused dog atria. Hypothermia shifted the dose-response curves to the right for the negative chronotropic and inotropic effects of verapamil and for the negative chronotropic and positive inotropic effects of Zatebradine, but not for the negative chronotropic and positive inotropic effects of E-4031. Hypothermia attenuated the positive chronotropic response to isoproterenol or Bay k 8644 (an L type Ca2+ channel agonist) and was attenuated more than the inotropic one. Zatebradine selectively inhibited the positive chronotropic response to isoproterenol at a normal temperature, but in hypothermia, it inhibited neither the chronotropic nor inotropic responses. E-4031 did not affect the positive responses to isoproterenol. These results suggest that verapamil and Zatebradine but not E-4031 influence the atrial rate and contractile force much less in hypothermia than in normothermia and that the I(f) and inward Ca2+ current are sensitive to hypothermia in the heart.
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Zatebradine inhibits tachycardia induced by bronchodilators without affecting respiratory resistance in dogs
European Journal of Pharmacology, 1997Co-Authors: Kyouhei Yamazaki, Yasuyuki Furukawa, Masamichi Hirose, Shigetoshi ChibaAbstract:Abstract Bronchodilators used for bronchial asthma reduce respiratory resistance but also increase heart rate to some extent. It is often difficult to use such bronchodilators with elderly patients and patients with heart disease. The object of our study was to investigate whether a specific bradycardic agent, Zatebradine, inhibited the heart rate increased by bronchodilators without affecting respiratory resistance. We evaluated the effects of Zatebradine on the increases in heart rate and inhibition of the respiratory resistance in response to the bronchodilators, isoproterenol, procaterol (a β 2 -adrenoceptor agonist), 6-(3-dimethylaminopropionyl)-forskolin, NKH 477 (an adenylyl cyclase activator) and aminophylline in the anesthetized and artificially ventilated dog. When Zatebradine in doses of 0.05–1.5 mg/kg i.v. decreased heart rate without affecting arterial blood pressure, it dose dependently attenuated the increase in heart rate in response to isoproterenol, procaterol, NKH 477 and aminophylline but did not affect the inhibition by these substances of the increase in respiratory resistance induced by histamine. Propranolol (0.01–0.3 mg/kg i.v.) dose dependently inhibited not only the increase in heart rate but also the inhibition of the respiratory resistance induced by isoproterenol and procaterol. The present results indicate that Zatebradine selectively inhibits the increase in heart rate in response to cyclic AMP-dependent bronchodilators without affecting their bronchodilator effects in anesthetized dogs and suggest that Zatebradine may be a useful drug for prevention of the tachycardia induced by bronchodilators used for patients with bronchial asthma.
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effects of Zatebradine on ouabain two stage coronary ligation and epinephrine induced ventricular tachyarrhythmias
European Journal of Pharmacology, 1996Co-Authors: Yasuyuki Furukawa, Shigetoshi Chiba, Keitaro HashimotoAbstract:To determine whether a hyperpolarization-activated current (If) participates in ventricular tachyarrhythmias, we investigated the effects of Zatebradine, an If inhibitor, on the ventricular tachyarrhythmias induced by ouabain, two-stage coronary ligation and epinephrine infusion in the dog heart. We determined atrial rate, ectopic ventricular rate, total heart rate and arrhythmic ratio (the number of ectopic ventricular beats divided by total heart beats). Zatebradine (0.15, 0.5 and 1.5 mg/kg, i.v.) dose dependently decreased the arrhythmic ratio, ectopic ventricular rate and atrial rate of the ouabain-induced ventricular tachyarrhythmias in pentobarbital-anesthetized dogs. The inhibition by Zatebradine of the ventricular arrhythmias needed larger doses than the inhibition of the atrial rate. Zatebradine weakly depressed the ectopic ventricular rate but not the arrhythmic ratio of the ventricular arrhythmias induced by two-stage coronary ligation 24 h after the ligation in conscious dogs. Although neither the ectopic ventricular rate nor the arrhythmic ratio of the epinephrine-induced ventricular arrhythmias was affected by Zatebradine, after treatment with Zatebradine, the arrhythmias elicited by epinephrine developed more slowly. Together with the previously reported spectra of the effects of the antiarrhythmic agents in three ventricular tachyarrhythmia models, our results suggest that Zatebradine may improve automaticity-related ventricular tachyarrhythmias due to If inhibition or to other undetermined mechanisms in the heart.
