PubMed Health⌕ Search

Biomedical subjects

D J Hearse

Publications and source records attributed to D J Hearse.

At least 55 records · Page 3Linked to original sources
PubMed1995

Can ischemic preconditioning ensure optimal myocardial protection when delivery of cardioplegia is impaired?

BACKGROUND: Ischemic preconditioning is a potent protective intervention that is effective in all species studied. We have previously shown it to be as effective as cardioplegia; however, we have also shown that their combined use does not afford greater protection than the use of either alone. In the present study we investigated whether coincident ischemic preconditioning could compensate for inadequate cardioplegic protection when the delivery of cardioplegia was impaired, such as occurs in the presence of severe coronary stenosis or occlusion. METHODS AND RESULTS: Isolated rat hearts were subjected to 30 minutes of global ischemia followed by 40 minutes of reperfusion. Four groups of hearts (n = 12 per group) were studied: group 1, controls (no intervention); group 2, cardioplegia administered to hearts with a proximally occluded coronary artery; group 3, ischemic preconditioning applied before ischemia; and group 4, ischemic preconditioning and cardioplegia given in combination to hearts with a proximally occluded coronary artery. The postischemic recovery of left ventricular (LV) developed pressure (LVDP), expressed as a percentage of preischemic values, was significantly greater (P < .05) in preconditioned hearts (64 +/- 3%) than in control hearts (24 +/- 4%) or hearts treated with suboptimal cardioplegia (43 +/- 5%). Hearts with preconditioning plus cardioplegia recovered to an extent similar to that seen with preconditioning alone (59 +/- 2%). LV end-diastolic pressure was greater in control hearts (58 +/- 4 mm Hg) than in hearts with cardioplegia (41 +/- 4 mm Hg; P < .05 versus group 1) despite the incomplete delivery of the cardioplegia; the best protection was observed in preconditioned hearts and hearts with preconditioning plus cardioplegia (24 +/- 1 and 26 +/- 2 mm Hg, respectively; P < .05 versus groups 1 and 2). CONCLUSIONS: When the delivery of cardioplegia was impaired, myocardial protection (postischemic LVDP) was better served by ischemic preconditioning. Under the same conditions, the combination of cardioplegia plus preconditioning afforded superior protection compared with cardioplegia alone. These results may be of clinical interest since most patients who undergo surgery for ischemic heart disease suffer from severe coronary artery lesions that can prevent the adequate delivery of cardioplegia.

Animals↗
PubMed1995

Dynamics of early postischemic myocardial functional recovery. Evidence of reperfusion-induced injury?

BACKGROUND: The present study was designed to explore the relation between the duration of ischemia and the rate and extent of myocardial functional recovery after reperfusion. METHODS AND RESULTS: Isolated rat hearts were perfused with blood from a support animal for 15 minutes (flow rate, 2.5 mL/min; perfusion pressure, 60.1 +/- 1.3 mm Hg). Control left ventricular developed pressure (LVDP) was measured, and the hearts (six per group) were subjected to 10, 20, 30, 40, 50, 60, 70, or 80 minutes of global ischemia (37 degrees C) and 60 minutes of reperfusion. Pacing (320 beats per minute) was instituted before and after ischemia. In all groups, transient arrhythmias occurred at the onset of reperfusion, to be followed by an early phase of recovery that peaked after 2 to 3 minutes of reperfusion. The relation between the extent of this initial recovery and the duration of preceding ischemia was described by a bell-shaped curve. Thus, the maximum initial mean recovery after 10, 20, 30, 40, 50, 60, 70, or 80 minutes of ischemia was 97%, 108%, 145%, 154%, 118%, 34%, 41%, and 24%, respectively, of preischemic LVDP. Possibly indicative of reperfusion-induced injury, LVDP then declined in all groups so that after 20 minutes of reperfusion, the mean recovery was 63%, 53%, 48%, 50%, 56%, 12%, 9%, and 5%, respectively. In the 10-, 20-, 30-, and 40-minute ischemia groups, there then was a secondary increase in LVDP, possibly indicating the start of recovery from stunning. After 60 minutes of reperfusion, the mean recovery of LVDP was 82%, 65%, 59%, 54%, 47%, 9%, 7%, and 4%, respectively; this second phase of recovery was inversely proportional to the duration of ischemia. To define the early phase of recovery that had been obscured by reperfusion-induced arrhythmias, we repeated the experiments with the inclusion of a cardioplegic infusion (St Thomas' solution for 2 minutes before ischemia). This significantly reduced the incidence of ventricular fibrillation during early reperfusion. The extent of the initial postischemic recovery of LVDP was similar to that observed without cardioplegia; however, the mean secondary recovery was greater in all groups. Again, the relation of early transient (2 to 5 minutes) recovery to the duration of ischemia was represented by a bell-shaped curve, whereas the secondary recovery was inversely related. CONCLUSIONS: Although the results of the present study confirm the protective properties of cardioplegia, they also shed some light on the nature of reperfusion-induced injury and myocardial stunning and their complex relation to the severity of the preceding ischemia.

