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Biomedical subjects

B A MacLeod

Publications and source records attributed to B A MacLeod.

At least 37 records · Page 2Linked to original sources
PubMed1991

Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K+ current blocker.

1. Rats were used to evaluate the antiarrhythmic properties of tedisamil, a novel agent with the electrophysiological properties of a Class III antiarrhythmic drug. Tedisamil was tested against coronary artery occlusion-induced arrhythmias in conscious animals. 2. The actions of tedisamil on the ECG, as well as responses to electrical stimulation, were compared with those on the configuration of epicardial intracellular action potentials recorded in vivo. 3. Tedisamil (1-4 mg kg-1, i.v.) caused bradycardia, elevated blood pressure and dose-dependently reduced ventricular fibrillation (VF) induced by occlusion of the left anterior descending coronary artery. Other ischaemia-associated arrhythmias were not so well suppressed. Antiarrhythmic activity was greatest when the tedisamil-induced bradycardia was prevented by electrically-pacing the left ventricle. 4. Tedisamil dose-dependently lengthened the effective refractory period and prevented electrically-induced VF. In vivo, tedisamil (0.5-4 mg kg-1, i.v.) prolonged the duration of epicardial intracellular action potentials by up to 400%. 5. Results showed that tedisamil possessed antifibrillatory actions in rats that were related to Class III electrophysiological actions as revealed by electrical stimulation and electrophysiological analyses.

Action Potentials↗
PubMed1990

Prehospital therapy past, present, and future.

Prehospital therapy has rapidly evolved over the last 25 years. Currently, controversies exist about the interventions, pharmacotherapy, and equipment available to the prehospital care provider. Strong medical control is imperative to better define the protocols and technologies of prehospital care.

Clinical Protocols↗
PubMed1989

Effects of halothane on arrhythmias induced by myocardial ischaemia.

The effect of halothane on arrhythmias induced by ischaemia was investigated in rats, isolated perfused rat hearts, and pigs. Responses to the occlusion of the left anterior descending coronary artery were determined in groups (n = 9) of chronically prepared rats treated with no halothane, 0.5, or 1.0 per cent halothane immediately after occlusion; in isolated rat hearts (n = 10) treated with no halothane, 0.5, 1.0, 2.0, or 4.0 per cent halothane for 15 min before and after occlusion; and 20-25 kg pigs (n = 11) anaesthetised with halothane or pentobarbital. The ECG, arrhythmias, blood pressure (BP), heart rate (HR) and extent of infarction were determined in each model. In pigs, left ventricular pressure, dp/dtmax and cardiac output were also measured. In chronically prepared rats, halothane anaesthesia started after occlusion was antiarrhythmic and decreased the incidence of ventricular fibrillation and resulting mortality. In isolated rat hearts, 0.5 or 1.0 per cent halothane had little effect on occlusion-induced arrhythmias. The highest concentration of halothane increased the incidence of ventricular fibrillation both before and after occlusion. Halothane decreased developed ventricular pressure in a dose-dependent manner. In acutely prepared pigs, halothane pre-treatment had no appreciable effect upon occlusion-induced arrhythmias when compared with pentobarbital anaesthesia. Thus, halothane is antiarrhythmic when treatment is initiated after occlusion in the rat but this action is not seen in isolated hearts or intact pigs. The antiarrhythmic action of halothane is, therefore, species and model dependent.

Animals↗
PubMed1989

The antiarrhythmic efficacy of intravenous anipamil against occlusion and reperfusion arrhythmias.

1. Anipamil, a long acting analogue of verapamil, was tested for its actions against arrhythmias induced by ischaemia and reperfusion in conscious and anaesthetized rats, as well as for effects on epicardial intracellular action potentials. 2. When given 15 min or 4 h before coronary occlusion, 1 and 5 mg kg-1 anipamil reduced ischaemia-induced arrhythmias in conscious rats. The same doses also reduced arrhythmias when given 15 min before occlusion in acutely-prepared anaesthetized rats. ED50 values were between 1 and 5 mg kg-1. 3. The incidence of reperfusion arrhythmias depended upon the period of regional ischaemia prior to reperfusion such that the peak incidence occurred after 5-7 min of ischaemia. Anipamil (2.5 mg kg-1, i.v.) selectively abolished the reperfusion arrhythmias induced by short periods of ischaemia, although some antiarrhythmic effects were seen for all periods of ischaemia. 4. Anipamil slowed the rate of development of R-wave increases and S-T segment elevations induced by ischaemia, but did not reduce the maximum values they attained. 5. Anipamil (2.5 mg kg-1 i.v.) lacked Class I or III electrophysiological actions on intracellular action potentials recorded in vivo from the epicardium of rat hearts. 6. In conclusion, the antiarrhythmic actions of anipamil appeared to depend upon calcium antagonism which may have reduced arrhythmias by a combination of anti-ischaemic and direct anti-arrhythmic actions. Presumed anti-ischaemic actions changed the relationship between the duration of preceding ischaemia and resulting reperfusion arrhythmias.