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Negative chronotropic and dromotropic effects of E-4031, an IKr blocker, on the atrioventricular node in anesthetized dog hearts.
European Journal of Pharmacology, 1996Co-Authors: Kyouhei Yamazaki, Yasuyuki Furukawa, Miho Kasama, Hiroshi Imamura, Shigetoshi ChibaAbstract:Abstract To investigate the effect of the delayed rectifier K+ current (IK) on the atrioventricular (AV) node of the heart in situ, we studied the direct effects of (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(methylsulfonyl-aminobenzoyl)piperidine (E-4031), an IKr (a rapid type of IK blocker, on the AV junctional rate, atrio-His interval (AH interval), and right ventricular pressure, and the cardiac responses to sympathetic nerve stimulation in the anesthetized dog heart. AV junctional rhythm was induced by clamping the sinoatrial (SA) pacemaker area. E-4031 (0.01–3 μmol/kg, i.v.) attenuated the AV junctional rate dose dependently. The junctional negative chronotropic effect was less than the decrease in sinus rate induced by E-4031 in the same doses. E-4031 did not affect the junctional rate increased by sympathetic stimulation. In the paced heart, E-4031 slightly increased the AH interval but did not change right ventricular pressure responses. E-4031 attenuated neither positive dromotropic nor positive ventricular pressure responses to sympathetic stimulation. After E-4031 treatment, Zatebradine (a hyperpolarization-activated current blocker) additively decreased the junctional rate and the junctional positive chronotropic responses to sympathetic stimulation. These results suggest that IKr has much less effect on AV nodal pacemaker activity than on SA nodal pacemaker activity, and an IKr blocker, E-4031, unlike Zatebradine, does not antagonize the junctional positive chronotropic responses to sympathetic activation in anesthetized dog heart.
Yasuyuki Furukawa - One of the best experts on this subject based on the ideXlab platform.
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effects of Zatebradine and propranolol on canine ischemia and reperfusion induced arrhythmias
European Journal of Pharmacology, 2000Co-Authors: Hisaya Naito, Yasuyuki Furukawa, Daisuke Chino, Chikaomi Yamada, Keitaro HashimotoAbstract:Abstract 1,3,4,5-Tetrahydro-7,8-dimethoxy-3[3-[[2-(3,4-dimethoxyphenyl)-ethyl]methylamino]propyl]-2 H -3-benzazepin-2-one-hydrochloride (Zatebradine) is a specific bradycardiac agent, blocking the hyperpolarization-activated pacemaker current ( I f ), and thus has no negative inotropic effect. The purpose of this study was to examine whether Zatebradine is effective against ischemia and reperfusion-induced arrhythmias in dogs compared to propranolol. Arrhythmia was induced by ligation of the left anterior descending coronary artery followed by reperfusion. Ischemia-induced biphasic arrhythmias were suppressed in both Zatebradine and propranolol groups. During ischemia, fatal ventricular fibrillation occurred in four dogs in the control group, 0 in the Zatebradine group, and two dogs in the propranolol group. Of the 31 dogs subjected to reperfusion, mortality rates in the Zatebradine, propranolol, and control groups were 56%, 75%, and 86%, respectively, and there were no significant differences. In the heart beating 10 beats/min faster than the predrug heart rate by atrial pacing, both Zatebradine and propranolol attenuated ischemia-induced arrhythmias but did not affect reperfusion arrhythmias. Our results suggest that I f and/or β-adrenoceptors rather than the bradycardiac action might be related to the antiarrhythmic effects during ischemia, but that they do not play a role in the generation of the reperfusion-induced ventricular arrhythmias.
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effects of verapamil Zatebradine and e 4031 on the pacemaker location and rate in response to sympathetic stimulation in dog hearts
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Yasuyuki Furukawa, Masamichi Hirose, Yusuke Miyashita, Koichi Nakajima, Fumio Kurogouchi, Shigetoshi ChibaAbstract:To investigate whether slow inward Ca2+ current (ICa), hyperpolarization-activated inward current (If), and a rapid type of delayed rectifier K+ current (IKr) similarly act on the pacemaker location, sinoatrial node region, and subsidiary superior and inferior pacemaker regions, we studied the effects of verapamil, Zatebradine, and E-4031 on the atrial rate and the 3-ms earliest activation region (EAR) determined from the isochronal activation sequence map in the autonomically decentralized heart of the anesthetized dog. Three blockers decreased atrial rate similarly. Verapamil shifted the EAR from the SA node region to the inferior pacemaker region. The EAR induced by Zatebradine was variable, but the EAR induced by E-4031 tended to shift to the inferior pacemaker region. Sympathetic nerve stimulation increased atrial rate and shifted the EAR to the superior pacemaker region. Verapamil attenuated the increased atrial rate by 28%, and it shifted the EAR to the lower pacemaker regions consistently. Zatebradine also attenuated the increased rate by 53% and shifted the EAR from the anterior to the posterior-superior right atrium. On the other hand, E-4031 affected neither the rate nor the EAR in response to sympathetic stimulation. These results suggest that ICa, If, and IKr inhibitors differentially influence the pacemaker activity among three pacemaker regions when sympathetic tone is absent or present and that the role of ICa, If, and IKr of the pacemaker cells distributed in the atrial pacemaker complex is different in the dog heart in situ.
