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Biomedical subjects

D J Hearse

Publications and source records attributed to D J Hearse.

At least 73 records · Page 4Linked to original sources
PubMed1994

Na+/H+ exchange and reperfusion arrhythmias: protection by intracoronary infusion of a novel inhibitor.

Activation of sarcolemmal Na+/H+ exchange has been proposed as a causal factor in reperfusion arrhythmogenesis. To test this hypothesis, we determined the antiarrhythmic efficacy of two structurally distinct but equipotent Na+H+ exchange inhibitors, 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and the novel drug, 3-methylsulfonyl-4-piperidinobenzoyl guanidine (HOE-694), in isolated rat hearts (n = 12/group) subjected to independent dual coronary perfusion. After 15 min of aerobic perfusion of both beds, flow to the left coronary bed (LCB) was terminated for 10 min; this was followed by 5 min of reperfusion. Various concentrations of each drug were selectively infused into the LCB either during the 5-min period preceding ischemia plus during reperfusion or during reperfusion alone. With the former protocol, 0.01, 0.1, 1, and 10 microM EIPA reduced the incidence of reperfusion-induced ventricular fibrillation (VF) from 92% in controls to 83, 83, 50, and 0% (P < 0.05); the number of hearts in sinus rhythm at the end of reperfusion was increased from 17 to 42, 25, 83 (P < 0.05), and 100% (P < 0.05). HOE-694, at the same concentrations, reduced VF incidence from 92% in control to 83, 58, 50, and 8% (P < 0.05); 25, 67, 75 (P < 0.05), and 100% (P < 0.05) of hearts were in sinus rhythm, compared with 17% of controls, at the end of reperfusion. Even when infused during reperfusion alone, both drugs afforded significant protection against reperfusion-induced VF, which did not differ significantly from that observed when the drugs were also given before ischemia. The similar antiarrhythmic efficacy of EIPA and HOE-694 is consistent with an arrhythmogenic role for activation of Na+/H+ exchange during early reperfusion.

Amiloride↗
PubMed1994

Cardioplegia and vascular injury. Dissociation of the effects of ischemia from those of the cardioplegic solution.

Although cardioplegic solutions successfully protect myocardial contractile cells against ischemic injury, their effect on the vasculature remains controversial. To address this we used a vascular bed preparation (isolated rat mesentery) that permits the study of vascular function without the coincident changes in contractile status that affect vascular tone (and hence the assessment of vascular function in isolated hearts). Smooth muscle cell contraction was assessed by measurement of the vasoconstrictor response to phenylephrine, and relaxation was assessed by measurement of the vasodilator responses to sodium nitroprusside and the endothelium-dependent relaxant adenosine triphosphate. After characterization of basal vascular function, mesenteries were subjected to normothermic ischemia for 60, 90, 120, 150, and 180 minutes (n = 12 for each time period; 6 preparations were subjected to ischemia alone and 6 to ischemia preceded by a 3-minute infusion of the St. Thomas' Hospital cardioplegic solution). The tissue was then reperfused for 20 minutes and vascular function reassessed. Ischemia alone caused progressive time-dependent deterioration in vasoconstrictor responses (99% +/- 13%, 90% +/- 10%, 63% +/- 6%, 51% +/- 10%, and 27% +/- 4%), endothelium-independent vasodilation (93% +/- 3%, 86% +/- 2%, 78% +/- 5%, 61% +/- 5%, and 38% +/- 9%), and endothelium-dependent vasodilation (93% +/- 3%, 96% +/- 2%, 94% +/- 2%, 87% +/- 7%, and 62% +/- 11%). There were similar time-dependent deteriorations in mesenteries subjected to ischemia coupled with cardioplegic solution that were not significantly different from any of the ischemia-alone groups when matched for ischemic times. Thus, for example, after 180 minutes of ischemia alone, the vasoconstrictor response was 18% +/- 3%, endothelium-independent vasodilation was 44% +/- 7%, and endothelium-dependent vasodilation was 40% +/- 9%. The results demonstrate that under the conditions of this experiment, the St. Thomas' Hospital cardioplegic solution neither protects nor injures the vasculature during an episode of ischemia and reperfusion. However, in studies with 150 minutes of normothermic ischemia, multiple infusions of cardioplegic solution (given every 30 minutes during ischemia) resulted in protection of smooth muscle and endothelial function. Thus, after multiple infusions, vasoconstriction to phenylephrine was 74% +/- 4%, vasodilation to nitroprusside was 81% +/- 6%, and vasodilation to adenosine triphosphate was 89% +/- 5%. In conclusion, when the St. Thomas' Hospital cardioplegic solution is used as a single infusion and coupled with ischemia, the solution fails to protect smooth muscle and endothelial function against ischemic injury, but some protection is obtained when the solution is infused intermittently throughout the ischemic period.

