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Biomedical subjects

D J Hearse

Publications and source records attributed to D J Hearse.

At least 37 records · Page 2Linked to original sources
PubMed1997

Acute increase of myocardial workload, hemodynamic instability, and myocardial histological changes induced by brain death in the cat.

Brain death-related hemodynamic instability may preclude donor heart procurement. The relationships between the initial changes of myocardial workload, hemodynamic deterioration, and myocardial histological changes caused by acute induction of brain death are unclear. Cats (n = 15) were submitted to brain death by rapid inflation of an intracranial balloon. A further 12 cats served as a sham-operated control group. The changes in heart rate, mean arterial blood pressure, systolic and diastolic arterial blood pressure, left ventricular developed pressure, LV dP/dtmax, rate-pressure product (RPP), and circulating noradrenaline and adrenaline were studied during 240 min after the induction of brain death. Central venous pressure was kept constant. The hearts were histologically examined afterward. Electrocerebral activity disappeared within 30 sec after balloon inflation. At 3 min, noradrenaline and adrenaline levels had increased 75- and 40-fold, respectively, compared to pre-induction levels. The hemodynamic response was characterized by an early and rapid increase of hemodynamic variables at 2.9 +/- 0.2 min. This was followed by a second phase of normalization or deterioration. Two distinct subgroups (n = 9) became hemodynamically unstable (HDU), characterized by a systolic arterial blood pressure < 90 mm Hg, at 108 +/- 29 min, and progressively deteriorated to 67 +/- 8 mm Hg at 240 min after inflation of the balloon. The hemodynamic variables of the other, hemodynamically stable (HDS), subgroup (n = 6) normalized at 60 min after inflation. Hemodynamic deterioration of the HDU subgroup compared to the HDS subgroup was significant at 10 min after induction of brain death. The maximum values of RPP were similar in the two subgroups. Respiratory and metabolic variables at the end of the experiment were not different in both subgroups. Histological evidence of myocardial damage was present in 73% (11/15) of the brain dead cats and absent in the control group. The histological changes were identified both in hearts of HDU (6/9) and HDS (5/6) cats. In the cat, no relationships were demonstrated between the acute increase of myocardial workload, the occurrence of hemodynamic deterioration, and myocardial histological changes after rapid induction of brain death. These results may contribute to the discussion whether hemodynamic instability of the donor is an appropriate exclusion criterion for heart transplantation.

Animals↗
PubMed1997

Impaired cardioplegic delivery and the loss of cardioprotection: a role for preconditioning.

We have previously shown that, while ischemic preconditioning and cardioplegia afford similar protection against injury during ischemia and reperfusion, this protection is not additive. However, it is not known whether the same applies when the delivery of cardioplegia is suboptimal, such as may occur in the case of a coronary stenosis. To investigate the protective effect of cardioplegia v preconditioning when the delivery of cardioplegia is impaired, isolated rat hearts were subjected to 40 min of global ischemia followed by 40 min of reperfusion. Seven groups of hearts (1 g wet wt) were studied (n = 8/group): Group 1: controls with unprotected ischemia (no intervention): Group 2: in which only 0.2 ml of the St Thomas' cardioplegic solution was administered (2 min) prior to ischemia: group 3: in which the volume of cardioplegic solution was increased to 0.5 ml: Group 4: received 1.0 ml of cardioplegia: Group 5: received 2.0 ml of cardioplegia: Group 6: were subjected to ischemic preconditioning (3 min ischemia, 3 min reperfusion, 5 min ischemia, 5 min reperfusion) prior to ischemia: and Group 7: in which ischemic preconditioning and cardioplegia (1.0 ml) were used in combination. The mean postischemic recovery of left ventricular developed pressure (LVDP), expressed as a percentage of its pre-ischemic value, was 33 +/- 3% in the control group: this was significantly improved (P < 0.05) in hearts receiving 2.0 ml of cardioplegia (59 +/- 5%), whereas volumes of 0.2, 0.5 or 1.0 ml of cardioplegia afforded no significant protection (recoveries of LVDP were 32 +/- 6%, 37 +/- 5% and 37 +/- 5%, respectively). Preconditioning alone and the combination of preconditioning plus 1.0 ml of cardioplegia afforded similar protection (57 +/- 3%, and 58 +/- 3%, P < 0.05 v controls). At the end of reperfusion, left ventricular end-diastolic pressure (LVEDP) was substantially increased in control hearts (57 +/- 3 mmHg): it was decreased in the groups receiving 2.0 ml of cardioplegic solution (40 +/- 5 mmHg; P < 0.05 v control group), but not in the group receiving 0.2, 0.5 or 1.0 ml of cardioplegic solution (59 +/- 4, 55 +/- 3 and 54 +/- 4 mmHg, respectively). Again, preconditioning alone or preconditioning plus 1.0 ml of cardioplegia afforded similar good protection (39 +/- 1 mmHg and 37 +/- 2 mmHg, respectively). A similar pattern was observed for the post-ischemic recovery of coronary flow. Under conditions where the delivery of cardioplegia is impaired (< 2.0 ml/g myocardium) preconditioning alone or preconditioning in combination with cardioplegia is more protective that cardioplegia alone. These results may be of clinical interest because most patients undergoing surgery for ischemic heart disease suffer from severe coronary artery lesions that may prevent the delivery of sufficient cardioplegic solution to ensure maximum protection.