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effects of low temperature on the chronotropic and inotropic responses to Zatebradine e 4031 and verapamil in isolated perfused dog atria
Japanese Journal of Pharmacology, 1998Co-Authors: Miho Kasama, Yasuyuki Furukawa, Takeshi Oguchi, Yuji Hoyano, Shigetoshi ChibaAbstract:: We investigated the effects of hypothermia (25 degrees C) on the chronotropic and inotropic effects of Zatebradine (a blocker of hyperpolarization-activated inward current, I(f)), E-4031 (a blocker of the rapid type of the delayed rectifier K+ current, I(Kr)) and verapamil, and on the positive cardiac responses to isoproterenol after treatment with Zatebradine and E-4031 in isolated, blood-perfused dog atria. Hypothermia shifted the dose-response curves to the right for the negative chronotropic and inotropic effects of verapamil and for the negative chronotropic and positive inotropic effects of Zatebradine, but not for the negative chronotropic and positive inotropic effects of E-4031. Hypothermia attenuated the positive chronotropic response to isoproterenol or Bay k 8644 (an L type Ca2+ channel agonist) and was attenuated more than the inotropic one. Zatebradine selectively inhibited the positive chronotropic response to isoproterenol at a normal temperature, but in hypothermia, it inhibited neither the chronotropic nor inotropic responses. E-4031 did not affect the positive responses to isoproterenol. These results suggest that verapamil and Zatebradine but not E-4031 influence the atrial rate and contractile force much less in hypothermia than in normothermia and that the I(f) and inward Ca2+ current are sensitive to hypothermia in the heart.
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Zatebradine inhibits tachycardia induced by bronchodilators without affecting respiratory resistance in dogs
European Journal of Pharmacology, 1997Co-Authors: Kyouhei Yamazaki, Yasuyuki Furukawa, Masamichi Hirose, Shigetoshi ChibaAbstract:Abstract Bronchodilators used for bronchial asthma reduce respiratory resistance but also increase heart rate to some extent. It is often difficult to use such bronchodilators with elderly patients and patients with heart disease. The object of our study was to investigate whether a specific bradycardic agent, Zatebradine, inhibited the heart rate increased by bronchodilators without affecting respiratory resistance. We evaluated the effects of Zatebradine on the increases in heart rate and inhibition of the respiratory resistance in response to the bronchodilators, isoproterenol, procaterol (a β 2 -adrenoceptor agonist), 6-(3-dimethylaminopropionyl)-forskolin, NKH 477 (an adenylyl cyclase activator) and aminophylline in the anesthetized and artificially ventilated dog. When Zatebradine in doses of 0.05–1.5 mg/kg i.v. decreased heart rate without affecting arterial blood pressure, it dose dependently attenuated the increase in heart rate in response to isoproterenol, procaterol, NKH 477 and aminophylline but did not affect the inhibition by these substances of the increase in respiratory resistance induced by histamine. Propranolol (0.01–0.3 mg/kg i.v.) dose dependently inhibited not only the increase in heart rate but also the inhibition of the respiratory resistance induced by isoproterenol and procaterol. The present results indicate that Zatebradine selectively inhibits the increase in heart rate in response to cyclic AMP-dependent bronchodilators without affecting their bronchodilator effects in anesthetized dogs and suggest that Zatebradine may be a useful drug for prevention of the tachycardia induced by bronchodilators used for patients with bronchial asthma.