Animals↗
PubMed1994

Early effects of hypothyroidism on the contractile function of the rat heart and its tolerance to hypothermic ischemia.

We have investigated the early effects of hypothyroidism on cardiac function and tolerance to hypothermic ischemia. Hypothyroidism was induced by thyroidectomy. Five days after operation, sham-operated and thyroidectomized rats were anesthetized and cardiac function was assessed. At this time, the plasma levels of triiodothyronine and thyroxine had fallen by eightfold and threefold, respectively, in thyroidectomized rats compared with the values in sham-operated rats. In vivo pump function was assessed by measuring mean arterial pressure, cardiac index, and stroke volume index: all were reduced by thyroidectomy (respectively 95 +/- 5 mmHg, 22 +/- 2 ml/min/100 gm body weight and 67 +/- 7 microliters/beat/100 gm body weight versus 112 +/- 4 mm Hg, 35 +/- 1 ml/min/100 gm body weight and 85 +/- 4 microliters/beat/100 gm body weight in the sham-operated group; p < 0.05 in each instance). Systemic vascular resistance index was higher in thyroidectomized than in sham-operated rats (4.4 +/- 0.4 versus 3.1 +/- 0.2 mmHg/ml/min/100 gm body weight; p < 0.05). In vivo indices of contractile function were also reduced by thyroidectomy: maximum rate of left ventricular pressure development fell by almost 50% (5190 +/- 790 versus 9600 +/- 900 mmHg/sec; p < 0.05) and left ventricular developed pressure and heart rate also fell (respectively 92 +/- 8 mmHg and 340 beats/min versus 129 +/- 6 mmHg and 398 +/- 6 beats/min; p < 0.05 in each instance). After excision, hearts were blood-perfused and ex vivo function assessed with intraventricular balloons. Systolic and diastolic functions were significantly impaired in the thyroidectomized group and the myocardial Na(+)-K(+)-adenosinetriphosphatase activity was reduced from a control value of 8.3 +/- 0.3 to 5.8 +/- 0.4 mean integrated extinction x 100. The hearts were then subjected to 2 minutes of cardioplegic infusion, 6 hours of hypothermic (4 degrees C) ischemia, and 40 minutes of reperfusion. In control hearts, left ventricular developed pressure (at an end-diastolic pressure of 8 mm Hg) recovered to 76% of its preischemic value (131 +/- 8 versus 173 +/- 8 mmHg; p < 0.05); in hearts from thyroidectomized rats, left ventricular developed pressure recovered to 81% of its preischemic value (110 +/- 8 versus 136 +/- 12 mmHg; p = not significant), an absolute value that was not significantly different from that in the sham-operated group. Diastolic function recovered to the same extent in both groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

The myocardial vasculature during ischemia and reperfusion: a target for injury and protection.