Animals↗
PubMed1995

Vascular and contractile function and tissue metabolites after prolonged hypothermic ischaemia and reperfusion: comparison of single- versus multi-dose infusions with two cardioplegic solutions in blood-perfused neonatal pig hearts.

The effects of single- and multi-dose cardioplegia on post-ischaemic vascular function and contractile activity were compared in 69 blood-perfused neonatal pig hearts, as were the protective properties of two different cardioplegic solutions. Hearts (n = 6 or 9 per group) from neonatal (3-5 days old) pigs were excised, arrested with a 2 min infusion (at 15 degrees C) of St Thomas' Hospital cardioplegic solution number 1 (STH1) or number 2 (STH2), and then maintained in a state of hypothermic (15 degrees C) ischaemia for 6 or 8 h. Hearts in the multi-dose groups received cardioplegia every hour (2 min at 15 degrees C). At the end of ischaemia all hearts were reperfused (60 +/- 2 mmHg perfusion pressure) for 40 min with blood from a support pig. Systolic and diastolic functions were assessed with an intraventricular balloon, and endothelial and smooth muscle functions by measuring the response to infusions of defined concentrations of acetylcholine (8, 16 and 32 micrograms/min) and glyceryl trinitrate (40, 80 and 160 micrograms/min). Hearts (n = 9) not subjected to ischaemia were perfused for the same duration to act as aerobic controls. At the end of the perfusion period, hearts were frozen and taken for metabolite analysis. After 8 h ischaemia, the recovery of left ventricular developed pressure was greatest in the multi-dose STH1 and single-dose STH2 groups (113 +/- 6 and 117 +/- 6 mmHg, respectively, v 128 +/- 9 mmHg in aerobic controls, at an end-diastolic pressure of between 3 and 9 mmHg; P = N.S.) and the poorest in the single-dose STH1 group (92 +/- 5 mmHg; P < 0.05 v controls). The recovery of diastolic function was greatest in the multi-dose STH2 group and again poorest in the single-dose STH1 group (left ventricular end-diastolic pressure 1 +/- 2 and 30 +/- 10 mmHg, at a ventricular volume of 3.0 ml, v -1 +/- 1 mmHg in aerobic controls). Vascular responses to acetylcholine and glyceryl trinitrate and the myocardial high-energy phosphates content were better preserved in multi-dose groups and with STH2. Inter-group differences were less when the duration of ischaemia was reduced to 6 h. In conclusion, the neonatal pig heart was best preserved with multi-dose cardioplegia and STH2 was more efficacious than STH1. However, not all indices were optimally protected by multi-dose STH2. Thus, the best protection of systolic function was obtained with multidose STH1 and this was followed by single-dose STH2. Diastolic function was best preserved with multi-dose STH2 as were vascular function and high-energy phosphates.

Animals↗
PubMed1995

Cardiac Na+/K+ ATPase activity and its relation to myocardial glutathione status: studies in the rat.