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effects of Zatebradine on ouabain two stage coronary ligation and epinephrine induced ventricular tachyarrhythmias
European Journal of Pharmacology, 1996Co-Authors: Yasuyuki Furukawa, Shigetoshi Chiba, Keitaro HashimotoAbstract:To determine whether a hyperpolarization-activated current (If) participates in ventricular tachyarrhythmias, we investigated the effects of Zatebradine, an If inhibitor, on the ventricular tachyarrhythmias induced by ouabain, two-stage coronary ligation and epinephrine infusion in the dog heart. We determined atrial rate, ectopic ventricular rate, total heart rate and arrhythmic ratio (the number of ectopic ventricular beats divided by total heart beats). Zatebradine (0.15, 0.5 and 1.5 mg/kg, i.v.) dose dependently decreased the arrhythmic ratio, ectopic ventricular rate and atrial rate of the ouabain-induced ventricular tachyarrhythmias in pentobarbital-anesthetized dogs. The inhibition by Zatebradine of the ventricular arrhythmias needed larger doses than the inhibition of the atrial rate. Zatebradine weakly depressed the ectopic ventricular rate but not the arrhythmic ratio of the ventricular arrhythmias induced by two-stage coronary ligation 24 h after the ligation in conscious dogs. Although neither the ectopic ventricular rate nor the arrhythmic ratio of the epinephrine-induced ventricular arrhythmias was affected by Zatebradine, after treatment with Zatebradine, the arrhythmias elicited by epinephrine developed more slowly. Together with the previously reported spectra of the effects of the antiarrhythmic agents in three ventricular tachyarrhythmia models, our results suggest that Zatebradine may improve automaticity-related ventricular tachyarrhythmias due to If inhibition or to other undetermined mechanisms in the heart.
Wolfgang Kübler - One of the best experts on this subject based on the ideXlab platform.
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Electropharmacology of the bradycardic agents alinidine and Zatebradine (UL-FS 49) in a conscious canine ventricular arrhythmia model of permanent coronary artery occlusion
Cardiovascular Drugs and Therapy, 1995Co-Authors: I. Aidonidis, Johannes Brachmann, I. Rizos, A. Zacharoulis, I. Stavridis, Pavlos Toutouzas, Wolfgang KüblerAbstract:Myocardial infarction was produced in 27 anesthetized dogs by ligating the left anterior descending (LAD) coronary artery proximal to the septal branch. Nineteen of these animals survived the operation and were studied by programmed stimulation in a random sequence between the third and seventh days after the infarct. Complete electrophysiologic testing was implemented in each animal prior to and after single doses of either alinidine (1 mg/kg IV) or Zatebradine (0.5 mg/kg IV). Alinidine prevented reinduction of sustained ventricular tachycardia (SVT) in only 2 of 9 dogs and Zatebradine in 1 of 8 dogs. The SVT cycle length was not significantly changed in all cases in which it was still inducible despite drug administration (p>0.05). Alinidine lengthened the effective refractory period (ERP) in the AV node (p
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electropharmacology of the bradycardic agents alinidine and Zatebradine ul fs 49 in a conscious canine ventricular arrhythmia model of permanent coronary artery occlusion
Cardiovascular Drugs and Therapy, 1995Co-Authors: I. Aidonidis, Johannes Brachmann, I. Rizos, A. Zacharoulis, I. Stavridis, Pavlos Toutouzas, Wolfgang KüblerAbstract:Myocardial infarction was produced in 27 anesthetized dogs by ligating the left anterior descending (LAD) coronary artery proximal to the septal branch. Nineteen of these animals survived the operation and were studied by programmed stimulation in a random sequence between the third and seventh days after the infarct. Complete electrophysiologic testing was implemented in each animal prior to and after single doses of either alinidine (1 mg/kg IV) or Zatebradine (0.5 mg/kg IV). Alinidine prevented reinduction of sustained ventricular tachycardia (SVT) in only 2 of 9 dogs and Zatebradine in 1 of 8 dogs. The SVT cycle length was not significantly changed in all cases in which it was still inducible despite drug administration (p>0.05). Alinidine lengthened the effective refractory period (ERP) in the AV node (p<0.01), whereas Zatebradine did not induce a statistically significant prolongation. Conversely, Zatebradine increased the left ventricular ERP, while alinidine left it almost unchanged. The rate-corrected QT interval (QTc) did not significantly differ from control values after the administration of either agents. Also, the duration and the ERP of infarctzone potentials, defined as late potentials, remained unaltered. The results indicate that the bradycardic agents alinidine and Zatebradine do not exert antiarrhythmic efficacy against SVT induced during subacute myocardial infarction in conscious dogs. None of these drugs substantially changed ventricular electrophysiology or showed a drug-specific proarrhythmic effect.
