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A model of sustainable atrial fibrillation in the chronic conscious dog
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Abstracts
Results: No statistically significant differences were found between or within event groups (NH, SI or IF) at any time point. The pharmacokinetic profile of cTnI indicated a small volume distribution (76 mL/kg) and a high clearance (224 mL/h/kg) with an elimination half-life of 0.618 h. Conclusion: Our results demonstrate that the routine restraint and anesthesia methods utilized in this study did not affect serum cTnI concentrations. In addition, our data confirm a low level baseline value of circulating cTnI in naive rats. The rapid clearance of cTnI, as shown in the kinetics study, supports increasing the sample density when assaying cTnI following acute cardiac events.
doi:10.1016/j.vascn.2011.03.172
Poster No: 168 Novel model to determine regional blood flow using stable labeled microspheres Dezhi Xing, Huabin Sun, James Hennan, Paul Levesque BMS, Princeton, NJ 08534, USA This study was to validate neutron activation of stable labeled microspheres in an anesthetized rat model (350–450 g) to determine if this is a reliable and facile method of assessing regional blood flow. L-NAME: (15 mg/kg or 30 mg/kg) and sodium nitroprusside (SNP, 10 μg/kg) were used as reference agents. Each agent was administrated intravenously over 5 min. Heart, spleen, and kidneys were removed and dried for analysis. (*p < 0.05 vs predose): In the control group (n = 3), blood flow increased by 11.2% in myocardium and 10% and 13% in left kidney and right kidney (p = NS) after infusion of saline, with no change in mean arterial pressure (MAP) or heart rate. L-NAME (15 mg/kg, n = 3) increased MAP by 16%, reduced heart rate by 5% (p = NS), and reduced blood flow in myocardium by 9% and in left and right kidneys by 36.8% and 37.9% (p = 0.09). L-NAME (30 mg/ kg, n = 3) increased MAP by 25%*, reduced heart rate by 6%, and significantly decreased blood flow by 31%* in myocardium and by 65.1%* and 64.2%* in left and right kidneys. L-NAME (30 mg/kg) also reduced spleen blood flow by 67.9%*. SNP decreased MAP by 29%*, increased heart rate by 4%, significantly increased regional blood flow by 104% in myocardium, and by 48%* and 41%* in left and right kidneys. SNP also increased blood flow in spleen by 91%* (n = 4). This study showed that L-NAME dose-dependently decreased regional blood flow in myocardium, kidneys and spleen. SNP increased the regional blood perfusion to these organs. Neutron activation detection with stable labeled microspheres is a safe and effective way to measure blood flow.
doi:10.1016/j.vascn.2011.03.173
Poster No: 169 A model of sustainable atrial fibrillation in the chronic conscious dog Michael R. Gralinski, Douglas L. Janssen, Hongjian Wang, Melissa D. Fisher, Peter B. Senese
anesthetized dog has demonstrated the development of burst-pacing induced atrial fibrillation following bilateral vagotomy and adrenergic stimulation. Initially, we determined that rapid atrial pacing for at least two weeks was associated with shortening of atrial effective refractory period (AERP) along with inducible periods of short AF. In order to optimize interrogation of multiple test articles for efficacy against AF, we refined the model as outlined below. Male beagle dogs (8–11 kg) were surgically instrumented with telemetry devices to monitor blood pressure, heart rate, and electrocardiogram. During this instrumentation, two sets of bipolar electrodes were placed on the right atrium with externalization of the electrode wires. These electrodes were subsequently used for chronic pacing, determination of atrial effective refractory period, and inducibility to AF. After one week of recovery, atrial pacing was initiated at 400 bpm continuously. Weekly interrogations of AERP, AF inducibility, and duration of AF were conducted until the incidence of successful AF induction reached ≥20% out of 25 consecutive attempts. During the weekly interrogation, AERP progressively decreased by ~ 44% while the incidence of long AF (>30 s in duration) increased from 0% to ~50%. Average duration of the AF episodes increased from <5 s (baseline) to ~ 80 s following at least three weeks of chronic pacing. Hemodynamics remained stable over the period of chronic atrial pacing. In summary, a model of atrial remodeling following chronic high-rate pacing was developed in the conscious dog. This model possesses utility as a paradigm to determine the efficacy of test articles against atrial fibrillation.
