Biomedical subjects

S W Mittelstadt

Publications and source records attributed to S W Mittelstadt.

18 recordsLinked to original sources

PubMed2006

Age-dependent effects on cisapride-induced QTc prolongation in the isolated guinea pig heart.

INTRODUCTION: The isolated guinea pig heart preparation has been suggested as a suitable small animal model for investigating potential for QTc prolongation. The purpose of this study was to investigate the effect of age on electrophysiological parameters measured in the isolated guinea pig heart preparation. In addition, the effect of a compound known to prolong the QT interval (cisapride) was investigated in both young and adult guinea pigs. METHODS: Male guinea pigs were divided into 2 groups (n=6). One group of guinea pigs was between 3 and 4 weeks old (young) and the other group was between 16 and 17 weeks old (adult). Concentrations (0, 1, 5, and 50 ng/mL; 2, 11, and 110 nM) of cisapride were perfused for 15 min from low to high concentration. Measurements of PR, QRS, RR and QT intervals were typically made on 5 consecutive electrocardiogram complexes during the last minute of each concentration. The QT interval was corrected for changes in heart rate using the cube root formula of Fridericia (QTcF). RESULTS: Adult guinea pigs had significantly longer RR and QTcF intervals when compared to young animals. Cisapride prolonged QTcF in both young and adult animals at the same concentrations (5 ng/mL and 50 ng/mL). The maximal change in QTcF at 50 ng/mL was similar in young (44+/-3 ms) and adult animals (40+/-1 ms). DISCUSSION: In summary, the present study demonstrated that there was an increase in the RR and QTcF intervals with age in isolated guinea pig hearts. However, this age difference does not appear to impact the sensitivity of the assay to drug-induced QTcF prolongation.

Aging↗

PubMed2005

Effects of moxifloxacin on QT interval in conscious dogs.

Moxifloxacin has been shown to induce QT prolongation in both clinical and preclinical models. However, the ability to observe this effect at clinically relevant concentration in normal conscious dogs has not been reported. The purpose of this study was to investigate the effects of moxifloxacin on the QT interval in conscious, healthy dogs. Four male mongrel dogs were chronically instrumented for the measurement of arterial blood pressure, left ventricular blood pressure, cardiac output, electrocardiograms (ECGs), and body temperature. Animals were administered a 1-h i.v. infusion of moxifloxacin once per day via a catheter in the cephalic vein. Each dog received all doses (0, 1, 10, 25 and 50 mg/kg) in an escalating fashion. Moxifloxacin caused a statistically significant increase in arterial blood pressure at 50 mg/kg. A dose-response effect on QT and QTc prolongation was observed. A statistically significant prolongation in the QT interval was observed at 10, 25 and 50 mg/kg and a prolongation of QTc was observed at 25 and 50 mg/kg. These effects occurred at clinically relevant plasma concentrations. This study demonstrate that a study design with four dogs was sensitive enough to measure moxifloxacin-induced QT prolongation at clinically relevant plasma concentrations.

Animals↗

PubMed1998

Physiological effects of technique and rolling resistance in uphill roller skiing.

OBJECTIVE: The double pole technique (DP) has been shown to be more economical than the V1 skate technique (V1 ) on flat terrain. The objective of the present study was to compare these two techniques during uphill roller skiing. In addition, the physiological effects of changing roller ski rolling resistance was examined for V1. METHODS: Five female and five male competitive cross-country skiers roller skied 4-min bouts on a 5.2% incline while physiological measurements were made. RESULTS: Oxygen uptake (VO2) values averaged 8% greater (P = 0.0004) with V1, whereas rating of perceived exertion (RPE) and blood lactate concentrations were higher (P < or = 0.002) with DP. Doubling the dynamic friction coefficient of the roller skis, which increased external power output by 16-17%, resulted in VO2 values with V1 that averaged 13% higher (P = 0.0006). This magnitude of change in roller ski rolling resistance did not cause a statistical change in the relationship of VO2 with RPE. CONCLUSIONS: These findings suggest that 1) grade has little effect on relative economies of DP and V1, possibly because of a lower effectiveness of force application with V1 when going uphill, and 2) large differences in roller ski rolling resistance should have no effect on the cardiovascular training adaptations that result from uphill roller skiing with V1.