David C Warltier - One of the best experts on this subject based on the ideXlab platform.
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increases in inotropic state without change in heart rate combined use of dobutamine and Zatebradine in conscious dogs
European Journal of Pharmacology, 1996Co-Authors: Douglas A Hettrick, Paul S Pagel, Dermot Lowe, John P Tessmer, David C WarltierAbstract:The cardiovascular and left ventricular functional effects of dobutamine (5, 10 and 20 μg kg−1 min−1) were examined in conscious, chronically instrumented dogs in the presence and absence of control of heart rate with the specific bradycardic agent, Zatebradine. Dobutamine increased heart rate, cardiac output, stroke volume, diastolic coronary blood flow velocity and pressure-work index (calculated myocardial oxygen consumption) and decreased systemic vascular resistance and diastolic coronary vascular resistance. Mean arterial pressure and left ventricular systolic and end-diastolic pressures were unchanged. Dobutamine-induced increases in heart rate and pressure-work index were attenuated by Zatebradine. Dobutamine alone increased preload recruitable stroke work slope (63 ± 6 to 116 ± 11 mmHg) and +dPdt. These positive inotropic effects were unaffected by Zatebradine. Dobutamine decreased the time constant of isovolumic relaxation (30 ± 3 to 25 ± 2 ms). Dobutamine-induced decreases in the time constant of isovolumic relaxation were not altered by Zatebradine, indicating that changes in the time constant occurred independent of heart rate. Dobutamine also increased the maximal segment lengthening velocity to a similar degree in Zatebradine-treated versus untreated dogs. Control of dobutamine-induced tachycardia by Zatebradine decreases myocardial oxygen consumption but does not alter the positive inotropic and lusitropic effects of dobutamine.
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Zatebradine a specific bradycardic agent alters the hemodynamic and left ventricular mechanical actions of levosimendan a new myofilament calcium sensitizer in conscious dogs
Journal of Pharmacology and Experimental Therapeutics, 1995Co-Authors: Paul S Pagel, Douglas A Hettrick, Christopher P Harkin, David C WarltierAbstract:The cardiovascular and left ventricular (LV) functional effects of levosimendan were examined (LSM; 0.5, 1.0, 2.0 and 4.0 micrograms.kg-1.min-1) in conscious, chronically instrumented dogs (n = 8) in the presence and absence of heart rate control with Zatebradine (ZAT) or ZAT alone (0.25, 0.5 and 1.0 mg.kg-1). LSM increased heart rate (HR) cardiac output (CO), diastolic coronary blood flow velocity (DCBFV) and pressure-work index (PWI; calculated myocardial oxygen consumption) and decreased mean arterial, LV systolic and end-diastolic pressures, systemic vascular resistance and diastolic coronary vascular resistance (DCVR). ZAT alone decreased HR and PWI and increased stroke volume. LSM-induced increases in HR and PWI were attenuated by ZAT. Increases in DCBFV and decreases in DCVR occurred without changes in PWI in the presence of ZAT. LSM increased preload recruitable stroke work slope (Mw, 68 +/- 6 to 159 +/- 13 mm Hg) and +dP/dt. These positive inotropic effects were partially attenuated by ZAT. LSM alone decreased the time constant of isovolumic relaxation (tau, 36 +/- 2 to 29 +/- 2 ms). LSM-induced decreases in tau were blunted by ZAT, indicating that changes in tau were partially dependent on heart rate. LSM increased the maximal rate of segment lengthening to a similar degree in ZAT-treated versus -untreated dogs. ZAT alone had minimal effects on LV function. Control of LSM-induced tachycardia with ZAT decreases myocardial oxygen consumption but also partially attenuates the positive inotropic and lusitropic effects of LSM.
