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D J Hearse

Publications and source records attributed to D J Hearse.

At least 91 records · Page 5Linked to original sources
PubMed1993

Single-dose versus multi-dose cardioplegia in the immature rat heart: studies with normothermic and hypothermic ischemia.

The efficacy of cardioplegia in the neonatal heart has been questioned and some studies have suggested that, in the rabbit, multi-dose hypothermic cardioplegia may be damaging. We have therefore compared the protective properties of multi-dose and single-dose cardioplegia in the immature rat heart with normothermic and hypothermic ischemia. Isolated Langendorff perfused hearts (n = 6 per group) from 8-10 day-old rats, were arrested with a single-dose (2 min at the onset of ischemia) or multi-dose (2 min at onset of ischemia and repeatedly throughout ischemia) of warm (37 degrees C) or cold (10 degrees C) St Thomas' Hospital cardioplegic solution. The hearts were then subjected to 1 h of normothermic global ischemia or 24 h of hypothermic ischemia, followed by normothermic reperfusion of 30 min. In the normothermic studies the post-ischemic recovery of left ventricular developed pressure was 44 +/- 6% of its pre-ischemic value with single-dose cardioplegia versus 56 +/- 4% with multi-dose (cardioplegic infusion every 15 min). In the hypothermic studies the trend was in the opposite direction; the postischemic recovery of left ventricular developed pressure was 46 +/- 2% in the single-dose group, whereas in the multi-dose (cardioplegic infusion every 6 h) group the recovery was 28 +/- 3% (p < 0.05). Thus, in accord with other studies in other species we have demonstrated that multi-dose cardioplegia fails to afford any substantial additional protection when compared with single-dose cardioplegia. Under conditions of extended hypothermia there may even be a detrimental effect of multi-dose cardioplegia.

Analysis of Variance↗
PubMed1993

Age-dependent changes in myocardial susceptibility to ischemic injury.

We studied the relation between age and the heart's ability to tolerate ischemia. Groups of 5-7 isolated Langendorff perfused hearts from neonatal (5 days old), immature (11-44 days old), and adult (54 days old) rats, were subjected to 60 minutes of global ischemia and 60 minutes of reperfusion at 37 degrees C. Pre-ischemic left ventricular developed pressure was 54 +/- 1, 56 +/- 2, 59 +/- 4, 80 +/- 3, 91 +/- 9, 91 +/- 8, 94 +/- 3, 101 +/- 10, 107 +/- 8 and 132 +/- 4 mmHg in the 5, 11, 14, 18, 23, 26, 33, 40, 44, and 54 day old groups, respectively. Left ventricular developed pressure recovered to 65 +/- 13, 69 +/- 4, 103 +/- 14, 84 +/- 10, 81 +/- 3, 59 +/- 11, 42 +/- 10, 34 +/- 6, 34 +/- 6 and 25 +/- 7% respectively. Ischemia-induced contracture was greater in adult hearts and the time-to-onset and the time-to-peak contracture decreased with increasing age. Leakage of creatine kinase after ischemia correlated poorly with the recovery of contraction. Left ventricular end-diastolic pressure, at the end of 60 minutes of reperfusion, increased in an age-dependent manner from a pre-ischemic value which was set at 2-8 mmHg to 14 +/- 4, 22 +/- 2, 21 +/- 5, 27 +/- 3, 47 +/- 16, 52 +/- 7, 71 +/- 7, 81 +/- 9, 73 +/- 5, and 82 +/- 8 mmHg in the 5, 11, 14, 18, 23, 26, 33, 40, 44, and 54 day old groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

PEG-SOD and myocardial antioxidant status during ischaemia and reperfusion: dose-response studies in the isolated blood perfused rabbit heart.