Animals↗
PubMed1997

Multiple cycles of preconditioning cause loss of protection in open-chest rabbits.

Although single or multiple bursts of ischemic preconditioning have been shown to protect against myocardial necrosis, the frequency-dependency of the protection afforded by multiple stimuli has not yet been systematically studied in the anesthetized animal. The aim of the present study was to characterize the effect of increasing numbers of preconditioning stimuli (5 min ischemia plus 10 min reperfusion) in a collateral-deficient species in vivo. Rabbits were anesthetized and divided into groups (n = 5-7/group) which were subjected to 0, 1, 2, 4, 6 or 8 cycles of preconditioning (each comprising 5 min of regional ischemia plus 10 min reperfusion) followed by 45 min of regional ischemia and 2 h reperfusion. An additional group, serving as a control, was subjected to eight cycles of preconditioning without a subsequent 45 min of regional ischemia. Infarct size (I) and risk zones (R) were delineated with the aid of tetrazolium staining and fluorescent particles and the I/R ratio was expressed as a percentage. Mean infarct size in the control group which had no preconditioning was 59.8 +/- 4.0%. This was reduced to 22.2 +/- 2.9%, 19.5 +/- 4.1% and 23.3 +/- 3.4% by one, two and four cycles of preconditioning. However, when the number of preconditioning cycles was increased to six or eight protection declined with infarct sizes of 41.8 +/- 6.9% (P < 0.05 v zero preconditioning control group) and 47.1 +/- 7.6% (N.S. v zero preconditioning control group). In the group subjected to eight cycles of preconditioning without subsequent ischemia, infarction was not detected. In conclusion, in the anesthetized rabbit, beyond 4 cycles, protection against infarction diminishes with increasing numbers of preconditioning cycles.

Anesthesia, Intravenous↗
PubMed1997

Myocardial hibernation. A form of endogenous protection?

The origins and mechanisms of myocardial hibernation are obscure and controversial. Indeed, there is even debate over whether the hibernating heart is 'ischaemic'. In attempting to clarify this last point, it is clear that there is no universally agreed definition of ischaemia. It is proposed that much of the confusion can be resolved distinguishing between biochemical and physiological ischaemia and ascertaining whether the tissue metabolism is in steady state equilibrium or is progressively deteriorating. On the basis of this, the hibernating heart would be designated as physiologically ischaemic but it would not exhibit the characteristics of biochemical ischaemia. This distinction also allows one to argue that hibernation is an adaptive phenomenon in which cardiac metabolism and function are down-regulated to match the available energy supply (perfusion-contraction matching). Such an adaptive response would be expected to avoid the occurrence of tissue injury but it would not be expected to prevent the occurrence of adaptive morphological changes that always occur with prolonged inactivity of muscle. However, the morphological characteristics of hibernation are controversial and, like so many other aspects of the hibernation controversy, the problem may not be resolved until an acceptable animal model of hibernation has been developed.

Acute Disease↗
PubMed1996

Dichotomy of ischemic preconditioning: improved postischemic contractile function despite intensification of ischemic contracture.

