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Biomedical subjects

M J Curtis

Publications and source records attributed to M J Curtis.

At least 73 records · Page 4Linked to original sources
PubMed1991

The rabbit dual coronary perfusion model: a new method for assessing the pathological relevance of individual products of the ischaemic milieu: role of potassium in arrhythmogenesis.

STUDY OBJECTIVE: The aim was to develop a new model for determining which factors associated with ischaemia and reperfusion are sufficient for arrhythmogenesis, and to use the model for examining regional hyperkalaemia and K+ washout. DESIGN AND EXPERIMENTAL MATERIAL: Rabbit hearts (n = 150) were perfused with a buffered solution containing K+ in the normal range (2,3,4, or 5 mM). The circumflex coronary artery was perfused independently with a similar solution at a similar rate. A regional increase in K+ concentration was produced, followed by restoration of control K+ to mimic regional changes in K+ during ischaemia and reperfusion. MEASUREMENTS AND MAIN RESULTS: Regional hyperkalaemia (K+ = 9, 12, 15, or 18 mM) mimicked (concentration dependently) the known effects of regional ischaemia on the ECG in three important respects, producing ventricular arrhythmias, regional changes in ECG configuration, and regional alternans. The relationship between arrhythmias and K+ was bell shaped with a peak in susceptibility at 15 mM K+. Arrhythmia susceptibility was reduced and onset delayed by raising the K+ concentration delivered to the adjacent coronary bed. Arrhythmogenesis could be replicated in five or more successive runs in a single heart, indicating a lack of preconditioning. Readmission of control K+ (washout of high K+) mimicked the effects of reperfusion by rapidly causing new episodes of ventricular arrhythmias. The concentration dependence of this effect was exponential, not bell shaped, with washout of 18 mM K+ most arrhythmogenic. There was no preconditioning phenomenon. CONCLUSIONS: Regional hyperkalaemia and K+ washout are factors sufficient to account for arrhythmogenesis during ischaemia and reperfusion, respectively. The new model is suitable for assessment of whether these factors are also necessary for arrhythmogenesis (by equivalent evaluation of other putative arrhythmogens).

Animals↗
PubMed1991

Influence of tedisamil on the initiation and maintenance of ventricular fibrillation: chemical defibrillation by Ito blockade?

We examined the effects of tedisamil on ventricular fibrillation (VF) elicited by regional ischemia and by reperfusion in isolated rat hearts (n = 12/group). During 30 min of ischemia, 0.1, 0.55, and 3 microM tedisamil had no influence on the incidence of VF (an index of VF initiation). However, sustained VF (SVF, defined as that lasting greater than 120 s, an index of VF maintenance) was reduced in a concentration-dependent manner from 73 to 54, 17 (p less than 0.05), and 0% (p less than 0.05), respectively. Tedisamil caused sinus bradycardia but this was not the basis for tedisamil's antiarrhythmic activity since SVF was also inhibited in separate groups of hearts that were paced throughout the study. Tedisamil had no effect on reperfusion-induced VF initiation. However, VF maintenance was, again, inhibited, with SVF incidence reduced from 75% to 40, 20, and 0% (p less than 0.05), respectively, by increasing concentrations of tedisamil. A similar effect was, again, observed in paced hearts. The average cycle length of the electrogram during VF correlated with preceding width of the ventricular complex; both of these variables were concentration-dependently increased by tedisamil and mean values of each correlated inversely with the incidence of SVF. The ratio of SVF cycle length to ventricular tachycardia cycle length was 1:3, and this ratio was conserved in the presence and absence of drug. The data are consistent with a drug-induced increase in the probability of spontaneous termination of multiple wave-front re-entry.

Action Potentials↗
PubMed1991

Independent dual perfusion of left and right coronary arteries in isolated rat hearts.

