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Biomedical subjects

S M Garthwaite

Publications and source records attributed to S M Garthwaite.

14 recordsLinked to original sources
PubMed1993

The effect of bidisomide (SC-40230), a new class Ia/Ib antiarrhythmic agent, on defibrillation energy requirements in dogs with healed myocardial infarctions.

UNLABELLED: Bidisomide is a Class Ia/Ib antiarrhythmic agent with activity against ventricular and supraventricular arrhythmias. The potential for bidisomide to increase defibrillation threshold (DFT) was tested in anesthetized dogs with healed left ventricular infarcts (> or = 10 days). Defibrillation patches were attached to each ventricle and shocks were delivered via an external cardioverter/defibrillator. Three groups were studied: placebo (saline), canine therapeutic bidisomide (TB, 2-5 micrograms/mL plasma concentration) and supratherapeutic bidisomide (STB, 6-14 micrograms/mL). Each animal received only one treatment. An abbreviated DFT curve was determined before and after treatment. Heart rate, blood pressure, PR, QRS, infarct size, and hematocrit were also measured before and after treatment. DFT was significantly increased (average +3 to +5 joules [J], P < 0.05) by TB and STB. TB (5/5) did not increase DFT beyond 40 J. In 6/7 experiments, STB did not increase DFT beyond 40 J. Placebo (n = 6) had no significant effect on DFT. Infarct size (mean = 11% of the left ventricle) was not significantly different between groups. Heart rate and QRS were not significantly altered but blood pressure was significantly decreased (16%-31% systolic, 29%-45% diastolic) and hematocrit was significantly increased (19% to 25%) in all groups. PR was significantly increased by STB only. CONCLUSION: therapeutic and supratherapeutic doses of bidisomide slightly but significantly increased DFT (3-5 J) in a canine infarcted heart model.

Animals↗
PubMed1992

Rapid infusions of bidisomide or disopyramide in conscious dogs: effect of myocardial infarction on acute tolerability.

The acute tolerability of rapid infusions of bidisomide or disopyramide was evaluated in normal conscious dogs and in conscious dogs 48 h after the creation of myocardial infarctions (MIs). Both drugs were given in total doses of 15 mg/kg (1.5 x the canine antiarrhythmic dose for each drug). Bidisomide was well tolerated at infusion rates of 3, 5, 11, and 15 mg/kg/min by normal dogs. Disopyramide was well tolerated, except for anticholinergic effects, by normal dogs given infusions at rates of 1.5 and 3 mg/kg/min. Disopyramide caused a ventricular arrhythmia at 4.5 mg/kg/min in one dog, however. Bidisomide (15 mg/kg/min) was well tolerated and antiarrhythmic in dogs with infarctions. Disopyramide (3 and 4.5 mg/kg/min) was lethal in dogs that had myocardial infarctions. A 1 mg/kg/min infusion rate of disopyramide was antiarrhythmic and well tolerated, except for anticholinergic effects, in the post-MI dogs. Both drugs prolonged the ECG lead II P duration, PR interval (bidisomide more so than disopyramide), and QRS duration. Both bidisomide and disopyramide shifted the mean electrical axis of the QRS complex from a right axis deviation to the normal range in dogs with infarctions. The data indicated that the desired cardiac electropharmacologic effects of bidisomide can be achieved in a 1 min infusion. Normal dogs, and especially dogs with infarctions, revealed the potential hazards of rapidly infusing disopyramide.

Animals↗
PubMed1990

Simple in vitro method to characterize antiarrhythmic agents.