We have previously shown that the polyethylene glycol conjugated superoxide dismutase (SOD), which has a plasma half-life of more than 24 h, protects the blood perfused rabbit heart against injury during ischaemia and reperfusion. However, the profile for the dose-dependency of protection was bell-shaped with loss of efficacy below 6000 and above 30,000 U/kg. In the present study, isolated rabbit hearts, perfused with blood from support rabbits, were subjected to a 2 min infusion with St Thomas' Hospital cardioplegic solution followed by 60 min of global ischaemia (37 degrees C) and 60 min of reperfusion. PEG-SOD was administered 1 h or 12-24 h before ischaemia. We assessed the effect of PEG-SOD on ischaemia- and reperfusion-induced changes in: (i) the tissue content of reduced glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde (MDA) and (ii) the activity of CuZn-SOD, Mn-SOD and glutathione peroxidase and reductase (GPD and GRD). Ischaemia and reperfusion reduced tissue GSH content by 70% and increased GSSG content by 400% (from their fresh aerobic values of 13.1.9 and 0.09 +/- 0.01 nmol/mg protein, respectively). PEG-SOD, given intravenously at various doses to donor and support rabbits 1 h or 12-24 h before ischaemia, protected against these changes with a bell-shaped dose-response relationship. Thus, with 0, 3000, 6000, 12,000, 30,000 and 60,000 U/kg, GSH content was 4.1 +/- 0.4, 4.8 +/- 0.4, 8.5 +/- 0.5, 12.3 +/- 1.6, 12.3 +/- 1.6 and 5.0 +/- 0.5 nmol/mg protein in the 1 h pretreatment group and 4.1 +/- 0.4, 4.2 +/- 0.5, 10.4 +/- 1.5, 11.2 +/- 1.1, 11.4 +/- 0.7 and 4.7 +/- 0.6 nmol/mg protein in the 12-24 h pretreatment group (means +/- S.E.M.). For GSSG the corresponding values were 0.36 +/- 0.04, 0.34 +/- 0.03, 0.12 +/- 0.01, 0.12 +/- 0.01, 0.11 +/- 0.01 and 0.41 +/- 0.03 nmol/mg protein for the 1 h group and 0.36 +/- 0.04, 0.35 +/- 0.02, 0.15 +/- 0.01, 0.12 +/- 0.01, 0.11 +/- 0.01 and 0.34 +/- 0.02 nmol/mg protein for the 12-24 h group. Ischaemia and reperfusion had no effect on tissue MDA content or CuZn-SOD, GDP and GRD activity, and in general, PEG-SOD also lacked significant effect on any of these variables at any dose studied. However, Mn-SOD activity was severely reduced by ischaemia and reperfusion (from 42 +/- 7 U/mg protein in fresh aerobic controls to 6 +/- 1 U/mg protein at the end of reperfusion).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Ischaemic preconditioning and contractile function: studies with normothermic and hypothermic global ischaemia.

A significant reduction in the extent of cell necrosis or the incidence of reperfusion-induced arrhythmias can be achieved with ischaemic preconditioning. If preconditioning was also found to be effective in protecting against global ischaemia, then this may have significant implications for the preservation of the heart during cardiac surgery. We therefore investigated this phenomenon in relation to recovery of contractile function after global ischaemia in the isolated rat heart. Isolated working rat hearts (n = 6 per group) were perfused aerobically at 37 degrees C for 20 min and contractile function recorded. This was followed by 10 min of aerobic Langendorff perfusion (control hearts) or 5 min global ischaemia (37 degrees C) + 5 min Langendorff reperfusion (preconditioned hearts). The hearts were then subjected to 10, 15, 20 or 25 min of global ischaemia (37 degrees C) and reperfusion (15 min Langendorff + 20 min working) after which function was again assessed. Preconditioning improved functional recovery after all durations of ischaemia. Thus aortic flow after 10, 15, 20 and 25 min of ischaemia and 35 min of reperfusion recovered to 84, 58, 16 and 5%, respectively, in controls and 88, 74, 55 and 20%, respectively, in the preconditioned groups. To assess whether preconditioning was effective in a surgically relevant model of hypothermic ischaemia, the experiments were repeated with longer periods (45, 70, 90, 115, 135 and 160 min) of ischaemia at 20 degrees C. Under these conditions, normothermic preconditioning increase the post-ischaemic recovery of aortic flow after 115, 135 and 160 min of ischaemic (from 36, 20 and 10%, respectively, in controls to 57, 39 and 26%, respectively, in preconditioned hearts). There was no consistent correlation between tissue high energy phosphate content and enhanced post-ischaemic recovery. Thus, we have demonstrated that ischaemic preconditioning can improve contractile function after global ischaemia in the isolated rat heart, we have defined the duration of ischaemia for which it is operative, and we have shown that this protection is additive to that of hypothermia-induced protection during ischaemia. This may have clinical implications for cardiac surgery.

Adenosine↗
PubMed1992

Developmental changes in tolerance to ischaemia in the rabbit heart: disparity between interpretations of structural, enzymatic and functional indices of injury.