A novel dual lumen aortic cannula was designed and constructed to permit independent perfusion of left and right coronary beds in isolated rat hearts without necessitating the cannulation of individual arteries. Stability of the dual-perfusion preparation was shown to be similar to that of the conventional Langendorff preparation, in terms of coronary flow, heart rate, and high-energy phosphate content. The independence of left and right perfusion beds was confirmed by unilateral infusion of disulfine blue dye and spectrophotometric detection of the dye in ventricular homogenates. Transient cessation of flow to the left coronary bed resulted in severe ventricular arrhythmias upon reperfusion, as in conventional models of regional ischemia and reperfusion. The dual-perfusion model is technically undemanding, reproducible, inexpensive, and can be used in several species. It enables studies with 1) regional low flow ischemia, 2) regional zero-flow ischemia without coronary ligation (with attendant damage to vasculature), 3) selective application of drugs or interventions to the ischemic-reperfused zone, and 4) selective application of components of ischemia and reperfusion to a site anatomically relevant to ischemic heart disease.

Animals↗
PubMed1991

The pathophysiological basis of arrhythmogenesis in myocardial ischemia and reperfusion: possible target for intervention.

Regional ischemia and reperfusion alter the homeostasis of many substances in the myocardium. Which, if any play a role as pathophysiological progenitors of the associated arrhythmias? The key questions which must be answered in relation to each are: (i) is the presence of the substance sufficient to account for arrhythmogenesis and (ii) is the presence of the substance necessary for arrhythmogenesis to occur? Although there are many candidates for the role of pathophysiological progenitor, and although there is much evidence in support of a role for various of these, the evidence is largely circumstantial. Some of this evidence is reviewed here. I am of the view that new models must be developed if unequivocal data are to be derived. An example which may be of value in this regard is the newly developed rabbit dual perfusion model. The technical aspects of this model are described herein. Using this model I have examined the role of one prospective pathophysiological progenitor of arrhythmogenesis, K+, the intra-extracellular homeostasis of which is disturbed by ischemia and reperfusion in a manner related on a temporal basis with development of susceptibility to arrhythmogenesis. The article concludes with some speculation on possible future research directions.

Angiotensin II↗
PubMed1990

Are reperfusion-induced arrhythmias caused by disinhibition of an arrhythmogenic component of ischemia?

Isolated rat hearts were used to examine whether reperfusion-induced arrhythmias may be caused by washout of substances accumulating during ischemia. This was achieved by subjecting hearts to 10 min of regional ischemia and rendering them transiently inexcitable during the first 1.5 min of reperfusion. Transient inexcitability was induced by switching to cold solution (4 degrees C) shortly before reperfusion (-1.5 min). In controls (no hypothermia), the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) were 83% and 92%, respectively, during the first 1.5 min of reperfusion. Transient hypothermia caused inexcitability and asystole, impaired recovery of coronary flow and abolished VT and VF (all P less than 0.05). On subsequent rewarming to 37 degrees C, coronary flow and sinus rate recovered in all hearts. However, VT and VF occurred in only 58% and 25%, respectively (P less than 0.05). These values were similar to those of new episodes of VT and VF occurring in controls during the equivalent period. Therefore arrhythmias had been abolished during transient hypothermia, not merely delayed. The relative contributions of transient impairment of recovery of coronary flow and transient asystole to the antiarrhythmic effects were examined in a further 10 groups of hearts (n = 12/group) in which reperfusion conditions were transiently manipulated. We utilized combinations of hypothermia, ventricular pacing, acetylcholine (ACh) 55 microM (to cause asystole and impairment of recovery of coronary flow), and right atrial excision and left atrial pacing (to permit bradycardia to be transiently induced during reperfusion by temporarily switching off the pacemaker). The results indicated that transient hypothermia was antiarrhythmic as a result of a reduction of excitability, not because of bradycardia or impairment of recovery of flow. The data support the hypothesis that reperfusion unmasks (disinhibits) latent arrhythmogenic components of ischemia (particularly during the first 1.5 min of reperfusion) and that, by inducing inexcitability, transient hypothermia allows these substances to be washed out without their arrhythmogenic effects being manifested. The identities of the arrhythmogenic and antiarrhythmic substances remain to be determined; we suggest that cyclic AMP and potassium, respectively, are likely candidates.