Cardiac Na+/K+ ATPase (which has previously been suggested to be regulated by a thiol-dependent process) is inactivated during ischemia. Moreover, myocardial glutathione (which controls the redox state of protein-thiol groups) is depleted during ischemia and thus may contribute to the changes in Na+/K+ ATPase activity. The objectives of the present study were to use the rat to: (1) pharmacologically manipulate myocardial glutathione to mimic ischemia-reperfusion-induced glutathione depletion and (2) determine (in the absence of ischemia) the relationship between myocardial glutathione content and Na+/K+ ATPase activity. Tissue glutathione was depleted by injecting rats with diethylmaleate (0, 55, 110, 215, 430 or 860 mg/kg; i.p.) 30 min before study. Total glutathione content fell from 1.72 +/- 0.03 to 1.66 +/- 0.04, 1.50 +/- 0.05, 0.93 +/- 0.03, 0.21 +/- 0.02 mumol/g wet weight, respectively. There was a linear correlation (r = 0.96) between Na+/K+ ATPase activity and glutathione content in diethylmaleate-treated animals. A separate group of animals were treated with phorone (0, 25, 50, 100, 150, 200 or 250 mg/kg; i.p. 120 min before study) which also depletes glutathione. Myocardial glutathione fell from its control value of 1.74 +/- 0.03 to 1.52 +/- 0.04, 1.35 +/- 0.06, 1.14 +/- 0.05, 0.84 +/- 0.04, 0.64 +/- 0.04, 0.54 +/- 0.03 mumoles/g wet weight, respectively. In these animals Na+/K+ ATPase activity was also linearly-related (r = 0.98) to glutathione content. We also characterized the temporal relationship between diethylmaleate-induced glutathione depletion and Na+/K+ ATPase activity. Diethylmaleate (216 mg/kg; i.p.) was given to rats and at various times (0-200 min), after administration the hearts were removed and assayed for glutathione. During the first 30 min after administration glutathione fell from 1.74 +/- 0.03 to its lowest value of 0.90 +/- 0.04 mumol/g wet weight. It then progressively recovered to within control levels by 150 min after administration. Na+/K+ ATPase activity paralleled the recovery of glutathione status. In additional studies, the cell-permeant glutathione analogue YM 737 (glutathione isopropyl ester: 1 mmol/kg, i.p.) accelerated the recovery of tissue glutathione and evoked a commensurate and parallel increase in the rate of recovery of Na+/K+ ATPase activity. Our studies suggest there is a close coupling between tissue glutathione content and Na+/K+ ATPase activity and that this may be an important factor in ischemia and reperfusion-induced changes in Na+/K+ ATPase activity.

Animals↗
PubMed1995

The effect of load on atrophy, myosin isoform shifts and contractile function: studies in a novel rat heart transplant preparation.

A novel heterotopic rat heart transplant preparation was used with the objective of investigating the effect of load on cardiac contractile function, mass, myosin and high energy phosphates over a 7-day period. Donor hearts were excised, arrested with a hypothermic (4 degrees C) cardioplegic solution and transplanted (90-min operation time) into the abdomens of recipient rats. The transplanted hearts were reperfused in situ for 7 days. Two groups of hearts (n = 14/group) were studied. Group 1: a conventional unloaded transplanted preparation in which the aorta and pulmonary artery were anastomosed to the abdominal aorta and inferior vena cava, respectively. Group 2: a novel loaded preparation in which, additionally, the left atrium was anastomosed to the inferior vena cava which was then ligated proximally so as to divert distal venous flow to the left ventricle of the transplanted heart. Non-transplanted, fresh hearts served as controls. Seven days after transplantation the hearts were excised and perfused aerobically for 20 min. Systolic and diastolic functions had deteriorated severely in Group 1: left ventricular developed pressure (LVDP) had fallen to 96 +/- 11 v 162 +/- 6 mmHg in fresh controls (at 12 mmHg of end-diastolic pressure) and left ventricular volume to 80 +/- 12 v 268 +/- 20 microliters (P < 0.05 in both instances). In Group 2, LVDP (134 +/- 6 mmHg) and left ventricular volume (144 +/- 6 microliters) were significantly higher than in Group 1 but were still significantly lower than in fresh controls. Coronary flow in absolute terms was similar in all groups; however, when expressed as ml/min/g wet wt, coronary flow tended to be greater in unloaded hearts (19.8 +/- 0.6) than in fresh hearts (15.0 +/- 0.8; P < 0.05) and loaded hearts (17.6 +/- 1.3; N.S.). Unloaded hearts exhibited a significant loss of left ventricular weight (0.40 +/- 0.02 g) when compared with fresh aerobic controls (0.57 +/- 0.02 g; P < 0.05). However, there was no significant weight loss in the loaded hearts (0.53 +/- 0.03 g). The content of V1 isoform of myosin in left ventricular muscle was 77.8 +/- 5.0% in fresh hearts; this was reduced to 60.0 +/- 3.6% in the unloaded hearts (P < 0.05). The value in the loaded hearts (73.2 +/- 3.4%) did not differ significantly from that in fresh controls. The adenine nucleotide pool was similar in all groups. In conclusion, imposing a load on the heterotopically transplanted heart prevents the loss of cardiac mass and the shift of myosin isoforms, however, it does not totally prevent the development of systolic and diastolic dysfunction. The contractile abnormalities do not appear to be related to high energy phosphate content but might well arise as a consequence of the denervation associated with transplantation or the transplantation procedure itself.