Ischemia and reperfusion may result in injury to one or more of the cellular components of the heart. In addition to damaging myocytes and their contractile capability, ischemia and reperfusion may inflict early and severe injury on the vasculature which, in turn, may further jeopardize the survival of the myocytes. While ischemia is known to cause progressive injury to endothelium and vascular smooth muscle it now appears that reperfusion can inflict additional, possibly severe, injury on the microcirculation which may compromise the return of normal coronary perfusion. This post-ischemic/reperfusion microvascular incompetence ranges from a transient exacerbation of the increase in vascular resistance initiated during ischemia, to a sustained loss of competent capillaries and eventually to the "no reflow" phenomenon which is characterized by the total inability of the affected tissue to be reperfused. Whereas "no reflow" may be of little importance if it occurs in already infarcted tissue, post-ischemic microvascular incompetence in potentially salvable myocardium could be of considerable significance. Evidence is presented that the vascular endothelium, and its ability to regulate coronary vascular tone, play a central and early role in the pathogenesis of myocardial injury. Mechanisms underlying microvascular injury have been identified and pharmacological strategies now exist for the effective manipulation of this injury--a prospect that is of considerable importance in the light of the widespread use of thrombolytic procedures for the reperfusion of the human myocardium.

Animals↗
PubMed1993

Preconditioning and post-ischaemic contractile dysfunction: the role of impaired oxygen delivery vs extracellular metabolite accumulation.

The aim of the present study was to identify components of ischaemia involved in the induction of preconditioning. Isolated rat hearts (n = 8 per group) were perfused with bicarbonate buffer. Following 10 min aerobic perfusion they were randomised and subjected to 5 min periods during which the perfusion conditions were: (i) normal aerobic perfusion (controls); (ii) zero flow ischaemia; (iii) low flow ischaemia (10% of control O2 delivery); (iv) hypoxia (10% of control O2 delivery); or (v) acidosis (pH 6.4). After these periods of "preconditioning", all hearts underwent 5 min aerobic perfusion followed by 40 min zero flow global ischaemia and 35 min reperfusion. Contractile function was measured at the beginning and at the end of the experiment. Despite profound differences in coronary flow during preconditioning, substantial and similar protection was observed in all groups preconditioned by transiently limiting oxygen delivery. Recovery of cardiac output was 66.7 +/- 6.3%, 58.7 +/- 5.1% and 62.6% +/- 3.3% in the zero flow, low flow and hypoxic groups, respectively, vs 31.0 +/- 3.0% in controls (all P < 0.05). In hearts subjected to acidosis there was no protection (recovery of cardiac output 38.1 +/- 2.7%). Impairment of oxygen delivery appears to be the principle component of ischaemia responsible for the induction of preconditioning. Metabolite accumulation appears to play no significant role.

Acidosis↗
PubMed1993

"Dose"-dependency and temporal characteristics of protection by ischaemic preconditioning against ischaemia-induced arrhythmias in rat hearts.

Brief episodes of ischaemia and reperfusion (preconditioning) can increase the resistance of the myocardium to ischaemic injury. We investigated the temporal characteristics of anti-arrhythmic protection by preconditioning. Rat hearts underwent regional ischaemia (+/- reperfusion) of the left coronary territory. Control isolated blood-perfused hearts underwent 40 min ischaemia; in the preconditioned groups this was preceded by one, two or three cycles of 5 min ischaemia and 5 min reperfusion. Control anaesthetized rats underwent 60 min ischaemia; this was preceded by three cycles of 3 min ischaemia and 3 min reperfusion in the preconditioned group. Preconditioning led to: (i) the abolition of ventricular fibrillation in both in vivo and in vitro preparations; (ii) a reduced incidence of ventricular tachycardia (from 100% to 8% in vitro and 100% to 25% in vivo); and (iii) a reduced incidence of ventricular premature beats (from 246 +/- 36 to 8 +/- 5 in vitro and 85 +/- 21 to 24 +/- 13 in vivo). In isolated hearts protection was proportional to the number of preconditioning cycles. Although preconditioning caused a dramatic reduction in the severity of arrhythmias it did not result in any significant alteration in their temporal profiles. We conclude that protection by preconditioning against ischaemia-induced arrhythmias is "dose"-dependent in rat hearts in vitro and results in an absolute reduction in the severity of ischaemia-induced arrhythmias rather than an alteration in their time-course, both in vivo and in vitro.