A simple, nonmicroelectrode method was developed for the in vitro identification and characterization of potential antiarrhythmic agents. To evaluate the method, standard antiarrhythmic agents from three different classifications (I, III, IV) were tested in isolated right ventricular guinea pig papillary muscles for their effect on developed tension (DT), excitability (EX), and effective refractory period (ERP). ERP was measured with the use of paired field stimuli. Depression or reversal of the force frequency relationship was an index of an agent's effect on DT. A shift in the stimulus strength-duration relationship was an index of an agent's effect on EX. A computer program was developed for data handling and analysis. Disopyramide phosphate (D, 3.0 x 10(-5) M), sotalol (S, 3.0 x 10(-5) M), clofilium phosphate (C, 1.0 x 10(-5) M), and N-acetyl procainamide hydrochloride (N, 3.0 x 10(-5) M) significantly prolonged ERP (+20, +35, +24, +16 ms, respectively), while verapamil (V, 3.0 x 10(-7) M) and the distilled water vehicle (W) did not. D and V significantly decreased DT (-78% and -57% at 1 Hz, respectively) while W, S, C, and N did not. Only D decreased EX. These data correspond well with findings in other models reported in the literature, supporting the use of this simple in vitro method for identification and characterization of potential antiarrhythmic agents.

Acecainide↗
PubMed1989

Cardiovascular profile of a new anti-arrhythmic agent, SC-40230.

The cardiac and general haemodynamic effects of SC-40230, a newly developed anti-arrhythmic agent with both class 1a and 1b properties, were assessed in two different types of experiments using anaesthetised dogs, and in experiments using isolated cat papillary muscles. At the canine anti-arrhythmic dose (9 mg.kg-1 intravenously), SC-40230 decreased the maximum rate of rise of the left ventricular pressure (LV dP/dtmax) by 20%. It decreased heart rate slightly, and lowered (greater than 10%) blood pressure only at doses greater than the canine anti-arrhythmic dose. In these experiments there were dose dependent increases in the P-R interval and the QRS duration. In isolated cat papillary muscles, SC-40230 had a weak negative inotropic effect (IC20 = 3.3 X 10(-5) mol.litre-1) which was less than that previously reported for disopyramide phosphate (IC20 = 1.8 X 10(-5) mol.litre-1) or mexiletine (IC20 = 2.1 X 10(-5) mol.litre-1). These findings suggest SC-40230 has a minimal cardiovascular and haemodynamic side effect potential in its anti-arrhythmic dose range. If these results are confirmed in clinical studies, SC-40230 may have an improved side effect profile versus other anti-arrhythmic drugs such as disopyramide.

Animals↗
PubMed1989

Efficacy and plasma concentrations of SC-36602 in canine models of ventricular arrhythmia.

The antiarrhythmic effectiveness of a new class I agent, SC-36602, was evaluated in two canine models of ventricular arrhythmia. In a Harris coronary ligation-induced arrhythmia model, SC-36602 significantly reduced ectopic rate at doses of 8 mg/kg i.v. and 15, 20 and 30 mg/kg per os. In a ouabain-induced arrhythmia model, a 9 mg/kg i.v. dose of SC-36602 had a sustained (greater than or equal to 60 min) antiarrhythmic effect. The approximate plasma concentration of SC-36602 necessary for measurable antiarrhythmic activity was estimated to be 2-7 micrograms/ml after either i.v. or oral administration. No adverse cardiovascular or central nervous system effects were observed in conscious or anesthetized dogs in response to SC-36602.

Administration, Oral↗
PubMed1988

Synthesis and structure-activity relationships of a new series of antiarrhythmic agents: monobasic derivatives of disobutamide.

Analogues of the dibasic antiarrhythmic agent disobutamide (2) were prepared and evaluated for antiarrhythmic efficacy, myocardial depression, and anticholinergic activity. The replacement of an isopropyl group in disobutamide by an acetyl group led to the monobasic analogue SC-40230, 7a, which demonstrated good antiarrhythmic activity accompanied by less myocardial depressant and anticholinergic activities. In addition, it did not induce clear cytoplasmic vacuoles as did the parent compound. SC-40230 was chosen from among other analogues as a candidate for clinical evaluation. Other compounds prepared and evaluated included indolizidinones and a secondary amine isomer of disobutamide.

Animals↗
PubMed1988

SC-36602, a new antiarrhythmic agent: comparison of its cardiovascular profile with that of other antiarrhythmic drugs.