The vulnerability of the heart to injury during ischaemia and reperfusion and its responsiveness to various protective and pharmacological interventions are age-dependent. Using three independent indices of tissue injury (cardiac structure, contractile function and creatine kinase leakage), we compared the response of adult (60-90 days old) and neonatal (7 days old) isolated perfused rabbit hearts to global ischaemia and reperfusion. Prior to ischaemia, heart rate was significantly higher in neonatal hearts, as were control values for coronary flow, aortic flow and cardiac output when expressed on a dry wt basis. In experiments in which adult and neonatal hearts (n = 8 per group) were subjected to 2 min of cardioplegia and 45 min of ischaemia, the post-ischaemic recovery of all indices of cardiac function (when expressed as a percentage of pre-ischaemic control) was significantly higher in neonatal than in adult hearts. Thus, cardiac output recovered to 82.9 +/- 3.6% in the neonate but to only 57.9 +/- 6.7% in the adult (P < 0.05). The functional evidence of a greater resistance to ischaemia in the neonate was, however, contradicted by the levels of creatine kinase leakage which tended to be greater in the neonatal than in the adult heart (32.0 +/- 4.7 vs 20.0 +/- 3.1 IU/15 min/g dry wt). Morphological studies indicated that injury was comparable (moderate-to-severe in degree) in both groups. To assess further the relationship between the three indices, additional experiments were undertaken in which the duration of ischaemia in the neonate was extended to 60 min so that the post-ischaemic recovery of function was reduced to a level similar to that seen in the adult after 45 min of ischaemia. Under these conditions cardiac output recovered to 55.6 +/- 4.8% in the neonatal heart (P = NS when compared with the adult) and creatine kinase leakage increased to 88.2 +/- 13.9 IU/15 min/g dry wt--a value over four times greater than that measured in adult hearts with a comparable degree of functional injury. Morphological examination of tissue obtained after 15 min of reperfusion revealed a remarkable recovery of structure in both age groups. In conclusion, in functional terms the neonatal heart was more resistant to ischaemia than the adult; enzymic leakage, however, indicated the opposite and structural assessment revealed no differences. Thus, in comparing injury during ischaemia and reperfusion between different age groups, it is clearly important to employ several independent indices.

Age Factors↗
PubMed1992

Diabetes and susceptibility to reperfusion-induced ventricular arrhythmias.

Studies using chemically-induced models of diabetes have shown the diabetic myocardium to exhibit abnormalities in cellular ion transport, which may affect susceptibility to reperfusion-induced arrhythmias. We studied the incidence of reperfusion-induced ventricular tachycardia (VT) and fibrillation (VF) in isolated hearts from rats with streptozotocin-induced diabetes and from age-matched and weight-matched control rats (n = 12 per group). Following 5 min of regional ischaemia, reperfusion resulted in a similarly low incidence of arrhythmias in all three groups. Following 10 min of regional ischaemia, the incidence of VT was 92, 100 and 92%, and the incidence of VF was 75, 92 and 92% in diabetic, age-matched control and weight-matched control groups, respectively (NS). However, among those hearts which exhibited VF, the incidence of sustained (greater than or equal to 120 s) VF was 73 and 55% in age-matched and weight-matched control groups, respectively, and 0% in the diabetic group (P less than 0.05 vs both controls). The mean duration of VF in the diabetic group was reduced from 201 +/- 33 and 171 +/- 36 s in age-matched and weight-matched control groups, respectively, to 9 +/- 3 s (P less than 0.05). Thus, streptozotocin-induced diabetes in the rat does not result in an increased susceptibility to reperfusion-induced arrhythmias. To the contrary, hearts from diabetic rats are less susceptible to potentially lethal arrhythmias during reperfusion. Likely contributory factors to this phenomenon include (i) increased myocardial content of free radical scavenging enzymes, (ii) prolonged action potential duration, and (iii) reduced activity of sarcolemmal Na+/H+ and Na+/Ca2+ exchange processes, all of which have previously been reported in similar models of diabetes.

Animals↗
PubMed1992

Effects of potassium channel modulation during global ischaemia in isolated rat heart with and without cardioplegia.