Adaptation, Physiological↗
PubMed1993

Contractile and vascular consequences of blood versus crystalloid cardioplegia in the isolated blood-perfused rat heart.

The protective effects of sanguineous and asanguineous St. Thomas' cardioplegia (SCP and ACP) on post-ischemic vasodilator responsiveness, left ventricular developed pressure and end-diastolic pressure (LVDP and LVEDP), tissue adenosine triphosphate (ATP) and creatine phosphate (CP) contents were compared in the isolated blood-perfused rat heart. Five groups of hearts were studied: the controls (n = 8) perfused with blood (from a support rat) for 50 min (37 degrees C), versus hearts (n = 14/group) arrested by a single infusion of either cardioplegic solution (15 degrees C) prior to global ischemia (15 degrees C) and blood reperfusion (37 degrees C). After 2 or 4 h of ischemia and 50 min of reperfusion, endothelium-dependent vasodilator acetylcholine (1 microgram) induced a 10 +/- 0.5 and 8.5 +/- 0.5% reduction, respectively, in coronary resistance, in the SCP groups, but only a 6.5 +/- 0.6 and 4.5 +/- 0.5% reduction (P < 0.05), respectively, in the ACP groups. However, there were no significant differences in LVDP, LVEDP, tissue ATP and CP contents, and endothelium-independent vasodilator response to nitroglycerin between the two cardioplegic groups. In a further study, rat hearts (n = 8/group) were arrested with SCP (magnesium concentration < 0.5, 5.0 or 16.0 mmol/l, in groups 1, 2 and 3) and subjected to 4 h of global ischemia (15 degrees C) followed by 50 min of blood reperfusion (37 degrees C). At the end of reperfusion, LVDP (at a ventricular volume of 180 microliters) was 60 +/- 3.4, 72 +/- 3.5 and 70 +/- 3.2 in groups 1, 2 and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Metabolic and functional effects of the nucleoside transport inhibitor R75231 in the ischaemic and blood reperfused rabbit heart.

OBJECTIVE: The ability of R75231, a nucleoside transport inhibitor, to influence adenine nucleotide metabolism and enhance postischaemic functional recovery was assessed in the blood perfused rabbit heart. METHODS: Hearts (n = 8 per group) from donor animals were excised and perfused with blood at 37 degrees C from a support rabbit. After 20 min of aerobic perfusion hearts were arrested with St Thomas' Hospital cardioplegic solution (2 min at 37 degrees C) and rendered globally ischaemic for 60 min. This was followed by 60 min of reperfusion. R75231 (0.1 mg.kg-1, intravenously) was given to donor and support rabbits 1 h before the experiment, control rabbits receiving the same volume of vehicle. RESULTS: Treatment with R75231 resulted in a 45% reduction in coronary vascular resistance in aerobically perfused control hearts, an effect that was absent during postischaemic reperfusion. Thus, before ischaemia, coronary flow was greater in R75231 treated hearts [6.6(SEM 0.8) ml.min-1] than in controls [4.3(0.6) ml.min-1; p < 0.05] but during reperfusion no significant difference was observed [4.0(0.6) v 3.6(0.3) ml.min-1]. The mean time to onset and extent of contracture during ischaemia was similar in R75231 treated and control groups, at 42(4) v 41(4) min and 27(3) v 26(6) mm Hg, respectively. Left ventricular developed pressure recovered to approximately 50% of its preischaemic value during the first 40 min of reperfusion in both groups; however, after longer durations of reperfusion, it tended to deteriorate in the R75231 treated group whereas it was maintained at a constant level in the controls [37(10) v 53(6) mm Hg, respectively; NS]. At the end of reperfusion, tissue adenosine content was 13-fold greater in the R75231 treated group, at 0.40(0.09) v 0.03(0.01) mumol.g-1 dry wt in controls; p < 0.05; the nucleotide pool, nicotinamide adenine dinucleotide phosphate content, and the energy charge potential were similar in groups. CONCLUSIONS: R75231 decreased coronary vascular resistance and increased coronary flow during aerobic perfusion in control hearts, an effect that was lost after ischaemia and reperfusion. R75231 also increased greatly the tissue content of adenosine but, despite this, failed to improve either the recovery of cardiac contractile function or the replenishment of the adenine nucleotide pool.

