Biomedical subjects

D J Hearse

Publications and source records attributed to D J Hearse.

At least 145 records · Page 8Linked to original sources

PubMed1990

Assessment of ischemic injury and protective interventions: the Langendorff versus the working rat heart preparation.

The isolated rat heart is widely used for investigating ischemia and evaluating protective interventions, particularly with global ischemia, in which Langendorff and working preparations have formed the cornerstone of much of the developmental work on cardioplegic solutions. The objective of the present study was to compare the vulnerability of the two preparations to global ischemia and their responsiveness to protection with the St Thomas' Hospital cardioplegic solution. Langendorff preparations (n = 6) were subjected to 15, 30, 45, 60, 75, 90, 105 or 120 mins of global ischemia, and working preparations (n = 6) to 10, 15, 20, 25, 30, 35, 40 or 45 mins of global ischemia; post ischemic recovery of cardiac function, creatine kinase leakage, tissue ATP and creatine phosphate content were measured. With 30 mins of global ischemia, the impairment of cardiac function was similar in both preparations. With reperfusion in the Langendorff, the left ventricular developed pressure (LVDP), maximum rate of pressure development (dP/dt), heart rate and coronary flow recovered to 54.7 +/- 5.7, 53.7 +/- 7.1, 88.9 +/- 3.0 and 67.2 +/- 1.8%, respectively, of their pre-ischemic control value. In working hearts, cardiac output, heart rate and coronary flow recovered to 17.9 +/- 2.5, 95.6 +/- 4.2 and 73.8 +/- 8.2%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Harvesting hearts for long-term preservation. Detrimental effects of initial hypothermic infusion of cardioplegic solutions.

Current procedure for harvesting human donor hearts for long-term storage before transplantation involves direct infusion of a hypothermic (4 degrees C) crystalloid cardioplegic solution into the normothermic (37 degrees C) heart in situ. We used the isolated perfused working rat heart preparation to investigate whether infusing cold crystalloid solutions into normothermic blood-containing hearts was consistent with maximal myocardial protection. Hearts (n = 6 per group) were excised and subjected to a primary (1 minute) infusion with either the St. Thomas' Hospital cardioplegic solution or a bicarbonate buffer solution, at 7.5 degrees C, 22 degrees C, or 37 degrees C. This was followed by a secondary infusion (2 minutes) with cold (7.5 degrees C) cardioplegic solution, after which all hearts were stored at 7.5 degrees C for 6 hours and then reperfused at 37 degrees C for 60 minutes, during which time creatine kinase leakage and cardiac function were measured. Primary infusion with warm solutions resulted in (1) decreased coronary vascular resistance during cardioplegic infusion and (2) greater postischemic cardiac function. This suggests that their use, before the standard cold infusion, might be beneficial to the long-term preservation of transplant donor hearts.

Animals↗

PubMed1989

The inotropic consequences of cooling: studies in the isolated rat heart.

To investigate the controversial effects of hypothermia on cardiac contractile performance, we have carried out ventricular volume-loading experiments in 23 perfused, paced (2 Hz), isolated rat hearts, contracting isovolumically at various temperatures. A water-filled, unstressed latex balloon was inserted into the left ventricle and its volume was controlled with a microsyringe. Left ventricular pressure (LVP), its first derivative (dP/dt) and coronary flow were recorded. One group of hearts (n = 7) were perfused at 37 degrees C over 2 h. Another group of hearts (n = 16) were cooled in a stepwise manner from 37 degrees C to 21 degrees C, with 10-min perfusion at each of seven different temperatures, and then rewarmed to 37 degrees C. Emax, an index of contractility, calculated as the slope of the regression line of the end-systolic pressure-volume relationship, was found to increase as temperature fell (3.9, 4.6, 4.9, 5.5, 5.5, 6.2, and 6.3 cm H2O/microliters at 37 degrees, 34 degrees, 31 degrees, 29 degrees, 27 degrees, 24 degrees and 21 degrees C, respectively) while it remained constant over the 2-h perfusion in the normothermic perfusion group. By contrast, peak positive dP/dt/peak-developed pressure (+dP/dt/DP) progressively decreased during cooling without any change in the normothermic perfusion group. The results indicate that hypothermia can be designated as a positive inotropic intervention in terms of force-generation (Emax) but as a negative inotropic intervention in terms of shortening velocity of contractile element in Hill's model (+dP/dt/DP).