The cardiovascular profile of SC-36602, a new class 1A/1B antiarrhythmic agent, was compared to those of disopyramide, lidocaine, mexiletine, flecainide, encainide, lorcainide, and quinidine. These drugs were compared at their respective canine antiarrhythmic doses in a hemodynamic evaluation using anesthetized dogs. In another test using anesthetized dogs, the cardiovascular effects of cumulative doses of SC-36602 were assessed. The direct negative inotropic potential of each drug was also determined using isolated cat papillary muscles. In the hemodynamic study, SC-36602 and quinidine did not cause significant myocardial depression, measured as a decrease in the maximal first derivative of the left ventricular pressure. (Heart rate and diastolic filling pressure were not controlled in order to mimic clinical conditions). SC-36602, mexiletine, flecainide, and quinidine increased heart rate. SC-36602 and mexiletine caused a small increase in mean arterial pressure, whereas disopyramide and quinidine decreased it. Disopyramide was the only drug studied that increased left ventricular end-diastolic pressure. SC-36602, quinidine, and mexiletine increased index of cardiac effort. Disopyramide caused a decrease in the latter. Disopyramide, flecainide, encainide, and lorcainide lengthened the ECG intervals. Cumulative intravenous doses of SC-36602 up to 50 mg/kg produced significant decreases in mean arterial pressure, increases in heart rate, and increases in P-R and QRS intervals of the ECG relative to placebo-matched controls. SC-36602 had the least direct negative inotropic action of the drugs studied, as measured in isolated papillary muscles. These data suggest SC-36602, when compared to the other antiarrhythmic drugs studied, has the least amount of hemodynamic side-effects at its antiarrhythmic dose.

Animals↗
PubMed1987

Adipocyte insulin resistance: effects of aging, obesity, exercise, and food restriction.

This study examined the effects of aging, exercise training, and food restriction on epididymal fat cell size and resistance to insulin in rats. The exercise group was given access to voluntary running wheels at age 6 mo. The rats were studied at ages 12 and 28 mo. Sedentary free-eating (SFE) rats were obese and their fat cells were extremely insulin resistant, showing minimal increases in glucose oxidation and 2-deoxy-D-glucose (2-DOG) uptake in response to high insulin concentrations. The runners' adipocytes were smaller and had a greater responsiveness to insulin (approximately 9-fold for 2-DOG uptake and approximately 30-fold for glucose oxidation) than those of the SFE rats. Sedentary rats that were food restricted to keep their body weights the same as those of the runners had fat cells that were intermediate both in size and insulin responsiveness relative to those of the SFE rats and runners. There was a close correlation between fat cell size and responsiveness to insulin of 2-DOG uptake and glucose oxidation independent of age. There were no significant differences in fat cell size, insulin sensitivity, or insulin responsiveness between the adult (12 mo) and old (28 mo) rats in the same treatment groups. We conclude that aging alone has little or no effect on the responsiveness to insulin of glucose metabolism in fat cells and that the insulin resistance of adipocytes from obese older rats is due to fat cell hypertrophy, not aging. Exercise is effective in protecting against development of fat cell hypertrophy and insulin resistance.

Adipose Tissue↗
PubMed1986

Ageing, exercise and food restriction: effects on body composition.

This study was undertaken to reevaluate the effect of ageing on body composition and to compare the effects of exercise and food restriction on body fat content in rats. Body fat content increased progressively between ages 12 and 28 months in sedentary freely eating male Long-Evans rats. A program of 3 h of swimming/day caused body weight to plateau at a level approximately 20% below that of the freely eating sedentary rats, primarily due to a more than 100 g lower body fat content in the swimmers. Lean body mass and protein content decreased progressively with ageing; in the sedentary animals, this decrease was significant by 18 months. The swimming protected against the decline in lean body mass and protein content up to age 18 months, but did not prevent a large decrease in lean body mass between ages 18 and 24 months. Food restriction that kept the sedentary rats at the same weight as the swimmers had its major effect on body fat content, which was approximately 40% lower than in the sedentary freely eating rats at all ages. The differences in body composition between the swimmers and food restricted sedentary animals were relatively small and consisted primarily of a lower body fat content in the swimmers. In conclusion, our results show that lean body mass declines with ageing in rats and that this loss of lean tissue is counterbalanced by an increase in fat. Exercise is highly effective in minimizing the increase in body fat, and may delay the decline in lean body mass, with ageing.