Adenine Nucleotides↗
PubMed1993

Preconditioning and reperfusion arrhythmias in the isolated rat heart: true protection or temporal shift in vulnerability?

OBJECTIVE: The relationship between arrhythmia severity during reperfusion and the duration of preceding ischaemia is bell shaped. Although ischaemic preconditioning can protect against reperfusion induced arrhythmias it is not clear if this is achieved by a true reduction in arrhythmia severity or by a temporal shift in the bell shaped relationship occurring as a consequence of increased ischaemic tolerance. METHODS: Isolated rat hearts (n = 12 per group) were Langendorff-perfused with whole blood from a support rat. Regional ischaemia and reperfusion were induced using a ligature around the left main coronary artery. Cardiac rhythm was recorded continuously. RESULTS: Repeated cycles of preconditioning (5 min ischaemia and 5 min reperfusion) led to a progressive reduction in the incidence of reperfusion induced ventricular fibrillation following 10 minutes of ischaemia (92%, 66%, 42%, and 8% following 0, 1, 2, and 3 cycles respectively). Three cycles of preconditioning reduced the incidence of reperfusion induced ventricular fibrillation after each of 10 (83% to 17%; p < 0.05), 15 (92% to 42%; p < 0.05), 20 (67% to 25%), 30 (33% to 0%), and 40 (25% to 0%) minutes of ischaemia. Preconditioning also led to a reduced incidence of reperfusion induced ventricular tachycardia following 10 minutes of ischaemia (100% to 42%; p < 0.05). There was no evidence of a temporal shift in the bell shaped relationships: peak incidences of reperfusion induced ventricular fibrillation and ventricular tachycardia each occurred after 15 minutes of ischaemia in both control and preconditioned groups. CONCLUSIONS: In isolated blood perfused rat hearts serial preconditioning cycles provide cumulative protection against reperfusion induced ventricular arrhythmias. This protection occurs over a wide range of ischaemic durations without altering the temporal relationship between the duration of ischaemia and arrhythmia severity. This may indicate that antiarrhythmic protection is not a consequence of anti-ischaemic mechanisms.

Animals↗
PubMed1993

Improved functional recovery by ischaemic preconditioning is not mediated by adenosine in the globally ischaemic isolated rat heart.

OBJECTIVE: A brief period of ischaemia (5 min) and reperfusion (5 min), prior to a longer period of ischaemia and reperfusion, has been shown to reduce the extent of injury (necrosis, arrhythmias, or postischaemic contractile malfunction) caused by a subsequent longer period of ischaemia and reperfusion. Adenosine has been identified as a factor in the protection afforded against regional tissue necrosis by such preconditioning. The aim of this study was to assess the role of adenosine in preconditioning induced protection of postischaemic function in the globally ischaemic isolated rat heart. METHODS: The ability of global ischaemia to precondition against postischaemic contractile malfunction was first confirmed in the isolated ejecting rat heart preparation. Hearts (n = 6 per group) were perfused aerobically (37 degrees C, paced at 350 beats.min-1) for 20 min, at the end of which contractile function was measured. This was followed by 10 min of Langendorff perfusion (control group) or 5 min of global ischaemia plus 5 min of Langendorff reperfusion (preconditioned group). The hearts were then subjected to 20 min of global ischaemia (37 degrees C) and 35 min of reperfusion (15 min Langendorff and 20 min ejecting); function was then reassessed. RESULTS: Postischaemic recovery of aortic flow was 26(SEM 8)% in the control group v 57(4)% in the preconditioned group (p < 0.05). To assess whether exogenous adenosine could mimic this protection, the experiments were repeated with the 5 min period of ischaemic preconditioning replaced by 5 min of aerobic Langendorff perfusion with adenosine-containing buffer (100, 50, or 10 mumol.litre-1). No protection of postischaemic function was observed in any of the adenosine treated groups. In further experiments, we assessed whether ischaemic preconditioning persisted in the presence of the A1/A2 adenosine antagonist, 8 (p-sulphophenyl) theophylline (8-SPT). Since pacing was not used in these studies, the ability of ischaemia to precondition the myocardium was again confirmed; the protocol was then repeated with 8-SPT (10 mumol.litre-1) present in the perfusate throughout. Although 8-SPT depressed recovery in both control and preconditioned hearts it failed to abolish the protective effects of ischaemic preconditioning. CONCLUSIONS: There is no evidence from these results to support the involvement of adenosine to any major extent in preconditioning induced protection of postischaemic contractile function in the isolated rat heart.