doi:10.1016/j.vascn.2011.03.174
Poster No: 170 Interest of telemetry in mice for early safety evaluation of new drugs Eric Delpy, Mathilde Loiseau, Christophe Drieu La Rochelle Biotrial Pharmacology, Non-Clinical Pharmacology Department, Rennes, France Early de-risking strategy between discovery and development process becomes more and more frequent. The use of a small animal model for early evaluation of the effects of new chemical entities on haemodynamic parameters may therefore be useful. The objective of the study was thus to set-up the model of telemetry in mice and to evaluate the effects of various pharmacological agents. Mice were anaesthetized with isoflurane for the initial implantation of a telemetry device (PA-C10, DSI). The catheter of the sensor was inserted into the left carotid artery and the implant placed subcutaneously. Mice were allowed to recover for 2 weeks. High quality arterial blood pressure (ABP) signals were obtained for a long period of time (at least 6 months post-surgery). Nifedipine (1– 100 mg/kg) and nicardipine (10–100 mg/kg) administered orally dose-dependently decreased ABP and induced a concomitant reflexly-mediated tachycardia. In vehicle-treated animals, gavage by itself transiently increased ABP and heart rate (HR). The gavageinduced increase in ABP and HR was partially abolished in animals pre-treated with prazosin (0.1 mg/kg p.o.) and propranolol (10 mg/ kg p.o.), respectively. These results show that the regulation of arterial blood pressure can be investigated using telemetry in mice and that this model could be used for early cardiovascular safety evaluation.
CorDynamics, Chicago, IL, USA The objective of this study was to develop a chronic model of atrial fibrillation (AF) in the conscious dog. Previous work in the
doi:10.1016/j.vascn.2011.03.175
Abstracts
Results: No statistically significant differences were found between or within event groups (NH, SI or IF) at any time point. The pharmacokinetic profile of cTnI indicated a small volume distribution (76 mL/kg) and a high clearance (224 mL/h/kg) with an elimination half-life of 0.618 h. Conclusion: Our results demonstrate that the routine restraint and anesthesia methods utilized in this study did not affect serum cTnI concentrations. In addition, our data confirm a low level baseline value of circulating cTnI in naive rats. The rapid clearance of cTnI, as shown in the kinetics study, supports increasing the sample density when assaying cTnI following acute cardiac events.
doi:10.1016/j.vascn.2011.03.172
Poster No: 168 Novel model to determine regional blood flow using stable labeled microspheres Dezhi Xing, Huabin Sun, James Hennan, Paul Levesque BMS, Princeton, NJ 08534, USA This study was to validate neutron activation of stable labeled microspheres in an anesthetized rat model (350–450 g) to determine if this is a reliable and facile method of assessing regional blood flow. L-NAME: (15 mg/kg or 30 mg/kg) and sodium nitroprusside (SNP, 10 μg/kg) were used as reference agents. Each agent was administrated intravenously over 5 min. Heart, spleen, and kidneys were removed and dried for analysis. (*p < 0.05 vs predose): In the control group (n = 3), blood flow increased by 11.2% in myocardium and 10% and 13% in left kidney and right kidney (p = NS) after infusion of saline, with no change in mean arterial pressure (MAP) or heart rate. L-NAME (15 mg/kg, n = 3) increased MAP by 16%, reduced heart rate by 5% (p = NS), and reduced blood flow in myocardium by 9% and in left and right kidneys by 36.8% and 37.9% (p = 0.09). L-NAME (30 mg/ kg, n = 3) increased MAP by 25%*, reduced heart rate by 6%, and significantly decreased blood flow by 31%* in myocardium and by 65.1%* and 64.2%* in left and right kidneys. L-NAME (30 mg/kg) also reduced spleen blood flow by 67.9%*. SNP decreased MAP by 29%*, increased heart rate by 4%, significantly increased regional blood flow by 104% in myocardium, and by 48%* and 41%* in left and right kidneys. SNP also increased blood flow in spleen by 91%* (n = 4). This study showed that L-NAME dose-dependently decreased regional blood flow in myocardium, kidneys and spleen. SNP increased the regional blood perfusion to these organs. Neutron activation detection with stable labeled microspheres is a safe and effective way to measure blood flow.
