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Biomedical subjects

J K Gibson

Publications and source records attributed to J K Gibson.

At least 37 records · Page 2Linked to original sources
PubMed1992

Effects of ibutilide fumarate, a novel antiarrhythmic agent, and its enantiomers on isolated rabbit myocardium.

Ibutilide fumarate is currently in Phase II clinical trials for the treatment of life-threatening cardiac arrhythmias. The cardiovascular effects of ibutilide and its d- and l-stereoisomers, U82208E and U82209E were tested in an isolated rabbit myocardium system. In a series of repeated measures experiments, threshold, effective refractory period, force of contraction, conduction time and rate were measured at various pacing frequencies in isolated papillary muscles, ventricular muscle strips and right atria exposed to 10(-7), 10(-6) and 10(-5) M drug. Although there were occasional instances where one form had a greater or lesser effect on a given parameter, overall there was little pharmacological difference between the racemic mixture and its constituent forms. At the highest dose, effective refractory periods at 1 and 3 Hz increased by 18-32 ms, conduction times measured at 3 Hz increased by 27-30% and atrial rate decreased by 19-32%, while threshold and force of contraction were generally unaffected. In this study there were no clear cut pharmacologic differences between the three forms of this class III antiarrhythmic agent. Parallel studies to determine pA2 values of ibutilide and sotalol demonstrated that ibutilide possesses weak beta-adrenoceptor blocking properties.

Adrenergic beta-Antagonists↗
PubMed1992

Effects of ibutilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction: a comparative study with sotalol and encainide.

The electrophysiologic and antiarrhythmic effects of ibutilide, sotalol, and encainide were compared in dogs 24 h after myocardial infarction. Ibutilide (0.03 to 0.3 mg/kg i.v.) prevented the induction of ventricular arrhythmias in 100% of the dogs that had demonstrated inducible ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Sotalol (1.0 to 10.0 mg/kg i.v.) increased the ventricular refractory period and monophasic action potential duration and prevented the induction of ventricular arrhythmias in 75% of the dogs that demonstrated inducible ventricular tachyarrhythmias at baseline. Although 10 mg/kg of sotalol was required to prevent the initiation of ventricular tachycardia, this dose produced marked cardiovascular depression and hypotension in 50% of the dogs tested. Neither ibutilide nor sotalol significantly decreased the incidence of spontaneous ventricular arrhythmias. The class IC agent encainide (0.3 to 3.0 mg/kg i.v.) was successful in preventing the induction of ventricular arrhythmias in only 20% of the dogs tested. However, in contrast to ibutilide and sotalol, encainide significantly reduced spontaneous arrhythmias. Atrial and ventricular refractoriness were significantly increased only after the highest dose of encainide tested (3.0 mg/kg). Over the dose ranges studied, the relative efficacy for prevention of pacing-induced ventricular arrhythmias was ibutilide greater than sotalol much greater than encainide. For suppression of spontaneous ventricular arrhythmias, the relative efficacy was encainide much greater than ibutilide = sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

N-[(omega-amino-1-hydroxyalkyl)phenyl]methanesulfonamide derivatives with class III antiarrhythmic activity.

N-[4-[4-(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamid e, (E)-2-butenedioate (2:1) salt (ibutilide fumarate, 2E), has been found to have Class III antiarrhythmic activity. In an in vitro rabbit heart tissue preparation designed to evaluate the cardiac electrophysiology of potential antiarrhythmic agents, it selectively prolongs the effective refractory period of papillary muscle. In vivo it increases the ventricular refractory period of the canine heart and prevents the ventricular arrhythmias induced by programmed electrical stimulation 3-9 days after a myocardial infarction. This paper describes the synthesis of 2E and a series of related compounds. The in vitro evaluation of the cardiac electrophysiology of these compounds has allowed us to determine the structural requirements for Class III antiarrhythmic activity in this series. Evaluation of the antiarrhythmic activity of 2E and one of the more potent analogues on the late postinfarction ventricular arrhythmias induced by programmed electrical stimulation of the canine myocardium is also described. This activity is compared with that of the Class III antiarrhythmic agent sotalol. Compound 2E appears to be as effective and 10-30 times more potent than sotalol in this model.