Acetylcholine↗
PubMed1990

Reperfusion and readmission of oxygen. Pathophysiological relevance of oxygen-derived free radicals to arrhythmogenesis.

We have examined the pathophysiological role of readmission of oxygen (and hence production of oxygen-derived free radicals) in the initiation of reperfusion-induced arrhythmias by separating, on a temporal basis, readmission flow from readmission of oxygen. Isolated rat hearts (n = 12/group) were subjected to 10 minutes of regional ischemia and 10 minutes of reperfusion. In controls reperfused with oxygenated solution (Po2 greater than 600 mm Hg), 92% of hearts developed ventricular fibrillation (VF) during the first 20 seconds of reperfusion, whereas in hearts reperfused with hypoxic solution (Po2 9.3-12.2 mm Hg), the incidence of VF was only 17% (p less than 0.05). Subsequent readmission of control solution (Po2 greater than 600 mm Hg) to the latter group led, within 20 seconds, to the appearance of VF in seven of the 10 hearts (70%) that had not previously fibrillated. To examine whether hypoxic reperfusion had prevented VF or merely delayed its onset, the studies were repeated in separate groups of hearts with the duration of hypoxic reperfusion extended to 5 minutes. In addition, to examine the partial pressure dependence of the relation, the Po2 in the reperfusion solution was set at one of five different levels: greater than 600, 150-192.7, 69-85.6, 9.2-14.8, or 0.0 mm Hg. It was found that hypoxia merely delayed VF onset by 20-40 seconds and did not significantly reduce the incidence of VF, which was 83%, 92%, 67%, 58%, and 58%, respectively. This indicated that readmission of oxygen is unnecessary for the initiation of VF during reperfusion. The hearts that reverted to sinus rhythm during the ensuing 5 minutes (n = 8, 4, 5, 9, and 8, respectively) were used to assess the arrhythmogenic consequences of readmission of oxygen. When control solution (Po2 greater than 600 mm Hg) was readmitted, new episodes of VF were elicited within 20 seconds in a manner that was inversely proportional to the preceding Po2 (p less than 0.05), the incidence of new episodes of VF being 0%, 0%, 40%, 67%, and 86%, respectively. The arrhythmogenic effect of readmission of oxygen was not the result of a sudden increase in heart rate, because a similar arrhythmogenic effect of readmission of oxygen was seen in separate groups of hearts that were paced (350 beats/min) throughout hypoxia and readmission of oxygen. In conclusion, readmission of flow and readmission of oxygen are independent determinants of reperfusion-induced arrhythmias.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Internal fixation for fractures of the patella. A comparison of two methods.

Cadaveric experiments in 10 knees were used to study the strength of two methods of internal fixation for a fractured patella. A modified AO tension band technique was compared with the combination of cerclage wiring and a tension band used at Pyrford. The repairs were stressed to failure; the combination of cerclage and tension band wiring proved to be significantly stronger and is recommended.

Adolescent↗
PubMed1990

Calcium antagonists and coronary artery disease: an opportunity missed?

Why are calcium antagonists not used clinically in myocardial protection to prevent sudden death despite evidence from animal experiments that such activity may exist? The reason is that calcium antagonists are relatively vascular-selective and, at the sub-vasodilatory doses which have been tested clinically, do not inhibit the slow inward current in the myocardium. As a result a belief has grown in the fallacious concept that calcium antagonist activity in the myocardium is not a protective mechanism. Animal studies suggest that the opposite is the case. In my view, in the 20 years since the cardioprotective actions of verapamil were first demonstrated, an opportunity for drug development has been wasted. To rectify this, new drug development should begin with the objective of designing calcium antagonists with inbuilt site-selectivity for ischaemic tissue.