BACKGROUND: Acceleration of ischemic contracture is conventionally accepted as a predictor of poor postischemic function. Hence, protective interventions such as cardioplegia delay ischemic contracture and improve postischemic contractile recovery. We compared the effect of ischemic preconditioning and cardioplegia (alone and in combination) on ischemic contracture and postischemic contractile recovery. METHODS AND RESULTS: Isolated rat hearts were aerobically perfused with blood for 20 minutes before being subjected to zero-flow normothermic global ischemia for 35 minutes and reperfusion for 40 minutes. Hearts were perfused at a constant pressure for 60 mm Hg and were paced at 360 beats per minute. Left ventricular developed pressure and ischemic contracture were assessed with an intraventricular balloon. Four groups (n=8 hearts per group) were studied: control hearts with 35 minutes of unprotected ischemia, hearts preconditioned with one cycle of 3 minutes of ischemia plus 3 minutes of reperfusion before 35 minutes of ischemia, hearts subjected to cardioplegia with St Thomas' solution infused for 1 minute before 35 minutes of ischemia, and hearts subjected to preconditioning plus cardioplegia before 35 minutes of ischemia. After 40 minutes of reperfusion, each intervention produced a similar improvement in postischemic left ventricular development pressure (expressed as a percentage of its preischemic value: preconditioning, 44 +/- 2%; cardioplegia, 53 +/- 3%; preconditioning plus cardioplegia, 54 +/- 4% and control, 26 +/- 6%, P<.05). However, preconditioning accelerated whereas cardioplegia delayed ischemic contracture; preconditioning plus cardioplegia gave an intermediate result. Thus, times to 75% contracture were as follows: control, 14.3 +/- 0.4 minutes; preconditioning, 6.2 +/- 0.3 minutes; cardioplegia 23.9 +/- 0.8 minutes; and preconditioning plus cardioplegia 15.4 +/- 2.4 minutes (P<.05 preconditioning and cardioplegia versus control). In additional experiments, using blood- and crystalloid-perfused hearts, we describe the relationship between the number of preconditioning cycles and ischemic contracture. CONCLUSIONS: Although preconditioning accelerates, cardioplegia delays, and preconditioning plus cardioplegia has little effect on ischemic contracture, each affords similar protection of postischemic contractile function. These results question the utility of ischemic contracture as a predictor of the protective efficacy of anti-ischemic interventions. They also suggest that preconditioning and cardioplegia may act through very different mechanisms.

Animals↗
PubMed1996

Impaired skeletal muscle fatigue resistance in rats with pressure overload-induced left ventricular hypertrophy.

In rats with left ventricular (LV) hypertrophy, we investigated whether abnormalities of skeletal muscle could result in reduced exercise tolerance in the absence of reduced cardiac function. LV pressure overload was induced by partial constriction of the abdominal aorta (AC) with controls subjected to sham operation. Cardiac and skeletal muscle function and blood flow were assessed in vivo 3 and 6 weeks later. AC induced LV hypertrophy of 41% and 37% at 3 and 6 weeks post-operation. In AC rats, cardiac index was 31 +/- 8 and 35 +/- 4 ml/min/100 g at 3 and 6 weeks compared to 38 +/- 4 and 34 +/- 2 ml/min/100 g in controls (N.S.). Fatigue index of the soleus (type-I rich) muscle in AC rats was reduced by 14% (P < 0.05) at both time points, while that of the tibialis anterior (mixed fiber) muscle was unchanged at 3 weeks but reduced by 18% (P < 0.05) at 6 weeks. Function of the extensor digitorum longus (type-IIB rich) muscle was unaltered at both time points. Blood flow at rest was paradoxically increased in muscles which exhibited increased fatigue susceptibility. At 3 weeks, blood flow during fatigue stimulation was reduced by 33% in the soleus muscle; the only muscle to exhibit impaired fatigue resistance at this time point. Blood flow during stimulation remained unaltered in the EDL and TA muscles. Thus, impaired fatigue resistance was observed in skeletal muscle with high oxidative and oxidative glycolytic fiber content during the compensatory phase of LV hypertrophy, prior to overt cardiac dysfunction. A selective impairment of blood flow to these muscles during exercise may play a causal role in exercise intolerance.