Animals↗
PubMed1990

Effects of U74006F, a novel inhibitor of lipid peroxidation, in stunned reperfused canine myocardium.

U74006F, a novel 21-amino steroid is a potent inhibitor of iron-mediated lipid peroxidation and has been shown to be of therapeutic benefit in central nervous system ischemia. As oxygen radicals have been implicated in the development of postischemic myocardial dysfunction, we examined the efficacy of U74006F to enhance the recovery of function in a canine model of stunned, reperfused myocardium. Twenty-six dogs were randomized to either a vehicle (n = 11), U74006F (n = 10), or U74006F-paced group (n = 5). U74006F (6 mg/kg i.v.) was administered 15 min prior to coronary artery occlusion. Myocardial blood flows were measured by the microsphere technique, and function data were obtained by sonomicrometry. Both U74006F-treated groups demonstrated a significant increase in posterior wall thickening as compared to the vehicle treatment (U74006F-paced, 27.0 +/- 12.8%; U74006F, 22.4 +/- 11%; vehicle, -13.5 +/- 9.9%, p less than 0.001 following 3 h of reperfusion). Enhanced function recovery was accompanied by lower heart rates in the U74006F-treated group following reperfusion (treated versus vehicle, 109 +/- 6.7 versus 131 +/- 8.8 beats/min, p = 0.004). The U74006F-paced group was maintained at the same rate as the vehicle group, with no diminution in function recovery compared to the unpaced group. No effects in systemic hemodynamics or nutrient blood flow were evident as a function of drug treatment. We conclude that pretreatment with U74006F enhances the recovery of function in stunned canine myocardium via the inhibition of oxygen radicals and lipid peroxidation products. This activity suggests that this compound represents a new therapeutic adjunct in reperfusion and recanalization therapies.

Animals↗
PubMed1989

Beneficial effects of oxypurinol pretreatment in stunned, reperfused canine myocardium.

The mechanism of reperfusion induced injury in acutely ischaemic myocardium is controversial but may be connected with oxygen free radical generation. However, chronic allopurinol treatment has beneficial effects in ischaemic myocardium which are not due to its inhibition of xanthine oxidase induced oxygen free radical production. Allopurinol is rapidly metabolised to oxypurinol, so we have examined the effects of this compound on nutrient blood flow and contractility in a canine model of stunned, reperfused myocardium. Twenty anaesthetised dogs underwent 15 min of total circumflex artery occlusion followed by 15 min restricted reflow and 2 h full reflow. Posterior wall thickening was determined by sonomicrometry and expressed as % control function. Regional myocardial blood flow was measured by microsphere technique and expressed in ml.min-1.g-1. Dogs in the treatment group (n = 10) received 25 mg.kg-1 oxypurinol as a 5 min left atrial infusion, 15 min prior to circumflex occlusion. Controls (n = 10) received a saline infusion. During occlusion mean circumflex pressure (17.6 v 18.2 mm Hg), endocardial flow [0.02(SEM 0.01) v 0.03(0.01) ml.min-1g-1], and area at risk [31.4(1.2%) v 34.6(2.4%)] were similar for both groups (control v treated respectively). Endocardial blood flow increased following acute administration of oxypurinol: 1.57(0.15) v 0.92(0.15) ml.min-1g-1 in control (vehicle) group, p less than 0.05. This effect persisted for the duration of the experiment, with a significant increase during early reflow: 1.83(0.32) v 0.74(.21), p = 0.03. There was also a marked increase in posterior wall function in the treated group, at 54.6(5.5)% v 5.1(8.4)% in the control group (p = 0.0003). These results show that pretreatment with oxypurinol protects acutely ischaemic myocardium, producing enhanced myocardial blood flow, diminished systolic bulge during occlusion, and markedly enhanced function recovery following reperfusion.

Animals↗
PubMed1988

Antiarrhythmic and arrhythmogenic actions of methyl lidocaine during the recovery phase after canine myocardial infarction.