Animals↗
PubMed1995

Protective effect of nicorandil as an additive to the solution for continuous warm cardioplegia.

Experiments were designed to assess whether (1) nicorandil given before global low-flow ischemia or (2) included in low-flow continuous cardioplegia improved the recovery of cardiac function in the isolated rat heart. The first investigated the effect of nicorandil (2, 10, or 100 mumol/L), given for 3 minutes before 30 minutes of normothermic global ischemia, on recovery after 30 minutes of reperfusion. In aerobically perfused hearts, doses of 10 and 100 mumol/L significantly increased coronary flow; the dose of 100 mumol/L exerted a negative inotropic effect. These doses shortened the time to contractile arrest (282 +/- 18 and 276 +/- 22 seconds versus 354 +/- 16 seconds in the control hearts with unmodified ischemia; p < 0.05 in both instances). Nicorandil also improved the postischemic recovery of coronary flow (79.1% +/- 1.7% and 78.0% +/- 1.6%, respectively, versus 71% +/- 1.8%; p < 0.05). However, there was no significant improvement in recovery of contractile function, creatine kinase leakage, or tissue adenosine triphosphate and creatine phosphate contents. Second, pretreatment with nicorandil (10 mumol/L) was shown to increase susceptibility of the hearts to reperfusion-induced ventricular fibrillation from 0% (n = 8) in control hearts to 50% in the drug-treated group (p < 0.05). Third, nicorandil (10 mumol/L) was added to cardioplegic and noncardioplegic solutions infused into the coronary tree throughout 100 minutes of low-flow (0.7 ml/min) ischemia: in eight of nine control hearts electrical activity was maintained throughout, whereas in all nicorandil-treated hearts electrical activity was suppressed for at least part of the time. Nicorandil also reduced the prevalence of ischemic contracture to 0% during continuous infusion of cardioplegic solution (compared with 30% in nicorandil-free control hearts) and improved the recovery of contractile function after 40 minutes of reperfusion. Thus, in the noncardioplegia groups, left ventricular developed pressure recovered to 77.8% +/- 4.0% versus 51.7% +/- 2.6% in control hearts (p < 0.05) and in the cardioplegia groups to 96.2% +/- 4.2% versus 79.7% +/- 5.5% (p < 0.05). Ventricular compliance (the ventricular volume required to achieve a left ventricular end-diastolic pressure of 4 mm Hg) was better preserved in the nicorandil-containing noncardioplegia group (133 +/- 6 microliters) than in the control group (88 +/- 10 microliters; p < 0.05). In conclusion, nicorandil has been shown to (1) reduce ischemic contracture, (2) lessen the effects of ischemic arrest, and (3) improve the postischemic recovery of contractile function. In this species and preparation it may, however, enhance vulnerability to reperfusion-induced arrhythmias.

Animals↗
PubMed1995

Protection against injury during ischemia and reperfusion by acadesine derivatives GP-1-468 and GP-1-668. Studies in the transplanted rat heart.