Animals↗
PubMed1996

The role of the rate of vascular collapse in ischemia-induced acute contractile failure and decreased diastolic stiffness.

We investigated the contribution of the rate of vascular collapse to the early contractile failure and decreased diastolic stiffness induced by ischemia. Isolated rat hearts (n = 8/group), perfused at 37 degrees C with blood through a roller pump and paced at 320 beats/min, were subjected to global ischemia either by switching off the roller pump (slow vascular collapse-group 1) or by reversing the direction of the roller pump for 5 s prior to switch-off (rapid vascular collapse-group 2). In group 1, residual coronary pressure declined progressively over the first 20 s of ischemia whereas in group 2 the pressure had fallen to zero within 2 s. The profile of ischemia-induced contractile failure was however, similar in both groups. Thus, after 2 s of ischemia, when residual perfusion pressure had declined by only 10% in group 1 (60.0 +/- 0.0 to 54.9 +/- 0.8 mmHg) but was virtually non-existent in group 2 (60.0 +/- 0.0 to 0.4 +/- 12.7 mmHg), left ventricular developed pressure had fallen to a similar extent in both groups (86 +/- 2% and 84 +/- 3%, respectively). Curve-fitting analysis for individual hearts showed that the profile of contractile failure was described by a double exponential process that was not significantly affected by the rapid vascular collapse. Left ventricular end-diastolic pressure in group 1 hearts progressively declined over the first 20 s of ischemia, the profile paralleling that of the dissipation of perfusion pressure. In contrast, in group 2 hearts, left ventricular end-diastolic pressure rose rapidly and leaked at 5 s, a period that coincided with the reversed direction of the perfusion pump. Similarly, in a separate study, the analysis of ventricular diastolic stiffness (n = 6/group) showed a rapid decline during the first 20 s of ischemia: this decline could be inhibited by the use of rapid vascular collapse. In additional experiments, hearts (n = 8/group) were paced at 220, 320 or 420 beats/min and ischemia was induced by reversing (5 s) and then stopping the perfusion pump. Myocardial oxygen consumption increased in parallel with heart rate and was matched by commensurate increases in the rate of contractile failure. Curve-fitting analysis showed that slow stimulation rates (220 beats/ min) significantly delayed contractile failure during the first 60 s of ischemia (first time constant = 14.5 +/- 4.1 s compared with 8.1 +/- 1.1 s at 320 beats/min and 6.3 +/- 1.1 s at 420 beats/min; P < 0.05 in both instances). In conclusion, vascular collapse associated with ischemia may contribute to the initial decrease in ventricular diastolic stiffness; however, it does not play a major role in determining the rate of acute contractile failure. Metabolic processes as reflected by oxygen consumption do however, appear to be important.

Animals↗
PubMed1996

Dichotomy in the post-ischemic metabolic and functional recovery profiles of isolated blood-versus buffer-perfused heart.

There is evidence that buffer- and blood-perfused hearts differ in their postischemic functional recoveries. The present study was designed to: (i) compare ischemia-induced contracture and post-ischemic functional recovery, and (ii) investigate whether the recovery profiles were related to either the release of purines and norepinephrine or high-energy phosphate content. Rat hearts (n = 8/group) were perfused at 37 degrees C with buffer (60 mmHg) or blood (60 mmHg from a support rat), made globally ischemic (15 min) and reperfused (15 min). The onset and severity of ischemic contracture were identical in both models [left ventricular end-diastolic pressure (LVEDP) at the end of 15 min ischemia was 30 +/- 5 and 27 +/- 4 mmHg respectively; P = N.S.]. However, the rate and extent of post-ischemic left ventricular developed pressure (LVDP) differed considerably. Blood-perfused hearts exhibited an initial rapid and complete recovery of LVDP followed by a steady decline to approximately 60% of pre-ischemic values. Buffer-perfused hearts recovered to only 80% after 5 min reperfusion and remained at this level for the duration of reperfusion LVEDP was higher in buffer-perfused than in blood-perfused hearts during the first 5 min of reperfusion; thereafter, LVEDP fell in buffer-perfused hearts to a level than was not significantly different from the observed in blood-perfused hearts. In buffer-perfused hearts, coronary flow recovered to 90% within 5 min and then remained constant; in blood-perfused hearts flow recovered to 100% by 1 min and continued to rise to a maximum by 7 min (201 +/- 15%). This increase appeared to mirror the secondary decline in LVDP. During the first 4 min of reperfusion, in both preparations, venous norepinephrine increased to six- to nine-fold of pre-ischemic values and then fell rapidly to near control levels by 6-9 min. Total purine release was high in early reperfusion in both groups. At the end of 15 min reperfusion, the tissue adenylate pool was similar in both groups. This study demonstrates that the nature of the perfusate used for an isolated rat heart preparation: (i) does not appear to influence the severity of ischemic injury as assessed by ischemic contracture, but (ii) does influence the qualitative and quantitative characteristics of the temporal profile that describes the recovery of systolic and diastolic function during the first 15 min of reperfusion: and (iii) it has no effect upon the changes seen in a number of metabolic indices that are often used for the assessment of injury and protection.