Animals↗

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

Reperfusion-induced arrhythmias in the conscious rat: a comparative study with three calcium antagonists.

The effects of three calcium antagonists (diltiazem, verapamil, and nifedipine) on reperfusion-induced arrhythmias were compared in a conscious rat preparation with coronary artery occlusion and implanted electrocardiogram limb electrodes. Upon reperfusion after a 5-min period of occlusion, all (15/15) untreated control rats exhibited immediate ventricular tachycardia, which rapidly deteriorated to ventricular fibrillation; 87% (13/15) of the rats died as a consequence of these rhythm disturbances. In the groups treated with calcium antagonists, each drug (diltiazem, verapamil, or nifedipine) was given as an intravenous bolus 10 min prior to coronary occlusion (n = 12 in each group). The incidence of ventricular fibrillation was significantly reduced by all three calcium antagonists and this antifibrillatory effect resulted in a significantly lower mortality in all drug-treated groups. With diltiazem (0.5 and 2.0 mg/kg) mortality fell from 87 to 42% (P less than 0.05) and 35% (P less than 0.01), respectively; with verapamil (0.5 and 5.0 mg/kg) it fell to 25% (P less than 0.01) and 0% (P less than 0.001); and with nifedipine (5.0 and 50 micrograms/kg), it fell to 25% (P less than 0.01) and 8% (P less than 0.001). At a dose of 5.0 mg/kg, verapamil caused a large reduction in heart rate both prior to and during coronary occlusion and reperfusion; however, with other doses and drugs no significant changes in heart rate were observed. ST segment elevation during the 5-min ischemic period was reduced by pretreatment with all drugs. In conclusion, in the conscious rat, pretreatment with diltiazem, verapamil, or nifedipine affords some protection against reperfusion-induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Cardioplegia: relation of myocardial protection to infusion volume and duration.

Clinically, initial infusion volumes of crystalloid cardioplegic solution are relatively low (500-1000 ml or 2-4 ml/g myocardium) compared to those used experimentally. In particular, rat hearts (in which many clinical solutions have been developed and evaluated) commonly use 20-30 ml/g myocardium (equivalent to 5.0-7.5 l in human heart). We used the isolated working rat heart to characterise the relationships between myocardial protection and (a) infusion duration, and (b) infusion volume of St. Thomas' Hospital cardioplegic solution (STH), Hearts were aerobically perfused (20 min) and subjected to varying durations of STH infusion (0-300 s) prior to normothermic global ischaemia (30 min). During reperfusion, maximal recovery of cardiac output occurred when infusion durations exceeded 30 s and infusion volumes exceeded 5.0 ml/g myocardium. To assess infusion volume rather than duration, hearts were infused with 1.0, 1.5 or 2.0 ml of STH for 120 s. Optimal recovery of cardiac output required 2.0 ml/g myocardium for 120 s. To assess infusion duration with low infusion volumes, 2.0 ml STH/g myocardium was infused for 10, 30, 60 and 120 s; optimal recovery of cardiac output occurred with infusions of 30 s or longer. Thus, even in the rat heart, optimal protection with STH can be achieved by infusion at a volume of 2.0 ml/g myocardium for a duration of not less than 30 s, similar to that now in current clinical use.

Animals↗

PubMed1989

Dissociation between reperfusion induced arrhythmias and increases in ventricular alpha 1 receptor density in the anaesthetised rat.