BACKGROUND: Acadesine (AICAr: 5-amino-4-imidazole carboxamide riboside) has been shown to afford sustained protection against injury during ischemia and reperfusion. The present studies used the heterotopically transplanted rat heart to assess the protective properties of two new acadesine analogs: GP-1-468 and GP-1-668. METHODS AND RESULTS: Hearts were excised, arrested with a 2-minute infusion of cardioplegic solution, and subjected to 4 hours of global ischemia (20 degrees C) with cardioplegic reinfusion for 2 minutes every 30 minutes. The hearts were then transplanted (1 hour of additional ischemia) into the abdomens of recipient rats and reperfused in situ for 30 minutes or 24 hours. The hearts were then excised, perfused aerobically for 20 minutes, and contractile function was assessed. GP-1-468 or GP-1-668 was administered to donor rats (20 mg/kg intravenously, 30 minutes before excision). They were also added to the cardioplegic solution (10 mumol/L for GP-1-468, 5 mumol/L for GP-1-343, the active metabolite of GP-1-668) and were also given to recipient rats (20 mg/kg intravenously, 30 minutes before transplantation, so that the drugs were present during reperfusion). Nine groups of hearts were studied. Three groups of studies were carried out (n = 24 transplants for each group). The first group of hearts was reperfused for 30 minutes, the second group was reperfused for 24 hours, and the third group was transplanted but not reperfused; instead, they were frozen at the end of 5 hours of ischemia and taken for metabolite analysis. Within each group were three subgroups (n = 8 per group) receiving GP-1-468, GP-1-668, or saline solution. In the 30-minute reperfusion group the recoveries of left ventricular developed pressure were 88 +/- 4, 87 +/- 7, and 50 +/- 9 mm Hg, respectively (p < 0.05 versus saline-treated controls); left ventricular volumes (recorded at 12 mm Hg) were 112 +/- 20, 132 +/- 28, and 41 +/- 9 microliters, respectively (p < 0.05 versus saline-treated controls), and coronary flows were 13.1 +/- 0.7, 13.4 +/- 1.0, and 9.9 +/- 0.5 ml/min, respectively (p < 0.05 versus saline-treated controls). In addition to improving functional recovery, the two analogs increased the tissue content of adenosine at the end of the ischemic period (5.4 +/- 0.6 and 7.3 +/- 0.5 mumol/gm dry weight, respectively, versus 2.7 +/- 0.4 mumol/gm dry weight in the saline-treated controls; p < 0.05); however, they did not influence adenosine triphosphate or its catabolites. In the 24-hour reperfusion group the corresponding values were 77 +/- 6 and 88 +/- 6 versus 35 +/- 4 mm Hg for left ventricular developed pressure (p < 0.05), 111 +/- 9 and 121 +/- 11 versus 41 +/- 8 microliters for left ventricular volume (p < 0.05), and 13.7 +/- 0.7 and 13.0 +/- 0.6 versus 11.7 +/- 0.7 ml/min for coronary flow (no significant difference). Thus both analogs afforded an early and comparable degree of protection of contractile function that was sustained even after 24 hours of reperfusion. CONCLUSIONS: Both GP-1-468 and GP-1-668 increase the rate and extent of early postischemic recovery, and this protection is sustained for at least 24 hours. These beneficial actions were associated with an increase of the tissue content of adenosine during ischemia, but they appeared to be independent of the status of the high-energy metabolism.

Adenosine↗
PubMed1995

Modulation of cardiac Na(+)-K+ pump current: role of protein and nonprotein sulfhydryl redox status.