Animals↗
PubMed1996

Ischemic preconditioning, cardioplegia or both? Differing approaches to myocardial and vascular protection.

We compared the anti-ischemic efficacy of cardioplegia and ischemic preconditioning and whether their effects are additive for both myocyte and vascular protection. Isolated blood-perfused rat hearts were subjected to zero flow global ischemia (37 degrees C) for 30 min and reperfusion for 40 min. Left ventricular developed pressure (LVDP) was assessed with an intraventricular balloon. Coronary flow and vascular reactivity (percentage change in coronary vascular resistance, CVR) to 5-hydroxytryptamine (5HT; 0.0215 mmol/l) and sodium nitroprusside (SNP; 0.0160 mmol/l) were measured. Study 1; "dose" effect of preconditioning in four groups (n = 6/group): (i) controls (unprotected ischemia) and (ii, iii and iv) 1, 2, or 3 cycles of preconditioning (3 min ischemia + 3 min reperfusion) prior to ischemia. LVDP recovery in controls was 31 +/- 9%; preconditioning by 1, 2 or 3 cycles afforded significant (P < 0.05) improvements (58 +/- 6%, 54 +/- 3% and 54 +/- 5%, respectively). Overall, the pre-ischemic change of CVR to SNP was -28 +/- 1%. The post-ischemic response in controls was -4 +/- 7% (P < 0.05); with 1, 2, or 3 cycles of preconditioning the values were -23 +/- 4%, -24 +/- 5%, and -26 +/- 3%, respectively (P < 0.05 v controls). With 5HT the overall pre-ischemic change in CVR was -18 +/- 2%; after ischemia a vasoconstrictor response was seen in all groups. Study 2: the effect of preconditioning added to cardioplegia with four groups subjected to 35 min ischemia (n = 8/group): (i) controls, (ii) one cycle of preconditioning (3 min ischemia + 3 min reperfusion), (iii) cardioplegia with St Thomas' solution immediately prior to ischemia, and (iv) preconditioning followed by cardioplegia prior to ischemia. The recoveries of LVDP were 26 +/- 6%, 44 +/- 2%, 53 +/- 3% and 54 +/- 4%, respectively (P < 0.05 all interventions v controls). Post-ischemic CVR increased greatly in controls (+ 167 +/- 60% of its pre-ischemic value) but was little changed in groups (ii), (iii), and (iv) (+ 11 +/- 7%, + 27 +/- 10% and -2 +/- 6% respectively; P < 0.05 v controls). The post-ischemic change in CVR to SNP was protected by all interventions (-21 +/- 1%, -21 +/- 1% and -22 +/- 1% v -14 +/- 2% in controls; P < 0.05). Again, the post-ischemic response to 5HT was vasoconstriction in all groups. In conclusion, preconditioning and cardioplegia alone afford similar and substantial protection of post-ischemic contractile and vascular functions. In general, the combination of the two techniques afforded no significant additional protection.

Animals↗
PubMed1996

Ventricular arrhythmias induced by ischaemia-reperfusion are unaffected by myocardial glutathione depletion.