Using anaesthetised rats we have assessed (1) whether the density of alpha 1 adrenergic receptors increases during coronary artery occlusion, (2) whether any change in density can be associated with the onset of reperfusion induced ventricular fibrillation, and (3) whether alpha 1 blockade with prazosin modifies the incidence of reperfusion induced ventricular fibrillation. The incidence of fibrillation upon reperfusion after 3, 5, 10, 20 and 30 min occlusion was 20, 75, 50, 16 and 10% (n = 10-12 in each group) respectively. alpha 1 Receptor density was measured using [3H]-prazosin in non-ischaemic and ischaemic tissue obtained after 0, 5 and 30 min ischaemia. Receptor density was not significantly altered at the time of maximum incidence of reperfusion induced ventricular fibrillation (5 min occlusion) but did significantly increase in both non-ischaemic and ischaemic tissue after 30 min occlusion, when the incidence of fibrillation upon reperfusion was very low (8%). At this time the values were 17.0(SEM 2.3) and 18.4(0.6)fmol.mg-1 protein in non-ischaemic and ischaemic zones as compared to 10.7(0.6) and 12.8(1.0)fmol.mg-1 protein in sham operated control animals (p less than 0.05 in both cases). Prazosin (0.1 or 1.0 mg.kg-1 body wt intravenously, 5 min prior to coronary occlusion) did not alter the incidence of ventricular fibrillation, ventricular tachycardia or total number of premature ventricular complexes upon reperfusion. We conclude that ischaemia induced changes in alpha 1 receptor density do not parallel changes in vulnerability to reperfusion induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Anti-arrhythmic effects of amiodarone and desethylamiodarone on malignant ventricular arrhythmias arising as a consequence of ischaemia and reperfusion in the anaesthetised rat.

The effects of amiodarone and its metabolite desethylamiodarone on arrhythmias induced by ischaemia and reperfusion were studied in vivo in the anaesthetised rat with transient regional ischaemia (7 min of left coronary artery occlusion) and reperfusion (10 min). Amiodarone or desethylamiodarone were administered intravenously either 10 min prior to ischaemia or 2 min prior to reperfusion. Control rats received an equivalent volume of vehicle. Administration of 5.0 mg.kg-1 amiodarone or desethylamiodarone prior to ischaemia reduced the incidence of ventricular tachycardia during the ischaemic period from 67% to 20% (p less than 0.02) and 47% respectively. During reperfusion, mortality was reduced from 53% to 7% and 7% (p less than 0.02) respectively, and reperfusion induced ventricular fibrillation from 73% to 20% (p less than 0.01) and 47% respectively. When the drugs were given prior to ischaemia, the plasma concentrations of amiodarone and desethylamiodarone were 1.03 (SEM 0.18) and 0.22(0.02) micrograms.ml-1 and the myocardial concentrations were 23.43(2.78) and 30.41(1.87) micrograms.g-1 respectively. Similar concentrations were found in plasma and myocardium with drugs given prior to reperfusion. No significant differences in plasma or myocardial concentrations of amiodarone or desethylamiodarone were observed between animals which developed ventricular fibrillation and those which did not. In conclusion, this study demonstrates that desethylamiodarone can, like its parent compound, protect the heart against malignant ventricular arrhythmias arising as a consequence of regional myocardial ischaemia and reperfusion.

Amiodarone↗

PubMed1989

Free radicals and cardioplegia: organic anti-oxidants as additives to the St Thomas' Hospital cardioplegic solution.

The isolated perfused working rat heart model of cardiopulmonary bypass and ischaemic cardiac arrest has been used to investigate whether addition of various organic anti-oxidants to the St Thomas' Hospital cardioplegic solution can enhance the recovery of function of the rat myocardium after normothermic (37 degrees C) global ischaemic arrest. Five anti-oxidants were studied: (i) ascorbate (1.0 and 10.0 mmol.litre-1), (ii) methionine (1.0 and 10.0 mmol.litre-1), (iii) reduced glutathione (1.0 and 10.0 mmol.litre-1), (iv) dimethylthiourea (0.1, 1.0, 10.0 and 50.0 mmol.litre-1), (v) N-2-mercaptopropionyl glycine (0.1, 1.0 and 10.0 mmol.litre-1). The recovery of aortic flow in control hearts which were free of anti-oxidant was 50.7(SEM 0.5)%; ascorbate (1.0 or 10.0 mmol.litre-1) improved this recovery to 72.1(1.7) and 70.2(0.3)% respectively; methionine (1.0 and 10.0 mmol.litre-1) improved the recovery to 74.1(5.7)% and 67.7(1.7)%, respectively; reduced glutathione (1.0 and 10.0 mmol.litre-1) improved the recovery to 66.7(1.4)% and 74.0(1.7)% respectively. In further studies, the addition of dimethylthiourea (0.1, 1.0 and 10.0 mmol.litre-1) to the cardioplegic solution failed to improve recovery of aortic flow [47.3(8.0), 24.6(7.3), 48.0(7.7)% respectively] when compared to its anti-oxidant free control value of 40.4(6.1)% and at a concentration of 50.0 mmol.litre-1 a very poor recovery of aortic flow of 7.7(4.8)% was observed. Mercaptopropionyl glycine (0.1, 1.0 and 10.0 mmol.litre-1) also failed to improve the recovery of aortic flow [34.7(1.6), 34.7(7.7) and 25.6(5.4)% respectively.2+ Since biological membranes are highly permeable to dimethylthiourea and mercaptopropionyl glycine, it is possible that they accumulate in the intracellular compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