Oxidant stress alters protein structure and function, possibly through the modification of the redox status of regulatory protein sulfhydryl groups. We used the sulfhydryl-blocking reagent p-chloromercuriphenylsulfonic acid (pCMPSA), applied selectively and independently to either the intracellular or extracellular environment, to study the relationship between blocking protein sulfhydryl groups and Na(+)-K+ pump current (i.p.). In guinea pig ventricular myocytes voltage clamped at -30 mV, extracellular pCMPSA (50, 100, and 400 microM) caused a concentration-dependent reduction in holding current. The selective intracellular administration of pCMPSA (100 microM) induced a similar inhibition of i.p., albeit over a longer time course. The inhibition of ip resulting from either the intracellular or extracellular application of pCMPSA (100 microM) was reversed, in part, by the extracellular application of dithiothreitol (3 mM). An intracellular oxidant stress was also imposed by using diethyl maleate to deplete the intracellular nonprotein sulfhydryl content [represented by reduced glutathione (GSH)]. In myocytes isolated from diethyl maleate-treated guinea pigs *860 mg/kg i.p., 30 min before study), intracellular GSH was depleted by 93% and i.p. was depressed by 38% at all membrane potentials tested. We propose that Na(+)-K+ pump function may be related to protein and nonprotein sulfhydryl status. Protein sulfhydryl oxidation and glutathione depletion may account, in part, for a depression in Na(+)-K+ pump activity during reperfusion-induced oxidant stress.

4-Chloromercuribenzenesulfonate↗
PubMed1995

Preconditioning accelerates contracture and ATP depletion in blood-perfused rat hearts.

We investigated the effect of preconditioning on the ischemia-induced depletion of ATP in the blood-perfused rat heart. Isolated hearts (n = 5/group) were aerobically perfused with whole blood from a support rat and subjected to zero-flow global ischemia (37 degrees C) for periods up to 35 min. Frozen hearts were taken for metabolic analysis. Ischemic contracture was assessed with an isovolumic intraventricular balloon. The study groups were 1) control (C) with unprotected ischemia, 2) preconditioning (PC; 2 cycles of 3-min ischemia/3-min reperfusion), and 3) cardioplegia (CP; St. Thomas') before ischemia. Preconditioning accelerated, whereas cardioplegia delayed, ischemic contracture (time to peak contracture: PC = 8.1 +/- 0.3 and CP = 25.1 +/- 0.2 min vs. C = 15.6 +/- 0.3 min, P < 0.05). The ischemia-induced decline in ATP was delayed by cardioplegia but accelerated by preconditioning (P < 0.05). In a parallel study, preconditioning and cardioplegia protected postischemic contractile function to a similar extent. Thus, in the blood-perfused rat heart, preconditioning accelerated ischemic contracture and depletion of ATP. In contrast, cardioplegia slowed ischemic contracture and ATP depletion.

Adenosine Triphosphate↗
PubMed1994

Brain-death-induced cardiac contractile dysfunction: studies of possible neurohormonal and blood-borne mediators.

The aim of these studies was to investigate the mechanism underlying the haemodynamic changes associated with brain death. The initial series of studies were to assess whether these changes involved some blood-borne factor. When control rats (n = 6) were exsanguinated whilst being simultaneously transfused with blood from rats that had been brain-dead for 60 min, their haemodynamic function did not deteriorate. Likewise, when brain-dead rats (n = 6) were exsanguinated and transfused with blood from control rats there was no improvement of haemodynamic function. The absence of any blood-borne factor was further confirmed in studies in which isolated hearts from control rats were perfused with blood from a support rat which had been brain-dead for 15 min (n = 6/group). The brain-death-induced haemodynamic changes in the support rat (mean arterial pressure increased from 98 +/- 6 to 176 +/- 9 mm Hg after 30 s and then fell to 44 +/- 5 mm Hg after 5 min) were not associated with changes in cardiac function of the perfused heart (left ventricular developed pressure was 146 +/- 4 mmHg before the induction of brain death and 147 +/- 4 and 151 +/- 7 mm Hg at 30 s and 5 min, respectively, after the induction). In further in vivo studies, we assessed the involvement of the autonomic nervous system in brain-death-induced haemodynamic instability. We achieved this by employing beta-adrenoreceptor blockade or bilateral vagotomy (n = 6/group); propranolol (1 mg/kg given as a bolus 6 min before brain death followed by 0.5 mg/kg/h continuous infusion) abolished the early transient tachycardia and positive inotropic response to brain death but did not alter the subsequent deterioration of function (mean arterial pressure fell from 75 +/- 7 mmHg before brain death to 49 +/- 5 mmHg after 30 min). Bilateral vagotomy had no effect on the functional changes induced by brain death. The effect of catecholamine depletion was then investigated; 6-hydroxydopamine (given over 15 days) depleted myocardial norepinephrine content by approximately 90% (from 2.3 +/- 0.1 to 0.3 +/- 0.1 nmol/g wet wt; P < 0.05). Depletion of cardiac catecholamines reduced brain-death-induced mortality to zero but did not affect cardiac dysfunction. Finally, we used L-NAME and naloxone in an attempt to identify roles for nitric oxide and endogenous opioid peptides but were again unable to influence the cardiac events. In conclusion, the initial transient hyperdynamic response induced by brain death appears to be mediated through cardiac innervation and can be inhibited by beta-adrenoreceptor blockade. However, the autonomic nervous system, nitric oxide, endogenous opioid peptides and blood-borne factors do not appear to be involved in the subsequent deterioration of cardiac function.