OBJECTIVE: The opening of potassium (K+) channels during regional ischaemia may, by inducing rapid contractile arrest, be an intrinsic energy sparing mechanism. Thus K+ channel openers (for example, lemakalim) exert significant anti-ischaemic effects, whereas glibenclamide exacerbates ischaemic contracture and limits postischaemic functional recovery. The aim of the study was to investigate the ability of these compounds to influence ischaemic injury when used either alone or in combination with rapid arrest induced by a high K+ cardioplegic solution. METHODS: Contractile function of isolated Langendorff perfused rat hearts was assessed using an intraventricular balloon. Hearts were subjected to normothermic global ischaemia (20 min) or cardioplegic arrest (35 min) with and without glibenclamide or lemakalim. Lemakalim (10 mumol.litre-1) or glibenclamide (10 mumol.litre-1) was given, in the presence or absence of cardioplegia, for 2 min immediately prior to the onset of ischaemia. The rate of ischaemia induced contractile failure, the severity of ischaemic contracture, and the degree of postischaemic functional recovery were all measured. RESULTS: In the absence of cardioplegia, the time to contractile arrest in control hearts was 133 (SEM 4) s. This was increased by glibenclamide, to 145(6) s, and decreased by lemakalim, to 112(6) s. The time to onset of ischaemic contracture [8(1) min] was accelerated by glibenclamide [4(1) min] and delayed by lemakalim [14(1) min]. Lemakalim significantly improved the recovery of left ventricular developed pressure from 49(7)% in control hearts to 65(3)%, and left ventricular end diastolic pressure from 41(3) to 21(4) mm Hg. Hearts pretreated with glibenclamide showed similar recoveries to control hearts. During reperfusion, lemakalim exerted a transient vasodilator effect whereas glibenclamide caused a transient vasoconstriction. When either glibenclamide or lemakalim was added to a high K+ cardioplegic solution and hearts rendered ischaemic for 35 min, the ability of both compounds to influence ischaemic contracture and postischaemic functional recovery was lost. In additional studies the effect of lemakalim on the relative times to ischaemia induced mechanical failure and electrical arrest was assessed. In control hearts the time to contractile failure was 128(5) s and the time to electrical arrest was 241(30) s, while in the lemakalim treated hearts the values were 103(2) s and 509(161) s, respectively. In the lemakalim group all the hearts showed sustained ventricular arrhythmias; in the control group there were no arrhythmias. CONCLUSIONS: Lemakalim can exert a significant anti-ischaemic effect when given alone. This effect is lost when it is used in combination with high K+ cardioplegia. The anti-ischaemic properties of lemakalim may thus be limited to its ability to accelerate contractile arrest.

Animals↗
PubMed1992

Reperfusion induced injury: manifestations, mechanisms, and clinical relevance.

Although reperfusion is an absolute prerequisite for the survival of ischaemic tissue, it is not necessarily without hazard. Many (but not all) cardiologists are of the opinion that some component of reperfusion may be detrimental and able to inflict injury over and above that attributable to the ischaemia. In this article we define four sequelae of reperfusion which might be designated as "reperfusion injury", we identify possible underlying mechanisms, and consider whether any of these forms of reperfusion injury are of clinical relevance.

Animals↗
PubMed1992

Rate of reflow and reperfusion induced arrhythmias: studies with dual coronary perfusion.

OBJECTIVE: The aim was to determine the relationship between the rate of reflow and vulnerability to reperfusion induced arrhythmias. METHODS: Isolated rat hearts, in which left and right coronary arteries were perfused independently, were subjected to transient (10 min) cessation of flow to the left coronary bed. During the subsequent 10 min of reperfusion, flow in the left coronary bed was regulated to create five different reflow profiles (n = 12 per group): (1) immediate restoration of 100% flow which was maintained throughout reperfusion (control); (2) stepwise restoration of flow with 10% flow from 0-1 min, 20% flow from 1-2 min, 40% flow from 2-3 min, 60% flow from 3-4 min, 80% flow from 4-5 min, and 100% flow from 5-10 min; (3) 10% flow from 0-5 min and 100% flow from 5-10 min; (4) 20% flow from 0-5 min and 100% flow from 5-10 min; and (5) 40% flow from 0-5 min and 100% flow from 5-10 min. RESULTS: There were no significant differences between the groups in the incidences of reperfusion induced ventricular tachycardia or fibrillation, which were 100% and 58-92%, respectively. However, the time to onset of reperfusion induced ventricular fibrillation was delayed (p less than 0.05) from 15 (SEM 1) s in group (1) to 191(39), 210(38), and 77(29) s in groups 2, 3, and 4, respectively. No significant delay was observed in group 5. There were no significant differences between the groups in size of ischaemic zone or heart rate. CONCLUSIONS: In crystalloid perfused hearts, restricted reflow delays the time to onset of reperfusion induced ventricular fibrillation but does not reduce the incidence of reperfusion induced ventricular tachycardia or fibrillation.