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↗

PubMed1989

Chronic whole body sympathectomy fails to protect ischemic rabbit hearts.

We determined whether chronic chemical sympathetic denervation could protect the rabbit heart against ischemia. Rabbits received 10 mg/kg 6-hydroxydopamine (6-HD) twice during the first week, then 100 mg.kg-1.wk-1 for the following 7 wk. After this interval the rabbits were anesthetized, the chests were opened, and in each a coronary branch was occluded for 45 min followed by reperfusion for 3 h. Collateral flow was determined with radioactive microspheres during coronary occlusion. Flow to the ischemic myocardium of the 6-HD group (0.06 +/- 0.03 ml.min-1.g-1) was not significantly different from that in the control group (0.04 +/- 0.02 ml.min-1.g-1). Infarct size was determined with triphenyltetrazolium chloride staining. Average infarct size calculated as a percentage of risk zone was similar in the 6-HD and control groups (59 +/- 15 and 60 +/- 12%, respectively). We conclude that chronic chemical sympathectomy does not induce collateral growth in the rabbit heart. Furthermore, endogenous catecholamines do not contribute to injury in the ischemic rabbit heart.

Animals↗

PubMed1989

Reperfusion arrhythmias: dose-related protection by anti-free radical interventions.

Isolated rat hearts (n = 15 per group) were subjected to regional ischemia (10 min) and reperfusion. Superoxide dismutase (SOD; 8 X 10(3), 2 X 10(4), 4 X 10(4), 6 X 10(4), 8 X 10(4), 1.2 X 10(5), or 1.6 X 10(5) IU/l) given early (i.e., throughout the experiment) reduced the incidence of reperfusion-induced ventricular fibrillation (VF), the dose-response characteristics describing an asymmetric U-shaped curve. The optimal dose of SOD (8 X 10(4) IU/l) reduced VF incidence from its control value of 87 to 27% (P less than 0.05). Given late (i.e., 2 min before reperfusion), this dose of SOD exerted a reduced but nonetheless significant antifibrillatory effect. Early administration of catalase (1 X 10(3), 1 X 10(4), 2.5 X 10(4), 5 X 10(4), 1 X 10(5), 1.5 X 10(5), or 1 X 10(6) IU/l) reduced VF incidence in a linear dose-dependent manner, from its control value of 87 to 7% with 1 X 10(6) IU/l (P less than 0.05). Late administration of this dose reduced VF incidence from its control value of 87 to 27% (P less than 0.05). Allopurinol (0.07, 0.15, 0.37, 0.73, 1.10, or 1.47 mM added to the perfusate throughout the experiment) significantly reduced VF incidence over a wide range of doses, but low and high doses were ineffective. Pretreatment with allopurinol (0, 0.01, 0.02, 0.05, 0.10, 0.20, or 0.50 g.kg-1.day-1 per os 48, 24, and 1 h before study) reduced VF incidence from its control value of 93 to less than 50% at several doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Allopurinol↗

PubMed1989

Singlet oxygen-induced arrhythmias. Dose- and light-response studies for photoactivation of rose bengal in the rat heart.