Animals↗
PubMed1994

Ischemic preconditioning, cardioplegia or both?

UNLABELLED: With the continuing search for superior methods of myocardial protection, we compared the protective efficacy of ischemic preconditioning with that of St Thomas' cardioplegia, alone and in combination, against vascular and myocyte injury during ischemia and reperfusion. Rat hearts were perfused with blood for 20 min, subjected to zero flow global ischemia for 35 min (37 degrees C) and reperfused for 40 min. Left ventricular developed pressure (LVDP) was assessed with an intraventricular balloon. Coronary flow was measured at a constant perfusion pressure. Study groups (n = 8 hearts/group) were: (i) controls (unprotected ischemia), (ii) preconditioning (PC, 3 min ischemia + 3 min reperfusion), (iii) cardioplegia (CP, infused for 1 min before ischemia) and (iv) PC + CP. The post-ischemic recoveries of LVDP were 26 +/- 6, 44 +/- 2, 53 +/- 3 and 54 +/- 4% respectively (P < 0.05 all others v control). Post-ischemic coronary vascular resistance increased in controls by 167 +/- 60% from its pre-ischemic baseline value but was well protected with PC, CP and PC + CP (changing by only + 11 +/- 7, + 27 +/- 10 and -2 +/- 6% respectively). CONCLUSIONS: Preconditioning and cardioplegia alone afford similar and substantial protection of post-ischemic contractile and vascular function. The combination of the two affords no significant additional protection.

Animals↗
PubMed1994

Comparison of single- and multi-dose crystalloid cardioplegia to protect the immature myocardium.

The primary objective of this study was to compare the protective effects of single-dose and multi-dose St. Thomas' Hospital cardioplegic solution number 1 in the ischemic and reperfused neonatal rabbit heart. In addition, the effect of including bicarbonate (a component of St. Thomas' Hospital cardioplegic solution number 2) was also studied. Hearts (n = 8 per group) were excised from rabbits (7-10 days old) and aerobically perfused in the working mode with crystalloid media for 20 min (37 degrees C). After assessing cardiac function, the hearts were arrested by an infusion of cold cardioplegic solution (2 min at 15 degrees C) with or without the addition of bicarbonate (10 mmol). The hearts were then subjected to 6 h of hypothermic ischemia (15 degrees C) and, during this period, some hearts received multiple infusions (2 min/h at 15 degrees C) of cardioplegic solution. All hearts were reperfused for 35 min (15 min Langendorff plus 20 min working), cardiac function was then re-assessed and expressed as a percent of the preischemic value. The coronary effluent, collected during the first 15 min of reperfusion, was assayed for creatine kinase activity. At the end of the reperfusion period, the hearts were freeze clamped and taken for metabolic analysis. With multi-dose cardioplegia (without bicarbonate) the postischemic recovery of cardiac output was 67.0 +/- 6.5% and with single-dose the value was 39.3 +/- 10.0% (NS). The same pattern of postischemic recovery (that varied between 30% and 60%) for aortic flow, stroke volume and stroke work was observed with both multi-dose and single-dose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Effects of trimetazidine on ischemic contracture in isolated perfused rat hearts.