Adult↗

PubMed1997

Effects of azimilide and d,l-sotalol on the heart rate and blood pressure response to isoproterenol in anesthetized rats.

The novel class III antiarrhythmic agent, azimilide, provides antifibrillatory protection in a rat model of ischemia-reperfusion arrhythmias. In other species azimilide's antifibrillatory mechanism is thought to be mediated predominantly through blockade of both the rapid and slow components of the delayed rectifier potassium current in ventricular myocytes. However, the delayed rectifier potassium current does not appear to control cardiac repolarization in the rat. One possible mechanism for antiarrhythmic efficacy in rats is the compound's beta-adrenergic blocking effect, previously seen in isolated guinea pig hearts. The purpose of this study was to evaluate the beta-adrenergic antagonistic effect of azimilide in the rat. Beta-adrenergic blockade was evaluated in the intact anesthetized rat by studying the effects of intravenous azimilide (at or above the antifibrillatory dose) and d,l-sotalol (a known beta-adrenergic antagonist) on heart rate and blood pressure responses to isoproterenol (0.14 Mg/kg i.v.). d,l-Sotalol (6.0 mg/kg) reduced (p < 0.05) the tachycardic response to isoproterenol from 133 +/- 11 to 80 +/- 10 beats/min, and 3.0 mg/kg of d,l-sotalol reduced the hypotensive response from -74 +/- 4 to -43 +/- 5 mmHg. Azimilide (5.0, 10.0, and 20.0 mg/kg) did not have a statistically significant effect on either the heart rate or blood pressure changes caused by isoproterenol. These data demonstrate that azimilide does not have a beta-adrenergic antagonist effect in the rat at antifibrillatory doses. Therefore, the antiarrhythmic effect of azimilide in the rat is mediated through a mechanism other than beta-blockade.

Adrenergic beta-Antagonists↗

PubMed1996

Perceived exertion and blood lactate concentration during graded treadmill running.

The purpose of this study was to investigate the influences of treadmill gradients on the rating of perceived exertion (RPE) at two fixed blood lactate concentrations ([La-]b). Ten subjects performed three different incremental treadmill protocols by running either uphill (concentrically-biased), downhill (eccentrically-biased), or on the flat (non-biased). Individual data of each protocol were interpolated to reflect [La-]b corresponding to 2.0 and 4.0 mmol.l-1. At 2.0 mmol.l-1 [La-]b, RPE and treadmill speed during downhill running were greater than during level running which was greater than during uphill running (p < 0.05). Also, the downhill heart rate (HR) was greater than the uphill HR, and downhill minute ventilation (VE) was greater than the level VE. Treadmill speed was the only measure at 4.0 mmol.l-1 [La-]b to differ between gradients. There was a moderate correlation of RPE with HR at both [La-]b (r = 0.73 at 2.0 mmol.l-1; r = 0.48 at 4.0 mmol.l-1) while treadmill speed was moderately correlated with RPE only at 2.0 mmol.l-1 [La-]b (r = 0.70). The results of this study demonstrated that the degree of eccentric-bias during running exercise is an influence of perceived exertion at a moderate but not at a high exercise intensity.

Adult↗

PubMed1996

Muscle chemoreflex causes renal vascular constriction.

The purpose of this study was to investigate the effects of the muscle chemoreflex on vascular conductance in innervated and denervated kidneys. During each experiment, six dogs ran at 10 km/h for 8-16 min, and the muscle chemoreflex was stimulated by reducing hindlimb blood flow (HLBF) (0%-74%) at 4-min intervals. Small reductions in HLBF did not cause changes in arterial blood pressure or renal vascular conductance. However, further reductions of HLBF caused increases in arterial blood pressure and decreases in renal vascular conductance. Decreases in renal vascular conductance occurred in the denervated kidneys when the HLBF was reduced below 1,500 +/- 215 ml/min and occurred in the innervated kidneys when HLBF was reduced below 1,402 +/- 161 ml/min. There was not a significant difference between the reductions in HLBF required to cause a decrease in vascular conductance in the innervated and denervated kidneys. These results demonstrate that reductions in HLBF cause decreases in renal vascular conductance, which are not dependent on renal sympathetic nerve activity.