In a study of aerobically perfused rat hearts, the in situ photoactivation (530-590 nm) of rose bengal (a process that leads to the production of singlet oxygen and superoxide) has been shown to lead to the rapid development of electrocardiographic abnormalities and arrhythmias. With rose bengal concentrations of 1,000, 500, 250, 100, and 50 nmol/l (n = 6/group), photoactivation (3,600 lx) led to electrocardiographic changes (inversion of the T wave, Q-T prolongation, or both) after 3.8 +/- 0.9, 4.5 +/- 0.7, 11.8 +/- 2.1, 24.8 +/- 3.9, and 65.3 +/- 6.0 seconds), respectively; ventricular premature beats occurred in 100% of hearts after 0.5 +/- 0.2, 1.1 +/- 0.3, 2.2 +/- 0.7, 4.4 +/- 0.8, and 6.6 +/- 1.2 minutes, respectively. Ventricular tachycardia occurred in 83%, 83%, 83%, 67%, and 50% of hearts after 2.1 +/- 0.2, 2.1 +/- 0.4, 2.8 +/- 0.7, 5.7 +/- 2.0, and 11.2 +/- 1.9 minutes, respectively, and complete atrioventricular block in 100%, 100%, 100%, 100%, and 67% of hearts after 3.8 +/- 0.7, 6.5 +/- 1.0, 5.5 +/- 0.9, 13.8 +/- 1.0, and 14.1 +/- 0.9 minutes, respectively. With a fixed concentration (250 nmol/l) of rose bengal, similar light-response relations were observed. Photoactivation of rose bengal had no effect on heart rate but caused a transient (0-4 minutes) vasodilation followed by a progressive vasoconstriction. In further studies in which rose bengal was washed out for 10 minutes before photoactivation, several arrhythmias still developed, indicating that rose bengal binds strongly to tissue and acts as a cellular level rather than in the vascular compartment. To assess the reversibility of rose bengal-induced effects, hearts (n = 6/group) were perfused with rose bengal (250 nmol/l) for 1, 2, 4, 6, and 20 minutes followed by perfusion in the dark for 19, 18, 16, 14, and 0 minutes, respectively. During dark perfusion, the incidence of arrhythmias declined and any decrease in coronary flow was reversed. However, analysis of contents of adenosine triphosphate, creatine phosphate, lactate, and creatine kinase leakage indicated the occurrence of severe injury that did not abate on termination of photoactivation. Finally, although many arrhythmias developed before the onset of vasoconstriction, the reduction in flow with consequent ischemia was shown to exacerbate vulnerability to arrhythmias. In conclusion, short-lived reactive oxygen intermediates such as singlet oxygen and superoxide, which are produced during the photoactivation of rose bengal, can cause rapid and major damage to the heart and its function.

Animals↗

PubMed1989

Rapid electrophysiological changes leading to arrhythmias in the aerobic rat heart. Photosensitization studies with rose bengal-derived reactive oxygen intermediates.

The objective of this study was to determine whether reactive oxygen intermediates (e.g., singlet oxygen and the superoxide radical) can rapidly induce electrophysiological disturbances leading to the genesis of arrhythmias, even in the absence of ischemia and reperfusion. Rat hearts (n = 6 per group) were perfused aerobically at 37 degrees C for 10 minutes without rose bengal and for 5 minutes with rose bengal (250 nmol/l), during which time no changes in coronary flow or heart rate were observed. Hearts were then uniformly illuminated for 20 minutes with green light (530-590 nm) from 200 fiber optic cables. With light and without rose bengal, or vice versa, all hearts remained stable. However, in the illuminated rose bengal group, electrophysiological changes (inversion of the terminal portion of the T wave and an increase in Q-T interval) were observed within 11.8 +/- 2.1 seconds (i.e., less than 60 beats). All hearts exhibited ventricular premature beats (within 2.2 +/- 0.7 minutes) and ventricular tachycardia (within 2.8 +/- 0.7 minutes) before the occurrence of complete atrioventricular block (within 5.5 +/- 0.9 minutes). During the illumination period, coronary flow progressively fell in the rose bengal-perfused hearts from 11.6 +/- 0.5 ml/min to 2.0 +/- 0.4 ml/min (p less than 0.05 when compared with any control group). When a similar progressive reduction in coronary flow was mimicked (with or without rose bengal), no arrhythmias occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerobiosis↗

PubMed1989

Inability of desferrioxamine to limit tissue injury in the ischaemic and reperfused rabbit heart.