Trimetazidine (1-[2,3,4-trimethoxibenzyl)]-piperazine, TMZ) is a drug with a proposed metabolically based antiischemic action. Because ischemic contracture is a serious complication of ischemia and is considered metabolic in origin, we studied the effect of trimetazidine (TMZ) on development of ischemic contracture in experimental low-flow ischemia. TMZ was either added to the perfusion fluid or given as pretreatment to the donor rats. Langendorff-perfused isolated rat hearts were submitted to 30-min subtotal global ischemia (residual flow = 0.2 ml/min, n = 6 per group) (normal flow = 12.4 +/- 0.8 ml/min, heart fresh weight = 0.9 +/- 0.3 g). Ischemic contracture was measured by a water-filled intraventricular balloon. Thereafter, the hearts were reperfused for 20 min and recovery of intraventricular pressure was monitored. Furthermore, because the mechanisms of action of TMZ may involve cellular energy metabolism, we assessed throughout glycolytic flux by collecting the coronary effluent every 5 min during control perfusion, ischemia, and reperfusion periods. Animals from the pretreated groups received TMZ [3 mg/kg orally (p.o.) twice daily] for 5 days. Animals from the control group received placebo for the same time period. Concentrations of 10(-6) and 10(-4) M were used when the drug was added to the perfusate. In our experimental conditions, TMZ pretreatment alone had no measurable cardioprotective effect, but addition to the perfusate of TMZ 10(-6) M, approximately a therapeutic concentration in humans, reduced ischemic contracture in both pretreated and control groups and improved postischemic recovery of developed pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effects of R-56865 on transient inward current, Na(+)-Ca2+ exchange, and Ca2+ release from SR in cardiac myocytes.

Voltage-clamp studies were performed on guinea pig ventricular myocytes to clarify the action of N-(1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl)-N-methyl-2-benzothiazo lamine (R-56865), an inhibitor of cardiac glycoside-induced arrhythmias. Transient inward current ((Iti)) was induced using low-K+/high-Ca2+ Tyrode solution. R-56865 (1 mM) was found to abolish I(ti). R-56865 had no influence on the peak Ca2+ current, steady-state current during the clamp, holding current, or the Ni(2+)-sensitive electrogenic Na(+)-Ca2+ exchange current. Fluorescence transients after repolarization (temporally related to the I(ti)) were abolished by R-56865 without affecting the fluorescence transients during depolarization. In separate experiments, the threshold of Ca2+ release from sarcoplasmic reticulum (SR) by the Ca2+ current was found to be unchanged, whereas Ca2+ transients (presumably triggered by Ca2+ entry through the Na(+)-Ca2+ exchanger) were depressed. Our results suggest that R-56865 inhibits spontaneous Ca2+ release from the SR when it is mediated by Ca2+ entry through the Na(+)-Ca2+ exchanger but that it has no direct effect on the well-known "physiological" Ca(2+)-induced Ca(2+)-release mechanism from SR.

Animals↗
PubMed1994

Oxidant stress inhibits Na-Ca-exchange current in cardiac myocytes: mediation by sulfhydryl groups?

The effects of oxidant stress (xanthine oxidase plus hypoxanthine or photoactivation of rose bengal) on the Na(+)-Ca(2+)-exchange current were studied in guinea pig ventricular myocytes with the use of voltage-clamp techniques. Oxidant stress depressed both the Ni(2+)-sensitive and extracellular calcium concentration ([Ca2+]o)-activated current in a time-dependent manner (e.g., xanthine oxidase plus hypoxanthine inhibited the Ni(2+)-sensitive current at +60 mV from 6.81 +/- 3.24 to 5.54 +/- 0.48 pA/pF; n = 6; P < 0.05). This effect was independent of the [Ca2+] of the pipette solution. Diamide, an alkylating agent that modifies protein sulfhydryl groups, also decreased the Ni(2+)-sensitive current (at + 60 mV: from 5.76 +/- 1.55 to 3.43 +/- 0.99 pA/pF; n = 6; P < 0.05). The stoichiometry (n) and partition coefficient (gamma) of the electrogenic Na(+)-Ca(2+)-exchange current seemed unchanged. Our results suggest that oxidant stress causes a direct or indirect sulfhydryl group-mediated decrease of the Na(+)-Ca2+ exchanger.

Animals↗