Action Potentials↗
PubMed1989

Antiarrhythmic properties of tetrodotoxin against occlusion-induced arrhythmias in the rat: a novel approach to the study of the antiarrhythmic effects of ventricular sodium channel blockade.

Blockade of ventricular sodium conductance (gNa) is believed to play an important role in the beneficial antiarrhythmic effects of class I antiarrhythmic agents. The present study was undertaken to examine the importance of ventricular gNa blockade by assessing the antiarrhythmic profile of tetrodotoxin (TTX), a selective sodium channel blocker. Experiments were performed in pentobarbital-anesthetized and artificially ventilated rats. Two doses of TTX were tested for antiarrhythmic action: a low dose (low TTX, 10 micrograms/kg of bolus + infusion of 10 micrograms/kg/hr) which blocked only neuronal activity, and a high dose (TTXh, 50 micrograms/kg of bolus + infusion of 50 micrograms/kg/hr) which also produced signs of ventricular gNa blockade in normal hearts. To control for the decreases in blood pressure and heart rate caused by TTX, hexamethonium, nitroprusside and propranolol were also used. Only TTXh possessed antiarrhythmic activity in rats subjected to myocardial ischemia (produced by ligation of the left anterior descending coronary artery). Arrhythmia scores (mean, n = 9) were: saline, 3.8; hexamethonium, 3.8; nitroprusside, 3.2; nitroprusside + propranolol, 4.3; low TTX, 3.9; and TTXh, 0.9. Only TTXh reduced dV/dt max. of the action potential (recorded in vivo by means of 3 M KCl filled microelectrodes) as well as action potential height, and concomitantly prolonged the P-R and QRS intervals of normal hearts. In conclusion, our study demonstrated that drugs which produced hypotension, bradycardia and loss of autonomic function were not antiarrhythmic. On the other hand, the marked antiarrhythmic activity of TTXh appeared to depend upon ventricular gNa blockade. Thus, TTX provides a useful tool for examining the antiarrhythmic properties of ventricular gNa blockade.

Action Potentials↗
PubMed1984

Antiarrhythmic actions of verapamil against ischaemic arrhythmias in the rat.

The actions of intravenous verapamil against arrhythmias induced by occlusion of a coronary artery were investigated in conscious rats. Verapamil (2-20 mg kg-1, i.v. given pre-occlusion) dose-dependently reduced arrhythmias in rats with either large or small occluded zones at an ED50 of 6 mg kg-1. This dose was effective when given immediately post-occlusion. Severe arrhythmias, as opposed to PVC, were preferentially reduced. In conscious, and pentobarbitone-anaesthetized rats, verapamil (6 mg kg-1) had different effects on electrically-induced arrhythmias, and the ECG, from an equi-effective anti-arrhythmic dose of quinidine (20 mg kg-1, i.v.). Quinidine decreased following frequency, but increased threshold current and pulse width, whereas verapamil did not. Both drugs increased P-R interval, but only quinidine increased QRS and Q-T intervals. Thirty minutes post-occlusion, the verapamil content of tissue and blood was determined after a 6 mg kg-1 dose given pre- or post-occlusion. Measurable levels of verapamil were found in both normal and ischaemic myocardium. Plasma and plasma water concentrations were 3.6 +/- 0.8 mumol l-1 and 0.6 +/- 0.1 mumol l-1 (mean +/- s.e. mean), respectively following post-occlusion administration vs. 2.7 +/- 1.2 and 0.24 +/- 0.04 for pre-occlusion administration. Plasma water concentrations were close to IC50 values for inhibition of contractility in rat atria and ventricles. Similar concentrations depressed slow action potentials induced in rat ventricles by raised K+ We suggest that the ability of verapamil to prevent severe ventricular arrhythmias following myocardial ischaemia in the conscious rat is largely due to the calcium antagonist effects of the drug.

Action Potentials↗
PubMed1984

Intracellular potential changes following coronary occlusion in isolated perfused rat hearts.