The role of iron-catalysed hydroxyl radical production in development of myocardial injury was examined in an in vivo rabbit heart with regional ischaemia (45 min) and reperfusion (3 h). Open-chest anaesthetised rabbits were assigned to control (saline) or desferrioxamine-treated [30 mg/kg subcutaneously (s.c.) plus 1, 10, 20, or 100 mg/kg/h intravenously (i.v.) starting 15 min before ischaemia] groups. Haemodynamics and ECG were monitored throughout. Following reperfusion, hearts were excised and perfused in vitro with buffer. The artery was religated, and fluorescent particles were injected to delineate the ischaemic zone. Tetrazolium staining was used to define necrosis. Planimetry was performed on photographed heart slices for calculation of the size of the hearts and of the ischaemic and infarcted zones. Infarct size (as a percentage of ischaemic zone size) in control hearts was 51.2 +/- 5.8% (n = 10) and in the groups treated with desferrioxamine 1, 10, 20, and 100 mg/kg/h it was 53.1 +/- 11.7% (n = 8), 45.3 +/- 6.3% (n = 9), 65.1 +/- 10.1% (n = 6), and 52.5 +/- 9.4% (n = 7), respectively (p = NS vs. control in each instance). In addition, no antiarrhythmic effects were observed at any dose. Thus, iron-catalysed hydroxyl radical damage may not play a role in the pathogenesis of tissue injury under these conditions.

Animals↗

PubMed1989

Protection of the immature myocardium during global ischemia. A comparison of four clinical cardioplegic solutions in the rabbit heart.

Controversy surrounds the reported beneficial effects of crystalloid cardioplegic solutions in the immature myocardium. In the present study we have investigated the efficacy of four clinical cardioplegic solutions in the immature myocardium to determine (1) whether cardioplegic protection could be demonstrated and, if so, (2) the relative efficacy of the four solutions. Isolated, working hearts (n = 6 per group) from neonatal rabbits (aged 5 to 8 days) were perfused aerobically (37 degrees C) for 20 minutes before a 2-minute infusion of one of four cardioplegic solutions: The St. Thomas' Hospital No. 2, Tyers, Bretschneider, and Roe solutions. Hearts were then rendered globally ischemic for 50 minutes at 37 degrees C before reperfusion for 15 minutes in the Langendorff mode and 20 minutes in the working mode. The postischemic recovery of cardiac function and leakage of creatine kinase were compared with results in noncardioplegic control hearts. Good protection was observed with the St. Thomas' Hospital and Tyers solutions: The postischemic recovery of cardiac output was increased from 21.2% +/- 12.7% in the cardioplegia-free group to 79.4% +/- 6.2% and 72.9% +/- 4.4%, respectively, in the St. Thomas' Hospital and Tyers groups (p less than 0.01). In contrast, no protection was observed with either the Bretschneider or Rose solutions: Cardiac output recovered to 31.7% +/- 10.3% and 5.1% +/- 3.2%, respectively, in these groups. Postischemic creatine kinase leakage was 72.4 +/- 12.3 and 92.1 +/- 18.6 IU/15 min/gm dry weight in the St. Thomas' Hospital and Tyers groups compared with 125.6 +/- 28.6 IU/15 min/gm dry weight in control hearts (p = no significant difference). In the Bretschneider group, creatine kinase leakage increased to 836.9 +/- 176.8 IU/15 min/gm dry weight (p less than 0.01 versus noncardioplegic control hearts), and with the Roe solution the value was 269.0 +/- 93.0 IU/15 min/gm dry weight (p = no significant difference). In conclusion, cardioplegic protection can be achieved in the immature rabbit myocardium with both St. Thomas' Hospital and Tyers solutions, but acalcemic solutions such as Bretschneider and Roe solutions (which may be effective in the adult heart) increased damage in this preparation. The reported lack of cardioplegic efficacy in the immature myocardium may therefore reflect the choice of cardioplegic solution rather than a greater vulnerability to injury in the neonatal heart.

Acetates↗