Animals↗

PubMed1995

Delta efficiency of uphill roller skiing with the double pole and diagonal stride techniques.

Delta efficiencies for uphill roller skiing with the double pole (DP) and diagonal stride (DS) techniques were determined among 4 female and 4 male cross-country ski racers in order to examine for differences between techniques and between the sexes. Each skier roller-skied on a motorized ski-treadmill at 1.7% and 7.1% grades with both techniques at 2 to 4 different speeds. Steady-state oxygen uptake values were used to calculate the differences in metabolic requirements for roller skiing at the 2 grades (delta E). The differences in external work rates between the 2 grades (delta W) were calculated from the work rates for overcoming rolling resistance and elevating the transported mass against gravity. Delta efficiencies (delta W/ delta E) ranged from 14 to 36%, were significantly greater (p < 0.001) for DS than DP, and showed a significant (p < 0.01) velocity effect for DS. Delta efficiencies were 27% greater (p < 0.05) for the women compared with the men for DP, and significant (p < 0.05) correlations were found between efficiency for DP and body mass. This suggests that the higher efficiency with DP for female skiers is at least partially due to their lower body mass.

Adipose Tissue↗

PubMed1995

Phenyl biguanide does not inhibit locomotion in conscious rabbits.

Stimulation of cardiopulmonary vagal C fibers with phenyl biguanide (PBG) reflexly inhibits locomotion in addition to causing depression of blood pressure (BP), heart rate (HR), and respiration in cats and rats. We investigated whether PBG caused somatomotor inhibition during exercise in the rabbit, a species in which it is known that the hemodynamic and respiratory responses to PBG are mediated by cardiac rather than by pulmonary receptors. In eight New Zealand White rabbits, BP, HR, and hindlimb electromyographic (EMG) responses to 60 and 120 micrograms/kg PBG and saline vehicle were evaluated during two separate 3-min exercise bouts at 10 m/min at 0% grade. During exercise, 60 micrograms/kg PBG decreased BP (-27 +/- 4 mmHg) and HR (-95 +/- 16 beats/min) but did not inhibit locomotion as suggested by the EMG response (+112 +/- 8% of preinfusion EMG). Hemodynamic and EMG responses to 120 micrograms/kg PBG were similar to 60 micrograms/kg PBG. Saline infusion during exercise had no effect on HR, BP, or locomotion (+114 +/- 8% of preinfusion EMG). Locomotion is not inhibited by PBG in rabbits, which suggests that PBG-induced reflex somatomotor inhibition observed in other species is primarily mediated by pulmonary rather than by cardiac receptors.

Animals↗

PubMed1995

Lactate response to uphill roller skiing: diagonal stride versus double pole techniques.

The purpose of this experiment was to investigate the lactate responses to roller skiing with double pole and diagonal stride techniques in eight collegiate or national level cross-country ski racers. Four-minute exercise stages were performed on a ski treadmill at 67, 94, 121, 148, and 174 m.min-1 on a 1.7% grade and at 67, 94, and 121 m.min-1 on a 7.1% grade. Whole blood lactate concentration, heart rate, oxygen consumption (VO2) and rating of perceived exertion (RPE) were determined at each exercise stage. Blood lactate concentrations were not significantly different between double poling and diagonal striding at the 1.7% grade. However, the blood lactate concentrations were higher during double poling at the 7.1% grade for all speeds. Blood lactate concentrations were also higher for double poling at the 7.1% grade when compared with diagonal striding at 70% of technique specific peak VO2, a heart rate of 145 and a RPE of 12. We conclude that blood lactate concentrations do not offer physiological justification for choosing one technique over the other when skiing on low grades, but low blood lactate concentrations may provide a physiological advantage for diagonal striding on steep grades.

Exercise↗

PubMed1994

Intrapericardial blocking agents have extracardiac effects in dogs.