A method of perfusing rat ventricles has been developed which permits the recording of intracellular potentials from up to 10 cell layers below the endocardial surface. Intracellular potentials from all layers remained the same for up to 1.5 h before occlusion. Regional occlusion of flow was produced by occluding the left anterior descending coronary artery and then intracellular potentials were recorded from normal and occluded cells for up to 2 h after occlusion. Immediately after occlusion, marked changes in potentials were recorded from occluded tissue. The greatest change was in the duration of the action potential which showed a marked shortening. There was also a reduction in the maximum rise rate and action potential height with smaller falls in resting membrane potential. Changes were greatest in the deeper cells (layers 6-10) and least in superficial subendocardial cells which were always superfused with perfusion fluid. Occlusion increased the number of quiescent cells (no action potential) as well as the number of cells showing aberrant action potential configurations (e.g., double peaks). Similar changes in intracellular potentials following occlusion were also recorded from the subepicardial surface of anaesthetized rats in situ. Arrhythmias induced by occlusion were similar to those seen in conscious rats following occlusion of a coronary artery.

Action Potentials↗
PubMed1983

Effects of halothane anesthesia compared with fentanyl anesthesia and no anesthesia during coronary ligation in rats.

The effects of halothane and fentanyl anesthesia on responses to ligation of a coronary artery in chronically prepared rats were compared with responses in conscious animals. A total of 86 rats were used; 24 were ligated under halothane anesthesia, 18 under fentanyl, and 23 were left conscious. Three other groups (each of seven rats) were identically prepared but not ligated. Non-ligated rats were left conscious or anesthetized with halothane or fentanyl. Ligation was performed with the aid of a permanently implanted snare around the left anterior descending coronary artery. The responses to ligation that were measured were: arrhythmias, blood pressure changes, heart rate changes, ECG changes, mortality rate, occluded zone, and infarcted cardiac tissue mass. It was found that 1% halothane anesthesia starting 30 min before and continuing for 4 h after permanent ligation, had an overall beneficial effect, when compared with controls. Fentanyl (200-1,000 micrograms/kg, iv) had no overall beneficial effect, compared with conscious controls. Halothane reduced arrhythmias and mortality rates, when compared with controls, while fentanyl did not. Halothane produced lower blood pressures, fewer ECG changes, and lower heart rates than those seen in conscious or fentanyl anesthetized rats. The occluded and infarcted zones produced by ligation were not influenced by the two anesthetics.

Anesthesia, General↗
PubMed1983

Effects of halogenated hydrocarbon anesthetics on responses to ligation of a coronary artery in chronically prepared rats.

Responses to ligation of the left anterior descending coronary artery (blood pressure, heart rate, ECG, arrhythmias, myocardial tissue loss, and mortality) were investigated in chronically prepared rats anesthetized with one of various halogenated hydrocarbon anesthetics. Halothane (inhaled concentrations of 0, 0.25, 0.5, 1.0, and 2.0%) reduced arrhythmias, mortality, and "S-T" segment changes in the ECG in a dose-related manner. The most effective antiarrhythmic concentrations were 0.5 and 1.0%. Other halogenated hydrocarbon anesthetics (chloroform, enflurane, isoflurane, methoxyflurane, and trichlorethylene) were investigated at minimal anesthetic concentrations. Of these, only chloroform and enflurane reduced arrhythmias. However, both increased mortality as a result of nonarrhythmic causes. At one-half anesthetic concentrations, chloroform (0.25%) and enflurane (0.75%) were not antiarrhythmic and mortality resulting from nonarrhythmic causes was not increased. In the chronically prepared rat, halothane at anesthetic and subanesthetic concentrations has antiarrhythmic actions against ligation-induced arrhythmias, reducing mortality. Of the other halogenated hydrocarbons tested, only enflurane and chloroform had antiarrhythmic actions, however, mortality was high with both agents because of accompanying cardiovascular depression.

Anesthesia↗
PubMed1983

Effects of aspirin and prostacyclin on arrhythmias resulting from coronary artery ligation and on infarct size.