Animals↗
PubMed1989

Skeletal injury in thermal trauma: a review of management.

This paper reports the results of treating 12 patients, from a total of 1011 admissions to the burns unit, who had a combination of extensive burns, fractures and exposed bone or joint. Our results suggest that the benefits of early skeletal stabilization outweigh the increased risks of infection in the burned patient, and that areas of exposed bone or joint less than 3 cm across the smallest axis may be successfully treated by repeated split-skin grafting, but larger areas require early excision and flap coverage for optimum rehabilitation.

Adolescent↗
PubMed1989

Reperfusion-induced arrhythmias are critically dependent upon occluded zone size: relevance to the mechanism of arrhythmogenesis.

The relationship between reperfusion-induced arrhythmias and the size of the occluded zone was examined. The isolated perfuse rat heart was used because its negligible collateral flow maximizes susceptibility to arrhythmias and reduces variability. Ischemia lasting 10 min was followed by 10 min of reperfusion. A constant-pressure perfusion system (which precludes coronary steal) permitted measurement of the rapidity of restoration of coronary flow. Mean occluded zone sizes of 0, 7.2 +/- 1.1, 19.5 +/- 1.5, 45.8 +/- 1.7, 30.1 +/- 4, and 100% of the total ventricular weight were obtained by sham ligation, distal, medial and proximal ligation of the left main coronary artery, right arterial ligation and the induction of global ischemia, respectively. Occluded zone size correlated positively (r = 0.86, P less than 0.001) with a linearly-additive arrhythmia score irrespective of the site of ischemia (left versus right ventricle). In globally ischemic hearts, ventricular fibrillation (VF) depended upon ventricular beating rate during ischemia, occurring only if the rate exceeded 150 beats/min. If this factor were taken into consideration, VF incidence exhibited a sigmoidal relationship with occluded zone size. During the first min of reperfusion, the rapidity of restoration of coronary flow was inversely related to occluded zone size (P less than 0.001) and had a small but significant effect on the severity of arrhythmias; slow recovery of flow increased susceptibility. We conclude that when reperfusion is elicited at the moment of peak susceptibility to arrhythmias, VF incidence is determined principally by occluded zone size. Heart rate during ischemia becomes relevant at rates less than 150 beats/min, when a protective effect is seen. Since VF incidence was 100% in hearts reperfused after global ischemia, an interface between non-ischemic tissue and reperfused tissue is therefore unnecessary for arrhythmogenesis during reperfusion, and flow of injury current between non-ischemic and reperfused tissue can be ruled out as a mechanism of arrhythmogenesis. The initiation of reperfusion-induced arrhythmias must therefore take place within the reperfused tissue.

Animals↗
PubMed1989

Ischaemia-induced and reperfusion-induced arrhythmias differ in their sensitivity to potassium: implications for mechanisms of initiation and maintenance of ventricular fibrillation.