Animals↗
PubMed1992

Influence of low-flow infusion and magnesium on tissue necrosis during regional ischemia in the canine myocardium.

Passive intracoronary perfusion of therapeutic agents has been used in the clinical setting to attenuate the effects of brief episodes of myocardial ischemia. The objective of this study was to assess the effects of low-flow coronary infusion with or without Mg2+ on tissue necrosis and cardiac hemodynamics after prolonged regional ischemia. In 33 anesthetized dogs (5 excluded during study), the left anterior descending coronary artery was occluded for 6 h. Dogs were assigned to three groups: the first group (n = 8) was subjected to 6 h coronary occlusion without low-flow perfusion (controls), the second group (n = 10) received a low-flow coronary infusion of Ringer's lactate (Mg(2+)-free), and the third group (n = 10) received a low-flow coronary infusion of Ringer's lactate plus Mg2+ sulfate (15 mM). Tissue necrosis was evaluated using tetrazolium staining and was normalized to the principal baseline predictors of infarct size including anatomic risk zone (microsphere autoradiography) and coronary collateral flow. In control hearts, infarct size comprised 51.1 +/- 4.1% of the risk zone (40.8 +/- 5.1% left ventricular cross-sectional area (LV)). In the Mg(2+)-free and Mg2+ groups, risk zone size was 17.3 +/- 2.2 and 16.8 +/- 1.8% LV (p < 0.05 vs. controls), while infarct size was 23.1 +/- 3.1 and 24.9 +/- 8.1% (p < 0.05 vs. controls), respectively. Coronary collateral flow in the endocardium was similar for all of the experimental groups; however, hearts subjected to ischemia with low-flow perfusion of Ringer's lactate demonstrated significantly higher epicardial coronary collateral flow levels compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

PEG-SOD improves postischemic functional recovery and antioxidant status in blood-perfused rabbit hearts.

The isolated blood-perfused rabbit heart, subjected to 60 min of cardioplegic arrest and 60 min of reperfusion, was used to assess the effects of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) on postischemic recovery of left ventricular developed pressure (LVDP), the tissue activity of SOD, and tissue redox state. The five groups studied were the following: PEG-SOD-free control (group A), PEG-SOD as a pretreatment and as an additive during cardioplegia and reperfusion (group B), PEG-SOD as a pretreatment and a cardioplegic additive (group C), PEG-SOD in cardioplegia alone (group D), and PEG-SOD in reperfusion alone (group E). The results show that pretreatment with PEG-SOD improves postischemic recovery of LVDP (72 +/- 2% and 66 +/- 7 vs. 47 +/- 4% in groups B, C, and A, respectively). This protection was associated with an improved tissue redox state. Thus the ischemia-induced rise in oxidized glutathione was reduced from 313 +/- 26% (group A) to 162 +/- 15 and 138 +/- 14% (groups B and C, respectively), and the fall in reduced glutathione was attenuated from 51 +/- 5% to 35 +/- 6 and 13 +/- 5%, respectively. Tissue Mn-SOD activity was also conserved from 36 +/- 4% (group A) to 71 +/- 6 and 94 +/- 4% (groups B and C, respectively). No significant effect was seen when PEG-SOD was applied in cardioplegia or during reperfusion alone.

Animals↗
PubMed1992

Sustained protection by acadesine against ischemia- and reperfusion-induced injury. Studies in the transplanted rat heart.