Programmed electrical stimulation was used to evaluate the electrophysiologic and antiarrhythmic actions of methyl lidocaine in both conscious and anesthetized dogs, 4-7 days after myocardial infarction. When administered to animals demonstrating sustained ventricular tachycardia (n = 6), methyl lidocaine (5 and 10 mg/kg i.v.) prevented the induction of the original ventricular tachycardia in 2 dogs, and in the remaining 4 dogs slowed the tachycardia (cycle length 163 +/- 18 ms vs. 198 +/- 11 and 219 +/- 11 ms, respectively, p less than 0.05). New morphologic forms of sustained tachycardia were observed after drug administration in 4 of 6 experiments. When administered to animals developing only nonsustained ventricular tachycardia or no arrhythmias with programmed stimulation, methyl lidocaine administration enabled programmed stimulation to produce monomorphic sustained ventricular tachycardia in 10 of 13 experiments. The drug increased activation delays in both normal and ischemically injured epicardium, with larger activation delays always observed in ischemically injured tissue. The drug increased refractoriness in ischemically injured myocardium without altering refractoriness in normal tissue. The data suggest that the depression of conduction and prolonged refractoriness produced by methyl lidocaine in ischemically injured tissue may extinguish or slow some forms of ventricular arrhythmia while promoting the formation of new reentry pathways.

Animals↗
PubMed1986

Electrophysiologic, antiarrhythmic and cardiovascular actions of UM301, a quaternary ammonium compound.

The electrophysiologic, antiarrhythmic and cardiovascular actions of UM301 were evaluated in a variety of animal models. UM301 (range, 4.5-10 mg/kg i.v.) converted ouabain-induced ventricular tachycardia to normal sinus rhythm in the anesthetized dog. UM301 (10 mg/kg i.v.) suppressed the ventricular arrhythmias observed in a modified 2 day postinfarction dog preparation; normal sinus rhythm was maintained in excess of 120 min in these conscious animals. The ventricular fibrillation threshold was elevated in four animals after pretreatment with UM301 (5 and 10 mg/kg i.v.) without interfering with electrical cardioversion. In one animal, the spontaneous conversion of ventricular fibrillation to normal sinus rhythm was observed after pretreatment with UM301. In anesthetized dogs, 2 to 8 days after myocardial infarction, UM301 (5 and 10 mg/kg i.v.) prevented the reinduction of re-entrant ventricular tachyarrhythmias using programmed pacing techniques. The antiarrhythmic and antifibrillatory actions of the therapeutic doses of UM301 (i.e., 5 mg/kg i.v.) were associated with significant increases in the refractoriness of atrial, ventricular and atrioventricular conducting tissue. Higher doses of UM301 (10 mg/kg i.v.) progressively increased refractoriness, and the highest dose of UM301 tested (20 mg/kg i.v.) increased refractoriness further and depressed cardiac conduction in these tissues. Acute cardiovascular studies in anesthetized dogs showed that only the highest dose of UM301 tested (20 mg/kg i.v.) produced a significant decrease in the right ventricular force of contraction, cardiac output and arterial pressure. These data demonstrate that UM301, a quaternary ammonium compound, possesses both antiarrhythmic and antifibrillatory properties in various experimental animal models. The antiarrhythmic efficacy of UM301 can be observed in the absence of depressant cardiovascular actions.

Animals↗
PubMed1984

Cellular basis for arrhythmogenicity of ionophores with different cation selectivities.

In high concentrations, the ionophores salinomycin, monensin and X-537A cause cardiac arrhythmias in vivo. To determine if these arrhythmias result from a direct action of these ionophores on cardiac electrophysiology, we studied their effects on automaticity and transmembrane action potentials of isolated canine left ventricular Purkinje fibers. High concentrations of the ionophores suppressed automaticity and shortened action potential duration. These data suggest that high concentrations of the ionophores provoke cardiac arrhythmias in vivo by similar mechanisms despite their diverse cation transport selectivities.

Action Potentials↗
PubMed1982

Effect of infarct size limitation by propranolol on ventricular arrhythmias after myocardial infarction.