Reduced glutathione (GSH) is a major myocardial antioxidant. Since reperfusion phenomena such as ventricular fibrillation (VF) are associated with oxygen free radical production during ischaemia, myocardial GSH depletion might be expected to increase susceptibility to such phenomena. This possibility was tested in isolated rat hearts using diethylmaleate (DEM) or L-buthionine-SR-sulfoximine (BSO) to deplete myocardial GSH. High dose DEM (860 mg/kg) depleted myocardial GSH from a control mean of 7.64 +/- 0.73 to 3.18 +/- 0.56, low dose DEM (215 mg/kg) to 4.29 +/- 0.53 nmol/mg protein and BSO (4 mmol/kg) from a control mean of 6.94 +/- 0.54 to 2.18 +/- 0.14 nmol/mg protein. Hearts were perfused in the Langendorff mode at 37 degrees C with bicarbonate buffer (K+ = 4.3 mM). Regional ischaemia was induced for 5, 8.5, 10, 20 or 40 min (DEM groups: n = 10/treatment/time point) or 8.5 min only (BSO groups: n = 10/treatment) then hearts were reperfused for 5 min. Reperfusion VF incidence showed a classical "bell-shaped" curve, but there was no difference in VF incidence, VF time-to-onset, arrhythmia duration and "arrhythmia scores" between GSH-depleted and control hearts. Depleting myocardial GSH is not proarrhythmic for reperfusion-induced arrhythmias. It would appear GSH is not significantly involved in protecting against the oxidant stress of reperfusion, or conversely that the reserve of this redox system is so high only severe depletion might show an effect.

Animals↗
PubMed1996

Paradoxical effect of ischemic preconditioning on ischemic contracture? NMR studies of energy metabolism and intracellular pH in the rat heart.

Using the blood-perfused rat heart, we have previously shown that although ischemic preconditioning (PC) and cardioplegia (CP) afforded similar protection against post-ischemic contractile dysfunction this effect was not additive even though PC accelerated whereas CP delayed ischemic contracture. Using NMR we examined the effects of these interventions on pHi and ATP metabolism during global ischemia. Isolated rat hearts (n = 6/group) with an intraventricular balloon were aerobically perfused with buffer, subjected to zero flow ischemia (37 degrees C) for 35 min and reperfused for 40 min. The groups were: (1) controls without protection, (2) PC (2 cycles), and (3) St Thomas' cardioplegia, prior to test ischemia. PC accelerated whereas CP delayed ischemic contracture (P < 0.05 v controls). Yet, after 40 min reperfusion, both interventions produced substantial improvements in the recovery of LVDP (P < 0.05 v controls). During 35 min ischemia, the decline of ATP was delayed by CP but accelerated by PC (P < 0.05 v controls). The pHi fell steeply in controls to a plateau of 5.9 after 14 min ischemia. PC had no effect on the rate of fall of pHi but reduced its extent (P < 0.05). CP delayed the onset of the decline in pHi (P < 0.05) but, once initiated, there was no effect on the rate of decline to a plateau. Thus, despite protecting post-ischemic contractile function, PC accelerated ischemic contracture and the depletion of ATP, but substantially reduced intracellular acidosis. In contrast, CP slowed ischemic contracture and the depletion of ATP; it also delayed the onset of acidosis.

Animals↗
PubMed1996

Electrophysiological characteristics of repetitive ischemic preconditioning in the pig heart.