BACKGROUND: We have shown that acadesine (AICAr: 5-amino-4-imidazole carboxamide riboside) improves the early recovery of function of the ischemic and reperfused rat heart. In the present studies we used the transplanted rat heart, with reperfusion for up to 24 hours, to assess whether the beneficial effect of acadesine is a transient or a sustained phenomenon (i.e., to determine whether the drug improves the extent of recovery or only the rate). METHODS AND RESULTS: Hearts (n = 8 per group) were excised and immediately arrested with an infusion (2 minutes at 20 degrees C) of the St. Thomas' Hospital cardioplegic solution with or without the addition of acadesine (20 mumol/l). They were then subjected to 4 hours of global ischemia (20 degrees C), and the cardioplegic solution (with or without acadesine) was infused for 2 minutes every 30 minutes. The hearts then were transplanted (1 hour additional ischemic time) into the abdomens of recipient rats, which had been given acadesine (100 mg/kg i.v.) or saline. They were reperfused in situ for 30 minutes or 24 hours and then excised and perfused aerobically for 20 minutes. Contractile function was assessed, and the hearts were taken for metabolite analysis. Two sets of four groups (n = 8 per group) were studied (one set with 30 minutes and the other with 24 hours of reperfusion): group A, acadesine-free control; group B, acadesine during cardioplegia alone; group C, acadesine during reperfusion alone; and group D, acadesine during both cardioplegia and reperfusion. With 30 minutes of reperfusion, a significant improvement in functional recovery was seen in the two groups (groups B and D) in which acadesine had been added to the cardioplegic solution. Left ventricular developed pressure (LVDP) at 12 mm Hg of left ventricular end-diastolic pressure (LVEDP) was 104 +/- 3 mm Hg in both groups versus 88 +/- 3 mm Hg in the acadesine-free controls (p less than 0.05). No protection was observed after 30 minutes of reperfusion when acadesine had been added during reperfusion alone (89 +/- 4 mm Hg). In contrast, after 24 hours of reperfusion there was a significant improvement in postischemic LVDP in all acadesine-treated groups (group B, 104 +/- 6 mm Hg; group C, 106 +/- 7 mm Hg; and group D, 117 +/- 3 mm Hg versus only 73 +/- 6 mm Hg in the acadesine-free controls; p less than 0.05 in each case). Metabolite analysis indicated that at the end of ischemia ATP was less depleted and levels of tissue adenosine were higher in the acadesine group. During early (30 minutes) reperfusion, acadesine produced higher mean ATP contents, although this achieved a level of statistical significance only when the drug was administered during both cardioplegia and reperfusion. After 24 hours of reperfusion, the adenine nucleotide pools were similar in all groups. CONCLUSIONS: Acadesine can afford sustained functional protection against injury during extended periods of ischemia and reperfusion. We present evidence that the beneficial effect of acadesine may be mediated by two different components, with one operative during ischemia and early reperfusion and the other acting later in the reperfusion period.

Abdomen↗
PubMed1992

Acadesine and myocardial protection. Studies of time of administration and dose-response relations in the rat.

BACKGROUND: Although there are many factors that might contribute to tissue injury during ischemia and reperfusion, the loss of adenine nucleotides has long been considered to be of importance. This has led to the study of interventions designed to limit the loss of nucleotides or to enhance the rate of nucleotide resynthesis during reperfusion. Alternatively, the breakdown of adenosine triphosphate to adenosine might represent a protective response of the ischemic heart because adenosine is considered an anti-injury autocoid. Augmentation of endogenous adenosine levels might be beneficial. For these reasons, the protective properties of acadesine (AICAr: 5-amino-4-imidazole carboxamide riboside) were assessed in a rat model of myocardial ischemia and reperfusion. METHODS AND RESULTS: The protective properties of acadesine were studied in the isolated, perfused rat heart subjected to global hypothermic (20 degrees C) ischemia and reperfusion. When acadesine was given as an in vivo pretreatment (100 mg/kg i.v. 15 minutes before study) followed by being administered as an additive (20 mumol/l) to the St. Thomas' Hospital cardioplegic solution (single dose) and then as an additive (20 mumol/l) to the initial reperfusion (15 minutes) solution, the recovery of aortic flow after 2.5 hours of ischemia was improved from its control value of 16.5 +/- 3.9 ml/min to 28.9 +/- 4.1 ml/min (n = 8 per group; p less than 0.05). Similar protection was seen with other indexes of cardiac function. Analysis of hearts obtained at the end of 2.5 hours of ischemia and 35 minutes of reperfusion revealed no significant differences in metabolite content between control and drug-treated hearts with the exception of inosine monophosphate, which was increased from its drug-free control value of 0.10 +/- 0.01 mumol/g dry wt to 0.86 +/- 0.06 mumol/g dry wt (p less than 0.05). In further studies (n = 8 per group), with multidose (every 30 minutes) cardioplegia and extended periods (6 hours) of hypothermic ischemia, acadesine consistently led to higher mean recoveries of function and lower levels of creatine kinase leakage. Again, the only significant metabolic effect was an increase in tissue inosine monophosphate content. In studies (n = 12 per group) to determine whether acadesine was acting before, during, or after ischemia, the drug was given 1) only as pretreatment (100 mg/kg i.v.), 2) only during single-dose cardioplegia (20 mumol/l), or 3) only during reperfusion (20 mumol/l). Significant protection was observed in the first two groups (recovery of aortic flow increased from 10.6 +/- 2.6 ml/min in the acadesine-free control to 22.6 +/- 2.8 and 23.6 +/- 3.1 ml/min, respectively; p less than 0.05). No significant protection was observed when acadesine was given only during reperfusion. In dose-response studies, acadesine (0, 5, 20, 50, 200, and 1,000 mumol/l; n = 12 per group) was given only as a cardioplegic additive; the postischemic recoveries of aortic flow were 15.4 +/- 2.8, 16.9 +/- 3.6, 29.5 +/- 3.8, 27.4 +/- 3.8, 26.7 +/- 4.2, and 27.1 +/- 2.7 ml/min, respectively. CONCLUSIONS: Acadesine improves the ability of the heart to recover from ischemia and reperfusion when administered before ischemia or with cardioplegia. The mechanism underlying the protection remains to be resolved.