Aging↗
PubMed1983

Carbohydrate feeding speeds reversal of enhanced glucose uptake in muscle after exercise.

Muscle contractile activity results in an increase in glucose uptake rate that can persist for hours. This study was undertaken to determine the effect of carbohydrate repletion on reversal of an exercise-induced increase in glucose uptake. Rats were exercised by swimming. In rats studied 60 min after exercise, muscle glycogen content was 75% depleted and glucose uptake rate was increased. The effect of exercise on glucose uptake was reversed, and glycogen concentration had increased 44 mumol/g muscle, within 18 h in rats fed carbohydrate. In rats fed a carbohydrate-free diet, muscle glycogen increased only 11 mumol/g, and glucose uptake rate had returned only 50% of the way to base line 18 h after exercise. The rate of 3-methylglucose accumulation in muscles was increased sixfold 60 min after exercise. This increase in permeability to sugar was reversed within 18 h in rats fed carbohydrate. In rats fed a carbohydrate-free diet the rate of 3-methylglucose accumulation was still threefold above base line 18 h after exercise. Our results provide evidence that decreased availability of carbohydrate slows reversal of an exercise-induced increase in permeability of muscle to sugar.

Animals↗
PubMed1982

Increased permeability to sugar following muscle contraction. Inhibitors of protein synthesis prevent reversal of the increase in 3-methylglucose transport rate.

Contractile activity is followed by an increase in the permeability of muscle to sugar. The increase in sugar transport rate persists unchanged for hours before gradually returning to base-line (Holloszy, J. O., and Narahara, H. T. (1965) J. Biol. Chem. 240, 3493-3500). This prolonged delay suggested that the recovery process might involve protein synthesis. We have investigated this possibility. A large increase in permeability to [3-3H]methylglucose occurred in frog sartorius muscles stimulated to contract 60 times/min for 30 min. Cycloheximide or puromycin at concentrations that inhibited protein synthesis completely blocked reversal of the increase in permeability to 3-methylglucose. The recovery process was not irreversibly impaired, as permeability returned to base-line in muscles that were washed and incubated without protein synthesis inhibitors for a second 24-h period. Reversal of the increase in permeability to 3-methylglucose induced by a high concentration of epinephrine was also prevented by cycloheximide. In contrast, cycloheximide did not prevent reversal of the increases in sugar transport rate induced by either insulin or trypsin. These results provide evidence that exercise and catecholamines activate sugar transport by a process that requires protein synthesis for its reversal, while the increases in permeability induced by insulin and trypsin involve a different mechanism.

3-O-Methylglucose↗
PubMed1981

Adaptation of fat cells to exercise: response of glucose uptake and oxidation to insulin.

The purpose of this study was to determine whether exercise training alters the sensitivity and responsiveness to insulin of glucose uptake and oxidation in fat cells. Female rats were exercised by swimming 6 h/day, 5 days/wk for 12 wk. The swimmers' fat cells were smaller than those of sedentary controls of the same age and similar body weight. A larger amount of insulin was specifically bound by fat cells of the trained rats because of an increase in the number of insulin receptors. The rates of 2-deoxyglucose uptake and of glucose oxidation were higher in fat cells of trained compared with sedentary rats at all insulin concentrations. A maximal insulin stimulus resulted in rates of sugar uptake and oxidation that were about sixfold higher in trained than in sedentary rats' fat cells. This greater responsiveness to insulin could not be explained by the increase in insulin binding but appears to be mediated by adaptation/s) at a step(s) beyond the binding of insulin to its receptors. Our findings suggest that fat cells of exercise-trained animals are adapted for rapid replenishment of energy stores.

Adaptation, Physiological↗
PubMed1980

Effect of high lipid diet on circadian rhythms of tissue glycogen.

The well defined circadian rhythms of glycogen content in heart, diaphragm and liver of the rat are drastically altered by a high lipid diet as shown by changes in amplitude, phase and tissue glycogen levels. If sampling times had been restricted to certain hours of the day the profound effect of the high fat diet on tissue glycogen would not have been apparent.

Animals↗