S-T segment changes have been cited as evidence for preconditioning in the human heart during repeated angioplasty inflations. Opening of preformed collaterals, however, could explain these observations. We have measured the profile of S-T segment and monophasic action potential (MAP) changes in a species with low collateralization. Open-chested pigs were subjected to two cycles of 8-min LAD occlusion and 8-min reperfusion prior to 60-min ischemia and 2-h reperfusion. Two epicardial ECGs and MAP were continuously recorded from the ischemic zone and one ECG from the normal zone. Flow was measured using Xenon washout. Infarct (IS) and risk zone (RZ) sizes were assessed after reperfusion in a subset of six pigs and confirmed profound protection with preconditioning (IS/RZ = 14 +/- 9% v 42 +/- 3% in controls, P < 0.05). S-T segment elevation was smaller early in the 2nd or 3rd (0-3 min) ischemic cycles than in the 1st. In contrast, in the 1st ischemic cycle, MAP duration after 3 min was reduced to 90 +/- 2% control and this was further reduced in the 2nd and 3rd ischemic episodes to 74 +/- 4% and 77 +/- 3% respectively. Thus, preconditioning increased APD shortening while simultaneously decreasing S-T segment elevation during the early minutes of ischemia. It therefore seems unlikely that the ability of preconditioning to limit S-T segment changes is related to limitations in APD shortening. All electrophysiological differences were lost later during ischemia. Collateral flow during the three ischemic cycles was 4.8 +/- 3.7, 5.8 +/- 2.3 and 5.6 +/- 2.9% (n = 5/grp, ns) respectively. Thus, in the absence of a significant increase in collateral flow. S-T segment and MAP changes provide an index of preconditioning but only during the first few minutes of occlusion. S-T segment changes observed during PTCA may therefore reflect genuine preconditioning in man although the contribution of ischemia-induced increases in collateral flow cannot be ignored.

Action Potentials↗
PubMed1996

Effects of cardioplegia on vascular function and the "no-reflow" phenomenon after ischemia and reperfusion: studies in the isolated blood-perfused rat heart.

The ability of cardioplegia to protect against cardiac contractile dysfunction caused by ischemia and reperfusion is well established. The effects of cardioplegia on vascular injury and the no-reflow phenomenon, however, remain controversial. We used the blood-perfused rat heart to study the effect of St. Thomas' Hospital cardioplegic solution on postischemic endothelium-dependent and endothelium-independent vascular function, the extent of the no-reflow phenomenon, and the temporal relationship between postischemic vascular and contractile function. Isolated rat hearts (16 per group) perfused with blood from a support rat at 60 mm Hg were subjected to 10, 20, 30 or 40 minutes of global ischemia and 40 minutes of reperfusion at 37 degrees C. Eight hearts in each group also received cardioplegia (45 mm Hg for 2 minutes) before ischemia. Left ventricular developed pressure was measured with an intraventricular balloon. At the end of reperfusion, a bolus of 250 micrograms nitro-L-arginine methyl ester was infused to assess endothelium dependent vascular function. After a 20-minute washout, 25 micrograms sodium nitroprusside was infused to assess endothelium-independent vascular function. Fluorescein (1 ml, 1% weight/volume) was then infused to assess no-reflow; this involved freezing the hearts, cutting them into transverse sections (10 x 1 mm), video recording the sections under ultraviolet light, digitizing the images, and analyzing density of fluorescence. No-reflow was defined as a flow of less than 5%. Compared with nonischemic control responses, endothelium-independent vascular function was significantly decreased only after 30 and 40 minutes of ischemia (48.1% +/- 3.8% and 24.3% +/- 7.4%, p < 0.05), but it was significantly protected by cardioplegia (66.6% +/- 3.9% and 64.5% +/- 5.2%, p < 0.05). A significant reduction in endothelium-dependent vascular function was observed after 40 minutes of ischemia (-31.8% +/- 6.6% vs -50.4% +/- 1.6% in control hearts, p < 0.05), and again this was improved by cardioplegia (-45.0% +/- 3.4%, p < 0.05 vs ischemic group). Areas of no reflow were present after 30 and 40 minutes of ischemia (11.9% +/- 6.8% and 33.4% +/- 14.1% of left ventricular mass), and at each time period they were significantly decreased by cardioplegia (0.7% +/- 0.4% and 3.8% +/- 1.6%, p < 0.05). Postischemic contractile dysfunction was observed before any vascular alteration was apparent. After only 20 minutes of ischemia, the postischemic recovery of left ventricular developed pressure fell to 56.7% +/- 4.0%, but both endothelium-dependent vascular function and endothelium-independent vascular function were unaffected. In conclusion, vascular alterations are apparent only after prolonged periods of ischemia, longer than those required to observe contractile dysfunction, and cardioplegia protects against postischemic endothelium-dependent and endothelium-independent vascular dysfunction and reduces the extent of the no-reflow phenomenon.

Animals↗
PubMed1996

Impact of extracellular buffer composition on cardioprotective efficacy of Na+/H+ exchanger inhibitors.