The purpose of this study was to determine if intrapericardial infusion of hexamethonium, propranolol, or atropine affected extracardiac receptors in anesthetized dogs. Intrapericardial hexamethonium (> or = 25 mg) decreased renal sympathetic nerve activity (RSNA) in a dose-dependent fashion. After 250 mg, RSNA began to decrease in 65 +/- 7 s. Whereas vagal stimulation caused a muscarinic receptor-mediated increase in tracheal smooth muscle tone (as indicated by a 9.6 +/- 1.1 mmHg increase in endotracheal cuff pressure), the increase in cuff pressure (1.8 +/- 0.4 mmHg) was attenuated after intrapericardial tropine (4 mg). When the ansa and vagus were stimulated simultaneously, beta-adrenergic receptor-mediated smooth muscle relaxation opposed the muscarinic receptor-mediated constriction resulting in an increase in cuff pressure of only 3.6 +/- 0.9 mmHg. After intrapericardial propranolol (8 mg), simultaneous ansa and vagal stimulation caused a 7.0 +/- 1.6 mmHg increase in cuff pressure, demonstrating that intrapericardial propranolol blocked beta-adrenergic receptor-mediated relaxation of tracheal smooth muscle. These results show that hexamethonium, atropine, and propranolol infused intrapericardially have extracardiac effects.

Animals↗

PubMed1994

Cardiac receptors modulate the renal sympathetic response to dynamic exercise in rabbits.

Activation of cardiac sensory receptors with vagal afferents can result in inhibition of sympathetic outflow to the peripheral circulation. This study investigated whether the regulation of renal sympathetic nerve activity (RSNA) during dynamic exercise was modulated by cardiac sensory receptors. RSNA, blood pressure, and heart rate were measured in seven New Zealand White rabbits during treadmill exercise while cardiac receptors were intact (saline), during cardiac neural block with 2% procaine (2% PCN), and during cardiac efferent receptor block with methscopolamine and atenolol (M + A). Drugs were infused into the pericardial space via a chronic catheter. Two exercise protocols were used: 7 m/min (5 min) and 12 m/min (2 min) at 0% grade. The increases in HR during exercise at 7 and 12 m/min were attenuated with 2% PCN or M + A. At 12 m/min, blood pressure was significantly lower with 2% PCN (76 +/- 4 mmHg) or M + A (76 +/- 3 mmHg) than with saline (86 +/- 2 mmHg). Abolition of cardiac afferent input with 2% PCN resulted in a potentiated RSNA response to exercise at 7 m/min (+134 +/- 37%) and 12 m/min (+234 +/- 45%) relative to saline (+62 +/- 24 and +101 +/- 28%) or M + A (+19 +/- 9 and +52 +/- 19%, P < 0.05). These results suggest that cardiac sensory receptors attenuate sympathetic drive to the kidney during dynamic exercise in conscious rabbits.

Animals↗

PubMed1994

Muscle chemoreflex alters vascular conductance in nonischemic exercising skeletal muscle.

Previous studies have shown that the muscle chemoreflex causes an augmented blood pressure response to exercise and partially restores blood flow to ischemic muscle. The purpose of this study was to investigate the effects of the muscle chemoreflex on blood flow to nonischemic exercising skeletal muscle. During each experiment, dogs ran at 10 kph for 8-16 min and the muscle chemoreflex was evoked by reducing hindlimb blood flow at 4-min intervals (0-80%). Arterial blood pressure, hindlimb blood flow, forelimb blood flow, and forelimb vascular conductance were averaged over the last minute at each level of occlusion. Stimulation of the muscle chemoreflex caused increases in arterial blood pressure and forelimb blood flow and decreases in forelimb vascular conductance. The decrease in forelimb vascular conductance demonstrates that the muscle chemoreflex causes vasoconstriction in the nonischemic exercising forelimb. Despite the decrease in vascular conductance, the increased driving pressure caused by the pressor response was large enough to produce an increased forelimb blood flow.

Animals↗

PubMed1994

Physiological comparison of uphill roller skiing: diagonal stride versus double pole.