1 The effects of pretreatment with aspirin, and of prostacyclin (PGI(2)) infusions, on responses to myocardial ischaemia and infarction produced by ligation of a coronary artery were investigated in conscious rats.2 Surgical preparation, under halothane anaesthesia, consisted of implanting exteriorized aortic and jugular cannulae, ECG leads and a polypropylene/polyethylene occluder for the left anterior descending coronary artery. Ligation of the coronary artery was performed six to nine days after surgery.3 Aspirin pretreatment consisted of 100 mg/kg given intravenously 1 or 36 h before ligation. PGI(2) infusions (10-400 ng kg(-1) min(-1), i.v.) were begun 2 min before ligation and continued for 4 h afterwards.4 ECG, blood pressure, heart rate and arrhythmias were recorded starting 30 min before, and continuing for 4 h after, ligation. Twenty-four hours after ligation, in surviving animals, the heart was removed for estimation of occluded and infarcted zones.5 Some treatments provided antiarrhythmic and other protection in the first 30 min post-ligation. By 4 and 24 h post-ligation, protective effects were lost.6 Both aspirin pretreatment and low doses of prostacyclin reduced arrhythmias occurring within 30 min of ligation. The highest dose of prostacylin (400 ng kg(-1) min(-1)) was arrhythmogenic.7 None of the treatments influenced the amount of cardiac tissue occluded or infarcted by ligation.8 The conclusions from this study in conscious rats were that acute aspirin pretreatment and low doses of infused prostacyclin have limited beneficial actions which are mainly confined to the earliest post-ligation period.

Animals↗
PubMed1983

Responses to ligation of a coronary artery in conscious rats and the actions of antiarrhythmics.

A method for ligating the left anterior descending coronary artery in conscious rats and measuring the resultant cardiovascular responses, arrhythmias, cardiac tissue loss, electrocardiogram (ECG), and mortality is described. Analyses of such responses identified statistically acceptable measures for which precision and interrelationships were defined. Responses to ligation were a variable function of the amount of ligated myocardial tissue. For example, arrhythmia score was a linear function of the square root of the occluded zone size. To test the ability of the model to detect beneficial drugs, verapamil, lidocaine, disopyramide, and quinidine were given. Low doses of verapamil (0.2 mg/kg i.v. + 0.3 mg X kg-1 X h-1), and of disopyramide (10 mg/kg) had few antiarrhythmic, or other actions, whereas high doses of verapamil (20 mg/kg) and disopyramide (40 mg/kg i.v. repeated) were markedly antiarrhythmic as measured by all indices. Quinidine (20 mg/kg i.v. repeated) was also antiarrhythmic but less so than high dose disopyramide and verapamil. Lidocaine (10 mg/kg i.v. + 5 mg X kg-1 X h-1) reduced the incidence of ventricular flutter and fibrillation. High-dose verapamil and quinidine, but not disopyramide, increased the number of nonarrhythmic deaths and the incidence of atrioventricular conduction defects.

Animals↗
PubMed1982

Blood pressure and cardiac tissue responses to prostacyclin (PGI2) in various species.

The effect of prostacyclin (PGI2) on blood pressure and heart rate (in vivo) and on isolated heart tissue has been investigated in different species. Isolated cardiac tissue had limited responses to PGI2 tested at 10(-13) to 10(-5) M. Cultured neonatal rat heart cells did not respond to PGI2, neither did intact rat hearts or rabbit cardiac tissue. Guinea pig and rat atria showed limited dose-dependent responses to PGI2 at concentrations greater than 10(7) M. In rat atria, 10(-5) M PGI2 produced a limited elevation of tissue cAMP content. When given by intravenous injection or infusion, PGI2 produced hypotension in anaesthetized primates (three species), rat, rabbit, pig, and dog. As a vasodepressor in all species, PGI2 (on a weight basis) was more active than prostaglandins of the B or E type and, in most species tested, it was approximately five times more active than PGE2. Heart responses in intact animals were often paradoxical in that decreases in heart rate often accompanied blood pressure falls.

Animals↗
PubMed1980

The absence of antagonism by naloxone during halothane/nitrous oxide anaesthesia in man.

Sixteen patients were studied to determine if naloxone could be shown to affect general anaesthesia with halothane and oxygen or nitrous oxide and oxygen with halothane. Changes in blood pressure, pulse rate, electroencephalogram and evidence of physical response were observed. The end-tidal halothane and carbon dioxide were controlled. The temperature and blood gases were held constant, as was the degree of neuromuscular blockade. Naloxone 1.2 mg was administered during general anaesthesia with either halothane in oxygen or halothane with nitrous oxide to 16 patients who were premedicated without a narcotic. No significant responses were recorded.

Adult↗
PubMed1977

Sodium nitroprusside-induced hypotension and renal blood flow.

Hypotension produced by sodium nitroprusside during halothane anaesthesia in a series of experiments in dogs was accompanied by the maintenance of renal blood flow. Renal blood flow was maintained at levels of systemic pressure at which flow is customarily reduced in man and experimental animals. The significance of this observation is the possibility that sodium nitroprusside has a protective effect on the kidney, not only in states of deliberate hypotension, but in other low flow states where renal perfusion and function may be compromised.

Anesthesia↗