The effects of four different K+ concentrations (2, 4, 6 or 8 mM) on arrhythmias resulting from ischaemia, and from reperfusion (after 3, 5, 7, 10, 15 or 30 min of ischaemia), in isolated perfused rat hearts were examined. A randomized experimental design with blind analysis was used. Regional myocardial ischaemia was produced by occlusion of the left main coronary artery. The incidence of ischaemia-induced ventricular fibrillation (VF) was inhibited by elevating K+ concentration, as reported previously. Furthermore, this effect was linearly and inversely related to the log of the K+ concentration (r = 0.99, P less than 0.001), a finding which has not been reported previously. This finding implies that the antiarrhythmic effect may result from depolarization in the non-ischaemic tissue, since resting membrane potential is also linearly related to the log of the K+ concentration. The maintenance of ischaemia-induced VF (its tendency to sustain) was also influenced by K+, in that a significantly higher incidence of sustained VF (defined as VF still present at the end of the period of ischaemia) was seen with 2 mM K+ compared with higher K+ concentrations (P less than 0.05). In contrast with its effect on the incidence of ischaemia-induced VF, K+ was without effect on the incidence of reperfusion-induced VF, indicating that reperfusion initiates VF independently of the K+ concentration in the perfusion fluid. However, the maintenance of reperfusion-induced VF was K+-dependent (in a similar manner to the maintenance of ischaemia-induced VF). In summary, the effects of K+ on ischaemia-induced VF were different from its effects on reperfusion-induced VF. We conclude that ischaemia-induced VF and reperfusion-induced VF are unlikely to be initiated by a common electrophysiological mechanism since only the former was influenced by K+. The mechanisms of maintenance of ischaemia-induced VF and reperfusion-induced VF might, however, be common, since the tendency for spontaneous defibrillation to occur (as reflected by the incidence of sustained VF) was equally sensitive to K+ in both settings. Finally, the nature of the time course of susceptibility to ischaemia-induced VF compared with that of reperfusion-induced VF raises the possibility that the reperfusion-induced VF may be clinically relevant as a cause of sudden death only when ischaemia-induced VF is suppressed.

Animals↗
PubMed1989

Effects of atrial natriuretic peptide on ischaemia-induced arrhythmias in the rat heart: arrhythmogen or endogenous antiarrhythmic agent?

Myocardial infarction and heart failure are associated with an elevation in plasma levels of atrial natriuretic peptide (ANP). The early stages of myocardial ischaemia and infarction are associated with serious ventricular arrhythmias. We examined the possibility that ANP may function in early ischaemia to alter the susceptibility of the heart to arrhythmias by perfusing rat hearts (n = 12 in each group) with various concentrations of ANP during periods of aerobic perfusion and regional ischaemia. The complications associated with the release of endogenous ANP were precluded by carrying out the experiments with an isolated Langendorff (nonrecirculating) preparation in which the atrial effluent does not gain access to the ventricular coronary arteries. When compared with control hearts, ANP (0.02, 0.2, 0.6, or 2.0 nM) had no significant influence on the ventricular arrhythmias (ventricular premature beats, tachycardia, and fibrillation) elicited by 30-min regional myocardial ischaemia. Heart rate and coronary flow were also unchanged. We conclude that in the isolated rat heart during myocardial ischaemia ANP probably has no significant mediatory or modulatory role in the pathogenesis of serious ventricular arrhythmias.

Animals↗
PubMed1989

Ischemia-induced and reperfusion-induced arrhythmias: importance of heart rate.

The relationship between heart rate and ischemia-induced and reperfusion-induced arrhythmias was studied using 573 isolated rat hearts. Hearts (12/group), subjected to 7 min of coronary occlusion and 10 min reperfusion, were paced at 300, 330, 360, 390, 420, 480, or 540 beats/min. Pacing either throughout the experiment or during ischemia alone led to a rate-dependent increase in the incidence of reperfusion-induced ventricular fibrillation (VF) from 25% in the unpaced hearts to greater than 90% when the rate was 420 beats/min or higher. However, pacing during reperfusion alone did not increase the incidence of reperfusion-induced VF. In separate hearts, the right atrium was removed to permit examination of both low and high rates (167 +/- 2, 240, 336 +/- 3, or 480 beats/min throughout the experiment) over a wide range of durations of occlusion (3, 5, 7, 10, 15, 20, or 40 min). Ischemia-induced VF incidence was critically dependent on heart rate, low rates being protective. During reperfusion, the incidence of VF was also highly rate dependent if reperfusion was initiated within 10 min of the onset of ischemia (ranging from 8% when rate was 167 +/- 2 beats/min to 100% when rate was 480 beats/min) but was unrelated to heart rate when reperfusion occurred at later times (ranging from 33 to 50% when ischemia duration was 40 min). Heart rate can therefore influence susceptibility to ischemia- and reperfusion-induced arrhythmias, probably as a result of an effect on the rate of development of ischemic injury.