The physiological responses to treadmill roller skiing with the double pole (DP) and diagonal stride (DS) techniques were compared at 1.7% and 7.1% grades among eight cross-country ski racers. Oxygen uptake (VO2) requirements were found to be lower (P < 0.05) for DP at the 1.7% grade, but similar at the 7.1% grade. In contrast, ratings of perceived exertion (RPE) and percentages of technique-specific peak VO2 were similar between techniques at the 1.7% grade, and lower (P < 0.05) for DS at the 7.1% grade. RPE and percentages of technique-specific peak VO2 were strongly correlated (r = 0.89). The primary findings indicate that 1) the economies for DP and DS are dependent upon the incline, 2) it is possible for the economy of DP to be greater than DS although the percentages of technique-specific peak VO2 are similar, and 3) the perceived effort associated with the use of DP and DS reflects the percentage of technique-specific peak VO2.

Adipose Tissue↗

PubMed1993

Respiratory alterations with intrapericardial procaine in the conscious rabbit.

1. Intrapericardial procaine, used to produce cardiac nerve blockade in both conscious and anaesthetized animals, has been reported to also produce changes in respiration. This study systematically investigated the effects of two doses of intrapericardial procaine on respiration in the conscious rabbit. 2. Rabbits were pre-instrumented with a chronic diaphragm electromyogram (dEMG) recording electrode and intrapericardial catheter. Arterial pressure, heart rate, dEMG and respiratory excursions (recorded with a pneumograph) were monitored in the conscious rabbit before and after intrapericardial and intravenous infusion of 2 and 5% procaine. Efficacy of cardiac nerve blockade was tested by intravenous infusion of phenyl biguanide. Arterial blood gases were determined at rest and during changes in respiration. 3. Following a low dose of intrapericardial procaine (12 mg), dEMG and respiratory excursions increased (65 +/- 13 and 76 +/- 32%, respectively) with no change in breathing frequency or arterial blood gases. Following a high dose of intrapericardial procaine (30 mg), four of six animals exhibited a similar response. However, four of the six rabbits also exhibited a second type of response pattern characterized by a further increase in respiratory efforts (430 +/- 336%), abolition of dEMG, and a mild hypoxaemia. 4. Intravenous infusion of a low dose of procaine was without effect, whereas intravenous infusion of a high dose of procaine produced minor behavioural responses. 5. In four additional anaesthetized rabbits, it was demonstrated that high doses of intrapericardial procaine anaesthetized the phrenic nerve to produce the observed alterations in respiration. 6. We conclude that if intrapericardial procaine is used to block cardiac nerves in conscious rabbits, it should be used in a low concentration and at the lowest possible total dose to avoid complications due to changes in respiration.

Absorption↗

PubMed1993

Physiological responses to specific maximal exercise tests for cross-country skiing.

The present study attempted to quantify differences in peak physiological responses to pole-striding (PS), double poling on roller skis (DP), and diagonal striding on roller skis (DS) during maximal exercise. Six expert cross-country ski racers (3 M, 3 F) with a mean age of 20.2 +/- 1.3 yrs served as subjects. Testing was conducted on a motorized ski treadmill with a tracked belt surface. Expired air was analyzed continuously via an automated open-circuit system and averaged each 20 s. Heart rate was monitored via telemetry and arterialized blood was collected within 1 min of test termination and analyzed immediately for lactate. Peak values for heart rate and blood lactate did not differ among techniques. Peak oxygen uptake was higher for PS and DS versus DP whereas no difference was found between PS and DS. The VO2peak for DP was 77 and 81% of VO2peak for PS and DS, respectively. It was concluded that despite similar peak heart rate and blood lactate values, DP elicits a lower VO2peak than DS or PS and that PS responses appear to closely reflect those of DS.

Adult↗

PubMed1993

Effect of dynamic exercise on renal sympathetic nerve activity in conscious rabbits.