These experiments show that pretreatment with propranolol was able to achieve significant infarct size reduction in this particular animal model of LAD occlusion followed by reperfusion through a critical stenosis. Despite infarct size reduction, the propranolol pretreatment prolonged the time course of spontaneous ventricular arrhythmias after acute myocardial infarction in the conscious dog. In contrast to this, propranolol pretreatment did not appear to protect against inducible ventricular arrhythmias in the late postinfarction period in the conscious dog. While it is, of course, impossible to extrapolate the results of animal studies to the clinical situation, future clinical studies designed to limit infarct size by pharmacologic intervention should specifically address the question of electrophysiologic instability after myocardial infarction, both in the early and late phases. The possibility exists that pharmacologic limitation of infarct size may preserve viable but potentially jeopardized areas of myocardium, leaving the risk of subsequent malignant arrhythmias and sudden death.

Animals↗
PubMed1981

Prevention of chronic canine ventricular tachyarrhythmias with bretylium tosylate.

The ability of chronic bretylium tosylate treatment to prevent the induction of ventricular tachycardia was assessed in the conscious dog subjected to serial programmed ventricular stimulation on days 3-6 after acute myocardial infarction. In 34 untreated control dogs, programmed ventricular stimulation produced nonsustained ventricular tachycardia in 11 dogs (32%), sustained ventricular tachycardia in 10 (29%), and ventricular fibrillation in 10 (29%) on the third and fourth day after occlusion and reperfusion of the left anterior descending coronary artery. Bretylium tosylate, 5 mg/kg i.v., was given every 12 hours to a separate group of seven dogs after the induction of ischemic myocardial injury. Programmed ventricular stimulation on the third and fourth days after the induction of myocardial ischemic injury failed to elicit ventricular arrhythmias. Induction of arrhythmias by programmed electrical stimulation could be induced in each of the seven dogs; however, 36 hours after discontinuing bretylium tosylate, two dogs (29%) had non-sustained ventricular tachycardia and five (71%) had sustained ventricular tachycardia. When retested at 60 hours after withdrawal of bretylium tosylate, five (71%) had sustained ventricular tachycardia and two (28%) developed ventricular fibrillation. Readministration of bretylium tosylate (5 mg/kg, i.v.) to four of the five surviving dogs prevented the induction of ventricular arrhythmias in response to programmed ventricular stimulation. The results of these investigations suggest that bretylium tosylate may be effective in preventing the onset of reentrant ventricular rhythms after myocardial ischemic damage, and therefore may be of value in preventing sudden coronary death.

Animals↗
PubMed1980

Potential organ- or tumor-imaging agents XIX: radioiodinated antiarrhythmic drugs as potential myocardial imaging agents.

Iodinated and radioiodinated analogs of propranolol and N,N-dimethylpropranolol were synthesized wherein an iodophenyl moiety replaced the naphthalene ring of the parent drug. These new compounds were evaluated not only for their beta-adrenergic blocking and antiarrhythmic activities but also for their ability to accumulate selectively in myocardial tissue. Like propranol, the iodinated analogs displayed comparable beta-blocking and antiarrhythmic activity, and the order of potency was ortho- > meta- > para-iodophenyl. Quaternization of propranolol and the iodinated analogs eliminated the beta-adrenergic blocking activity but retained the antiarrhythmic property of the secondary amine precursors. Among the quaternary salts, the antiarrhythmic potency was meta- > ortho- > para-iodophenyl. Tissue distribution of the radioiodinated derivatives revealed that only the quaternary derivatives were selectively accumulated in myocardial tissue. These results demonstrate that an iodophenyl ring can substitute for th naphthalene ring in propranolol and its quaternary salt without significant alteration of pharmacological properties. The radioiodinated quaternary derivatives may be useful pharmacological tools in experiments aimed at relating antiarrhythmic activity to myocardial uptake.

Adrenergic beta-Antagonists↗
PubMed1980

Electrophysiologic effects of disopyramide phosphate on reentrant ventricular arrhythmia in conscious dogs after myocardial infarction.