There is controversy over whether the cardioprotective effects of Na+/H+ exchanger inhibitors are exerted primarily during ischemia or during subsequent reperfusion, possibly because of interstudy differences in experimental conditions. We studied the impact of perfusate buffer composition on the relative degree of protection afforded by Na+/H+ exchanger inhibition during ischemia vs. reperfusion. Isolated rat hearts (n = 8/group) were perfused (37 degrees C, 75 mmHg) with bicarbonate- or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium and subjected to 20 min of global zero-flow ischemia and 45 min of reperfusion. One of two structurally distinct Na+/H+ exchanger inhibitors [5-(N,N-dimethyl)amiloride (DMA) or (3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate (HOE-694), 10 mumol/l] was transiently (5 min) infused 1) immediately before ischemia, 2) during initial reperfusion, or 3) during both of these periods. With bicarbonate-buffered medium, neither drug improved the postischemic recovery of left ventricular developed pressure (LVDP) when given only during reperfusion. In contrast, HOE-694 improved the postischemic recovery of LVDP from 39 +/- 5% in control to 66 +/- 6% (P < 0.05) when given before ischemia and from 33 +/- 4% in control to 65 +/- 4% (P < 0.05) when given before ischemia plus during reperfusion. With the latter protocol, the cardioprotective effect of HOE-694 occurred in a dose-dependent manner at 0.1-10 mumol/l. In contrast to the results with bicarbonate-buffered medium, in the presence of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium, DMA and HOE-694 significantly improved recovery of LVDP (from 34 +/- 5% in controls to 56 +/- 3 and 71 +/- 8%, both P < 0.05) when given only during reperfusion. They also provided significant protection when given before ischemia or before ischemia plus during reperfusion; with the latter protocol, HOE-694 produced an almost complete recovery of LVDP (88 +/- 9 vs. 30 +/- 7% in controls, P < 0.05). In conclusion, our results suggest that the influence of Na+/H+ exchanger activity during reperfusion on the extent of functional recovery is modulated significantly by perfusate buffer composition. As a consequence, the cardioprotective efficacy of Na+/H+ exchanger inhibitors may be overestimated under bicarbonate-free conditions.

Amiloride↗
PubMed1996

Anti-arrhythmic protection by ischaemic preconditioning in isolated rat hearts is not due to depletion of endogenous catecholamines.

OBJECTIVES: The present study addresses whether the mechanism of anti-arrhythmic protection by ischaemic preconditioning involves depletion of myocardial catecholamines. METHODS: In a randomised series of studies isolated rat hearts, perfused with whole blood, underwent episodes of regional ischaemia and reperfusion induced with a snare around the left coronary artery. Control hearts (Group 1, n = 12) were subjected to 40 min aerobic perfusion, 30 min ischaemia and 10 min reperfusion. Preconditioned hearts (Group 2, n = 12) were subjected to 10 min aerobic perfusion, three cycles of ischaemia and reperfusion (5 min each), 30 min ischaemia and 10 min reperfusion. Cardiac rhythm was recorded continuously and arrhythmias quantified during the final periods of ischaemia and reperfusion. At the end of the experiment samples of right ventricular (RV; non-ischaemic) and left ventricular (LV; ischaemic territory) tissue were separated and frozen. In 5 additional groups (n = 6/group) tissue samples were taken after 10 min aerobic perfusion, after 10 min aerobic perfusion followed by 1, 2 or 3 preconditioning cycles and after 40 min of aerobic perfusion. All tissue samples were analysed for catecholamine content. RESULTS: Preconditioning resulted in reductions in the incidence of ischaemia-induced VF from 67% in Group 1 to 8% in Group 2, the incidence of ischaemia-induced VT from 100% to 17% and the number of ischaemia-induced VPBs from 246 +/- 25 to 59 +/- 19 (each P < 0.05). The mean content of noradrenaline and adrenaline was consistently higher in RV than LV tissue. Within the LV, however, neither preconditioning nor prolonged ischaemia had any significant effect upon tissue catecholamine content at any time in the experimental protocol. CONCLUSIONS: Depletion of myocardial catecholamines is not involved in the mechanism of anti-arrhythmic protection by ischaemic preconditioning in isolated rat hearts.

Animals↗