Adenine Nucleotides↗
PubMed1992

PEG-SOD and myocardial protection. Studies in the blood- and crystalloid-perfused rabbit and rat hearts.

BACKGROUND: Polyethylene glycol, covalently linked to superoxide dismutase (PEG-SOD), has a long plasma half-life (greater than 30 hours) and has been proposed as an effective agent for reducing free radical-mediated injury ischemia and reperfusion. METHODS AND RESULTS: Using an isolated rabbit heart perfused with arterial blood from a support rabbit, we have demonstrated that pretreatment with PEG-SOD (30,000 units/kg, intravenous bolus, 12-24 hours before 60 minutes of normothermic global ischemia), combined with addition of PEG-SOD to the blood perfusion circuit (30,000 units/kg to the support rabbit) and inclusion of PEG-SOD (150 micrograms/ml) in a cardioplegic solution, enhanced the postischemic recovery of left ventricular developed pressure (LVDP) from 51 +/- 6 to 74 +/- 9 mm Hg (p less than 0.05; n = 9 per group). In further studies we showed that, whereas maximum protection was obtained when PEG-SOD was given as a combined pretreatment and additive to both the cardioplegic and the reperfusate solutions (postischemic LVDP recovery increased from 44 +/- 4% in the control group to 70 +/- 3% in the PEG-SOD group), the administration of PEG-SOD during pretreatment plus cardioplegia or during reperfusion alone also resulted in a significant improvement in postischemic function (62 +/- 7% and 60 +/- 3%, respectively). However, the use of PEG-SOD as a cardioplegic additive alone failed to afford protection (47 +/- 4% recovery of LVDP). In dose-response studies (with 0, 3,000, 6,000, 12,000, 30,000, or 60,000 units/kg; n = 8 per group), maximum recovery of LVDP was obtained with the administration of 12,000 units/kg of PEG-SOD. Studies of the plasma activity of PEG-SOD confirmed its long half-life and showed that the treatment with PEG-SOD either 1 hour or 12-24 hours before the study resulted in similar levels of plasma activity. In an attempt to assess any involvement of blood-borne elements in the protection afforded by PEG-SOD, studies were also carried out in the crystalloid-perfused rabbit heart, and no protection was observed. Similarly, no protection was observed at any one of a variety of doses in the crystalloid-perfused rat heart. CONCLUSIONS: PEG-SOD can afford protection in the blood-perfused rabbit heart; this protection is dose dependent and probably involves some action of PEG-SOD on blood-borne elements, possibly leukocytes.

Animals↗
PubMed1992

Brain death-induced impairment of cardiac contractile performance can be reversed by explantation and may not preclude the use of hearts for transplantation.

The shortage of suitable donor hearts for cardiac transplantation is exacerbated by the exclusion of those that exhibit contractile malfunction during the period after brain death but before excision. We have replicated the phenomenon of brain death-induced hemodynamic deterioration in the rat in vivo. After 60 minutes of brain death (defined as the absence of electrical activity in the brain), a variety of indicators of cardiac contractile function fell by approximately 50% (thus cardiac index fell from 21 +/- 2 to 11 +/- 1 ml/min per 100 g body weight). However, once excised and perfused ex vivo, the hearts recovered a level of cardiac function that was identical to that from control animals that had not been subjected to brain death. Similarly, when hearts were excised, stored (6 hours at 4 degrees C), and reperfused ex vivo with blood, they also recovered a functional capability identical to that of normal hearts from animals that had not been subjected to brain death. Our results question whether hemodynamic instability in brain-dead individuals is necessarily an irreversible detrimental cardiac phenomenon and whether these hearts should be excluded from transplantation.