The electrophysiologic actions of disopyramide phosphate on reentrant ventricular tachycardia induced by premature ventricular stimuli were evaluated in conscious dogs 2 to 4 days after myocardial infarction. Disopyramide was administered as a series of intravenous infusions to obtain successive steady state plasma disopyramide concentrations of 1.02 +/- 0.02, 2.05 +/- 0.08, 3.94 +/- 0.09 and 7.69 +/- +/- 0.18 micrograms/ml (mean values +/- standard error of the mean). Disopyramide plasma concentrations of 1.02 +/- 0.02 micrograms/ml produced an increase in the rate and duration of ventricular tachycardia as well as in the interval during which premature ventricular stimuli produced ventricular tachycardia. The effective refractory period of normal myocardium was decreased and conduction (activation time) was improved in ischemic myocardium. Increasing steady state plasma disopyramide concentrations slowed the rate of ventricular tachycardia without decreasing its duration. Slowing of the rate of tachycardia occurred simultaneously with a depression of conduction in normal and ischemic myocardium and an increase in ventricular refractoriness. Induction of ventricular tachycardia was prevented only at steady state plasma disopyramide concentrations of 7.69 +/- 0.18 micrograms/ml. The results of this study suggest that subtherapeutic plasma concentrations of disopyramide may facilitate the development of reentrant ventricular arrhythmia in the electrically unstable heart. Ventricular tachycardia or fibrillation, or both, may be prevented only by plasma disopyramide concentrations that are in excess of the normal therapeutic range of 2 to 4 micrograms/ml.

Animals↗
PubMed1977

Direct and beta adrenergic blocking actions of nadolol (SQ 11725) on electrophysiologic properties of isolated canine myocardium.

Effects of nadolol, a new beta adrenergic antagonist, were determined on transmembrane potentials of canine Purkinje fibers and ventricular and atrial muscle. Significant alterations in Purkinje fiber potentials occurred only with nadolol concentrations of 10(-4) M or greater. After 1 hour exposure to 10(-4) M, resting potential and action potential amplitude were reduced; at 3 hours, action potential rate of rise, phase 2 duration and action potential duration at 75% repolarization also were decreased. 10(-3) M nadolol also was depressant and, additionally, consistently reduced membrane responsiveness. Nadolol (10(-8)-10(-4) M) had no significant effects on effective refractory period. Ventricular and atrial muscle were less sensitive to all drug concentrations. Nadolol (10(-8)-10(-4) M) had little action on automaticity in normal, ouabain-treated or stretched Purkinje fibers but markedly decreased catecholamine-enhanced automaticity. In isoproterenol-treated Purkinje fibers, pA2 for nadolol was 8.2 and 7.7 for propranolol. Nadolol (10(-3) M or less) did not affect isometric force developed by isolated canine atrial trabeculae. We suggest that direct membrane depressant effects of nadolol do not contribute to its antiarrhythmic activity and that its beta adrenergic blocking ability is beneficial in catecholamine-related cardiac ectopia.

Action Potentials↗
PubMedDate not supplied

Electrophysiologic actions of lidocaine in a canine model of chronic myocardial ischemic damage--arrhythmogenic actions of lidocaine.

Lidocaine facilitated the induction of ventricular arrhythmias by programmed electrical stimulation in 16 dogs, 5 to 14 days after a temporary (90-min) occlusion of the left anterior descending coronary artery. In these 16 animals, programmed stimulation failed to produce ventricular tachyarrhythmias in any animal before lidocaine administration (3 mg/kg), while after lidocaine administration, programmed stimulation produced nonsustained ventricular tachycardia in four animals (25%), sustained ventricular tachycardia in nine animals (56%), and ventricular fibrillation in one animal (6%). Delayed electrical activity in ischemically injured ventricular myocardium produced by premature ventricular stimuli (mean +/- SD = 179 +/- 34 ms) was delayed further by the administration of lidocaine (237 +/- 42 ms, p less than 0.01), resulting in continuous local electrical activity between the final premature ventricular stimulus and the initial beat of the resultant ventricular tachycardia. Lidocaine administration did not alter myocardial refractoriness in normal ventricular tissue, but it prolonged refractoriness in ischemically injured ventricular myocardium. These results show that lidocaine can have arrhythmogenic actions when administered in the presence of existing ischemic injury, possibly the result of increased delay in activation of ischemically injured ventricular myocardium with localized reentry of myocardial electrical activity.

Animals↗