Renal sympathetic nerve activity (RSNA) increases abruptly at the onset of treadmill exercise in conscious rabbits. This study investigated whether the rise in RSNA is related to the intensity of the exercise and whether an elevated level of RSNA is maintained during submaximal exercise. RSNA, arterial blood pressure (BP), and heart rate (HR) were recorded in 10 New Zealand White rabbits during two treadmill exercise protocols at 0% grade: 7 m/min for 5 min and 12 m/min for 2 min. Peak levels of RSNA were observed in the first 10 s of exercise at 7 and 12 m/min. Through 2 min of exercise, the rise in RSNA was greater (P < 0.05) at 12 m/min (delta 83 +/- 22%) compared with 7 m/min (delta 49 +/- 8%). At 7 m/min, HR and BP reached steady-state levels during the 2nd min of exercise. RSNA remained elevated at delta 43 +/- 10 to delta 54 +/- 13% over resting levels as exercise continued from the 2nd through the 5th min of exercise (P < 0.05). These data demonstrate that the RSNA response to exercise is intensity related and suggest that RSNA remains elevated and thus may contribute to the control of renal blood flow during submaximal dynamic exercise.

Animals↗

PubMedDate not supplied

Sensitivity and specificity of isolated perfused guinea pig heart to test for drug-induced lengthening of QTc.

INTRODUCTION: The purpose of this study was to determine the sensitivity and specificity for predicting the liability of a compound to lengthen QTc using isolated, perfused guinea pig hearts (Langendorff preparation). METHODS: QTc (Fridericia correction) was calculated from bipolar transventricular electrograms. Hearts were exposed to escalating concentrations of 26 compounds thought to lengthen, and 13 compounds thought not to lengthen, QTc in humans. RESULTS: In this preparation, QTc was found to lengthen in 26 of 26 compounds thought to be positive (sensitivity 1.00) and not to lengthen or to lengthen insignificantly in 13 of 13 compounds thought to be negative (specificity 1.0) in man. Probucol and ontazolast could not be studied because of limited solubility. Successful experiments were conducted on over 98% of guinea pigs anesthetized. DISCUSSION: We believe that the isolated perfused guinea pig heart is an in vitro preparation that could be utilized early in preclinical testing for identifying a liability to lengthen QTc in humans, but we do not believe--as is true also for other in vitro methods--that the concentration at which the liability is demonstrated in vitro necessarily predicts the concentration at which a liability exists in man.

Animals↗

PubMedDate not supplied

Effects of fasting on evaluation of gastrointestinal transit with charcoal meal.

INTRODUCTION: At the present time, most studies investigating gastrointestinal transit time with charcoal are conducted in fasted rats. It seems reasonable to hypothesize that the fasting state of rats could influence the effect a compound had on gastrointestinal transit time. The purpose of this study was to investigate the effects of food on the pharmacological effects on gastrointestinal transit. METHODS: For each drug investigated, two sets of 32 male Sprague-Dawley rats were used. One set was studied after being fasted for approximately 6 h, the second set was studied after free access to food. Each set had 4 groups of animals (n=8/group) that were administered different doses, allowing the assessment of the drug effect after fasting and after free access to food. Animals were administered 0, 10, 25, and 75 mg/kg of morphine; 0, 10, 20, and 40 mg/kg loperamide, or 0, 0.05, 0.5, and 3.0 mg/kg clonidine. At predetermined times, an activated charcoal suspension was administered by oral gavage. Thirty minutes after receiving the charcoal meal, rats were euthanized and the small intestine was removed. The length of the small intestine and the distance traveled by the charcoal were recorded. For each animal, gastrointestinal transit was calculated as the percentage of the distance traveled relative to the total length of the small intestine. RESULTS: Baseline (vehicle dosed animals) gastrointestinal transit was significantly greater in fasted versus fed rats. In fasted rats, morphine did not have a significant effect on transit. In fed rats, 25 and 75 mg/kg morphine caused a significant decrease in transit. In fed and fasted rats, 0.5 and 3 mg/kg clonidine caused a significant decrease in transit. Loperamide did not affect gastrointestinal transit in fed or fasted rats at doses up to 40 mg/kg. DISCUSSION: These data demonstrate that food does not reduce the sensitivity of the gastrointestinal transit time.

Animals↗