Animals↗
PubMed1992

Transient hypocalcemic reperfusion does not improve postischemic recovery in the rat heart after preservation with St. Thomas' Hospital cardioplegic solution.

We used the isolated perfused working rat heart to investigate the effects of transient hypocalcemic reperfusion after cardioplegic arrest with the St. Thomas' Hospital cardioplegic solution and 25 minutes of global normothermic (37 degrees C) ischemia. Hearts were reperfused (Langendorff mode) transiently (20 minutes) with solutions containing various concentrations of calcium; this was followed by 30 minutes of reperfusion with standard (1.4 mmol/L, the physiologic concentration) calcium buffer (10 minutes in the Langendorff mode and 20 minutes in the working mode). Recovery of cardiac output in control hearts (calcium concentration 1.4 mmol/L throughout) was 51.7% +/- 4.6%; in hearts transiently reperfused with hypocalcemic buffer (0.25, 0.5, 0.75, or 1.0 mmol/L) the recoveries of cardiac output were 49.3% +/- 6.4%, 52.2% +/- 7.2%, 58.7% +/- 3.2%, and 47.2 +/- 4.7%, respectively (all not significant), whereas recovery was only 14.7% +/- 2.8% (p less than 0.05) in hearts transiently reperfused with calcium 0.1 mmol/L. Creatine kinase leakage was significantly (p less than 0.05) greater in the group reperfused with calcium 0.1 mmol/L, but it did not vary significantly between the other groups. Tissue high-energy phosphate content was similar and in the normal range in all groups except for the group reperfused with calcium 0.1 mmol/L. In further experiments, the duration of hypocalcemic (0.5 mmol/L) reperfusion was varied (0, 5, 10, 15, 20, or 30 minutes). No significant differences in recovery of cardiac output were observed (58.2% +/- 5.0%, 52.3% +/- 5.7%, 52.0% +/- 8.2%, 61.2% +/- 5.0%, 62.2% +/- 4.3%, and 66.2% +/- 3.2%, respectively). In additional studies, the standard calcium concentration (1.4 mmol/L) used before and after ischemia was replaced by hypercalcemic solution (2.5 mmol/L). Despite this, transient (10 minutes) hypocalcemic (0.5 mmol/L) reperfusion did not improve recovery. Finally, studies were undertaken with a longer duration of ischemia (40 minutes), and although recovery of cardiac output in the hypocalcemic group (0.5 mmol/L for 10 minutes) tended to be higher than in the control group (29.7% +/- 4.8% versus 18.5% +/- 4.9%, respectively), statistical significance was not achieved. We conclude that in these studies transient hypocalcemic reperfusion did not afford any additional protection over and above that afforded by cardioplegia alone.

Adenosine Triphosphate↗
PubMed1992

Mechanical unloading and infarct size: studies with the heterotopically transplanted rabbit heart.

The possibility that unloading the heart during regional ischemia and/or reperfusion may limit infarct size was investigated by inducing regional ischemia in both a heterotopically transplanted heart (unloaded) and the recipient's heart (loaded control). In this way, the extent of myocardial infarction was compared in paired hearts in the same animal under similar experimental conditions. Hearts excised from donor rabbits, were arrested with St. Thomas' Hospital cardioplegic solution and maintained at 15 degrees C for 1 hour during which time they were transplanted into the necks of recipient rabbits. 24 hours later, rabbits were reanesthetized and the left circumflex coronary artery ligated in both the transplanted and the recipient's hearts. After 1 hour of regional ischemia hearts were reperfused for 3 hours. The transplanted heart was paced at 205 beats per minute (bpm) throughout the experiment. Similar values for infarct size were obtained in both the loaded and unloaded hearts (73 +/- 4% vs 75 +/- 6%, respectively). No significant differences were seen in any other parameters. In conclusion, our results suggest that during regional ischemia the amount of work performed by the heart does not appear to be a major factor in determining the ultimate size of an infarct.

Animals↗