Animals↗
PubMed1988

The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion.

The Lambeth Conventions are guidelines intended to be of practical value in the investigation of arrhythmias induced by ischaemia, infarction, and reperfusion. They cover the design and execution of experiments and the definition, classification, quantification, and analysis of arrhythmias. Investigators are encouraged to adopt the conventions in the hope that this will improve uniformity and interlaboratory comparisons.

Animals↗
PubMed1988

Quantification of arrhythmias using scoring systems: an examination of seven scores in an in vivo model of regional myocardial ischaemia.

Arrhythmia scores have been used in recent years to facilitate the analysis of arrhythmias, particularly in relation to regional myocardial ischaemia. The recent Lambeth Conventions recommended caution in the use of arrhythmia scores since their use may be misleading. In the present study seven scoring systems were examined in an attempt to validate the use of arrhythmia scores. A strong positive correlation was present between all seven scores. Furthermore, the scores all correlated with the incidences of ventricular fibrillation, ventricular tachycardia, and ventricular premature beats in early myocardial ischaemia. All seven scores successfully detected statistically significant reductions in the incidence of ventricular fibrillation resulting from the administration of two drugs. Some of the scores occasionally showed statistically significant reductions when effects on the raw arrhythmia data were not statistically significant. In this respect, parametric statistical analysis of arrhythmia scores may be a more sensitive method of quantifying arrhythmias than non-parametric analysis of binomially distributed raw data such as the incidence of ventricular fibrillation (in accordance with the power of such tests) indicating that the scores have precision. However, none of the scores incorrectly showed a statistically significant reduction when the raw data expressed a statistically significant or non-significant increase, indicating that the scores have accuracy. In conclusion, it is possible to design many arrhythmia scores that show changes in arrhythmia severity when more conventional analyses show only non-statistically significant trends. When used in conjunction with raw arrhythmia data, comprehensive drug dose ranges, and appropriate parametric statistical tests, arrhythmia scores facilitate the quantification of arrhythmias. It is recommended that arrhythmia scores should be used only for quantifying group data and model building and not for prognostic purposes in individuals.

Animals↗
PubMed1988

The mechanism of action of calcium antagonists on arrhythmias in early myocardial ischaemia: studies with nifedipine and DHM9.

1. Nifedipine and DHM9 (carboxymethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate) were studied for their effects on arrhythmias resulting from regional myocardial ischaemia in conscious rats, and for their effects on left ventricular developed pressure in vitro. 2. Nifedipine possessed antiarrhythmic activity at a high dose of 10 mg kg-1 i.v., but not at 0.5 or 2 mg kg-1. Ventricular fibrillation (VF), tachycardia (VT), and ventricular premature beats (VPB) were all attenuated to a similar degree; nifedipine did not have a selectivity of action for high frequency arrhythmias. 3. Before coronary occlusion, the three doses of nifedipine reduced arterial blood pressure by a similar magnitude, indicating a similar (maximal) degree of systemic vasodilatation. The reductions in blood pressure were accompanied by reflex tachycardia. Heart rate and blood pressure did not correlate with the incidence or severity of arrhythmias. 4. DHM9 had no influence on arrhythmias, haemodynamic variables or the ECG, even at 20 mg kg-1 i.v. 5. Nifedipine concentration-dependently reduced contractility in perfused paced (5 Hz) rat ventricles in vitro. Raising the concentration of K+ in the perfusion fluid from 3 to 10 mequiv.l-1 increased the potency (-log10 EC50) of nifedipine up to four fold, and caused a significant depression in excitability. 6. DHM9 at up to 3 x 10(-5) M had no significant influence on ventricular contractility in vitro. 7. The results provided indirect evidence in support of the hypothesis that calcium antagonists inhibit ischaemia-induced arrhythmias by virtue of inhibition of the slow inward current (Isi) in the ischaemic ventricular myocardium.

Animals↗