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Zatebradine a specific bradycardic agent enhances the positive inotropic actions of dobutamine in ischemic myocardium
Journal of the American College of Cardiology, 1994Co-Authors: John C Wynsen, Patrick D Obrien, David C WarltierAbstract:Abstract Objectives . This investigation determined whether attenuation of the tachycardia produced by dobutamine administration would improve perfusion and function distal to a severe coronary artery stenosis. Background . Tachycardia adversely affects perfusion and function distal to a coronary artery stenosis. It is not known whether a specific bradycardic agent can improve blood flow and function in an ischemic zone during administration of dobutamine. Methods . The effects of dobutamine (2, 5 and 10 μg/kg body weight per min) alone and in combination with Zatebradine (0.5 mg/kg), a specific bradycardic agent, on hemodynamic status, segment shortening (ultrasound length transducers) and myocardial perfusion (microspheres) were studied in anesthetized dogs with severe left circumflex coronary artery stenosis. Results . A 50% reduction in left circumflex coronary artery blood flow (58 ± 4 to 29 ± 2 ml/min [mean value ± SEM]) produced a decrease in systolic shortening in the ischemic zone. Only a dose of dobutamine that did not elevate heart rate (2 μg/kg per min) produced an increase in segment shortening in the ischemic zone. High doses of dobutamine (10 μ/kg per min) caused an increase in heart rate without improvement in function and a reduction in the subendocardial/subepicardial flow ratio (0.74 ± 0.06 to 0.48 ± 0.05). Zatebradine administered in the presence of dobutamine caused a decrease in heart rate, an increase in subendocardial/subepicardial blood flow ratio (0.48 ± 0.05 to 0.78 ± 0.09) and allowed an increase in ischemic zone segment shortening. When normalized for changes in heart rate, ischemic zone subendocardial flow increased by 123 ± 41% (0.39 ± 0.09 to 0.71 ± 0.12 ml/100 g per beat). Atrial pacing abolished the effects of Zatebradine. Conclusions . The present data suggest that the perfusion-contraction matching that accompanies a decrease in heart rate results in enhancement of inotropic stimulation of an ischemic zone. The actions of Zatebradine are related to an increase in subendocardial blood flow per beat that allows improvement of regional contractile function.
Pieter D. Verdouw - One of the best experts on this subject based on the ideXlab platform.
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The selective bradycardic effects of Zatebradine (UL-FS 49) do not adversely affect left ventricular function in conscious pigs with chronic coronary artery occlusion
Cardiovascular Drugs and Therapy, 1992Co-Authors: Leon J. Woerkens, Willem J. Giessen, Pieter D. VerdouwAbstract:This study was designed to test whether the selective bradycardic effects of Zatebradine (UL-FS 49) were altered in the setting of chronic mild left ventricular dysfunction secondary to a myocardial infarction. We therefore administered four doses of UL-FS 49 at 15-min intervals (cumulative doses of 10, 30, 100, and 300 μg/kg) to eight normal conscious pigs and to seven pigs in which the left circumflex coronary artery was occluded 3 weeks previously. Left ventricular dysfunction in this second group of animals was manifested by an increase in left ventricular end-diastolic pressure (LVEDP 11±2 mmHg vs. 7±1 mmHg, respectively; p
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the selective bradycardic effects of Zatebradine ul fs 49 do not adversely affect left ventricular function in conscious pigs with chronic coronary artery occlusion
Cardiovascular Drugs and Therapy, 1992Co-Authors: Leon J. Woerkens, Willem J. Giessen, Pieter D. VerdouwAbstract:This study was designed to test whether the selective bradycardic effects of Zatebradine (UL-FS 49) were altered in the setting of chronic mild left ventricular dysfunction secondary to a myocardial infarction. We therefore administered four doses of UL-FS 49 at 15-min intervals (cumulative doses of 10, 30, 100, and 300 μg/kg) to eight normal conscious pigs and to seven pigs in which the left circumflex coronary artery was occluded 3 weeks previously. Left ventricular dysfunction in this second group of animals was manifested by an increase in left ventricular end-diastolic pressure (LVEDP 11±2 mmHg vs. 7±1 mmHg, respectively; p<0.05) and a decrease in LVdP/dtmax (3020±210 mmHg vs. 3720±210 mmHg, respectively; p<0.05). The results showed that UL-FS 49 was equally effective in reducing heart rate in both groups of animals [from 126±4 to 95±2 beats/min and from 140±5 to 98±6 beats/min for the normal animals and for the animals with a chronic myocardial infarction (MI), respectively]. The duration of left ventricular systole was not affected, but the duration of diastole was prolonged from 290±10 msec to 420±20 msec in the normal animals and from 250±10 msec to 430±30 msec in the animals with MI (both p<0.05). Up to 100 μg/kg UL-FS 49 did not affect arterial blood pressure, whereas LVdP/dtmax and cardiac output decreased by less than 10% in either group. With the highest dose there were decreases in cardiac output (20%) and LVdP/dtmax (15%) and a 5–6 mmHg increase in left ventricular end-diastolic pressure in both groups. The data suggest that UL-FS 49 in doses up to 100 μg/kg may also, in the setting of chronic mild left ventricular dysfunction, be an attractive agent when heart rate has to be reduced selectively.