doi:10.1016/j.vascn.2011.03.173
Poster No: 169 A model of sustainable atrial fibrillation in the chronic conscious dog Michael R. Gralinski, Douglas L. Janssen, Hongjian Wang, Melissa D. Fisher, Peter B. Senese
anesthetized dog has demonstrated the development of burst-pacing induced atrial fibrillation following bilateral vagotomy and adrenergic stimulation. Initially, we determined that rapid atrial pacing for at least two weeks was associated with shortening of atrial effective refractory period (AERP) along with inducible periods of short AF. In order to optimize interrogation of multiple test articles for efficacy against AF, we refined the model as outlined below. Male beagle dogs (8–11 kg) were surgically instrumented with telemetry devices to monitor blood pressure, heart rate, and electrocardiogram. During this instrumentation, two sets of bipolar electrodes were placed on the right atrium with externalization of the electrode wires. These electrodes were subsequently used for chronic pacing, determination of atrial effective refractory period, and inducibility to AF. After one week of recovery, atrial pacing was initiated at 400 bpm continuously. Weekly interrogations of AERP, AF inducibility, and duration of AF were conducted until the incidence of successful AF induction reached ≥20% out of 25 consecutive attempts. During the weekly interrogation, AERP progressively decreased by ~ 44% while the incidence of long AF (>30 s in duration) increased from 0% to ~50%. Average duration of the AF episodes increased from <5 s (baseline) to ~ 80 s following at least three weeks of chronic pacing. Hemodynamics remained stable over the period of chronic atrial pacing. In summary, a model of atrial remodeling following chronic high-rate pacing was developed in the conscious dog. This model possesses utility as a paradigm to determine the efficacy of test articles against atrial fibrillation.
doi:10.1016/j.vascn.2011.03.174
Poster No: 170 Interest of telemetry in mice for early safety evaluation of new drugs Eric Delpy, Mathilde Loiseau, Christophe Drieu La Rochelle Biotrial Pharmacology, Non-Clinical Pharmacology Department, Rennes, France Early de-risking strategy between discovery and development process becomes more and more frequent. The use of a small animal model for early evaluation of the effects of new chemical entities on haemodynamic parameters may therefore be useful. The objective of the study was thus to set-up the model of telemetry in mice and to evaluate the effects of various pharmacological agents. Mice were anaesthetized with isoflurane for the initial implantation of a telemetry device (PA-C10, DSI). The catheter of the sensor was inserted into the left carotid artery and the implant placed subcutaneously. Mice were allowed to recover for 2 weeks. High quality arterial blood pressure (ABP) signals were obtained for a long period of time (at least 6 months post-surgery). Nifedipine (1– 100 mg/kg) and nicardipine (10–100 mg/kg) administered orally dose-dependently decreased ABP and induced a concomitant reflexly-mediated tachycardia. In vehicle-treated animals, gavage by itself transiently increased ABP and heart rate (HR). The gavageinduced increase in ABP and HR was partially abolished in animals pre-treated with prazosin (0.1 mg/kg p.o.) and propranolol (10 mg/ kg p.o.), respectively. These results show that the regulation of arterial blood pressure can be investigated using telemetry in mice and that this model could be used for early cardiovascular safety evaluation.
CorDynamics, Chicago, IL, USA The objective of this study was to develop a chronic model of atrial fibrillation (AF) in the conscious dog. Previous work in the
doi:10.1016/j.vascn.2011.03.175