Adenosine↗
PubMed1993

The antiarrhythmic action of ischaemic preconditioning in rat hearts does not involve functional Gi proteins.

OBJECTIVE: Ischaemic preconditioning has been reported to be mediated by inhibitory G (Gi) proteins in rabbits; however, the mechanism of preconditioning in rats appears to differ from that in other species. The aim of this study was to determine whether functional Gi proteins are required for the antiarrhythmic action of preconditioning in rats. METHODS: Donor rats were randomised to receive pertussis toxin (25 micrograms.kg-1 intravenously) or saline. After 48 h the hearts were isolated and Langendorff perfused with blood from untreated support rats. Cardiac rhythm was recorded continuously. Ischaemia and reperfusion were induced by occluding and releasing a snare around the left coronary artery. Following 10 min of aerobic perfusion hearts were further randomised to: (1) control groups (n = 12 per group) which underwent a further 30 min of aerobic perfusion, or (2) preconditioned groups (n = 12 per group) which were subjected to three cycles of 5 min of ischaemia and 5 min of reperfusion. All hearts subsequently underwent 30 min of regional ischaemia and 10 min of reperfusion during which arrhythmias were quantified. RESULTS: In hearts not pretreated with pertussis toxin, preconditioning limited the severity of ischaemia induced arrhythmias. The incidence of ventricular tachycardia was reduced from 100% to 33% and the mean number of ventricular premature beats from 164(SEM 42) to 23(14) (each p < 0.05). Although pretreatment with pertussis toxin completely abolished the bradycardic response to both acetylcholine and adenosine (indicating functional blockade of Gi proteins), it did not significantly influence the degree of antiarrhythmic protection afforded by preconditioning. In pretreated hearts preconditioning reduced the incidence of ventricular tachycardia from 83% to 33% and the mean number of ventricular premature beats from 267(66) to 62(32) (each p < 0.05). CONCLUSIONS: The antiarrhythmic action of preconditioning in isolated blood perfused rat hearts does not require functional Gi proteins.

Acetylcholine↗
PubMed1993

Combined administration of an IK(ATP) activator and Ito blocker increases coronary flow independently of effects on heart rate, QT interval, and ischaemia-induced ventricular fibrillation in rats.

The effects of combined administration of the ATP-dependent K+ channel opener cromakalim and the transient outward K+ current (Ito) blocker tedisamil on ventricular tachyarrhythmias, QT interval, and coronary flow were investigated in isolated rat heart (n = 12/group) subjected to 30-min regional ischaemia. When administered alone, beginning 5 min before onset of ischaemia and continuously thereafter, neither cromakalim (10 microM) nor tedisamil (3 microM) had any significant influence on the incidence of VF, although tedisamil abolished sustained VF (SVF, defined as VF lasting > 2 min). Cromakalim did not affect tedisamil's ability to abolish SVF when administered concurrently with tedisamil and had no effect on SVF when administered alone; incidences of SVF were 64, 0 (p < 0.05), 66, and 0% (p < 0.05) in control, tedisamil, cromakalim, and combined treatment groups, respectively. Occurrence of SVF was related to the width of the ventricular complex at 50% of repolarisation (QT50). Pretreatment with tedisamil widened QT50 (p < 0.05), and this effect was not attenuated by combined treatment with cromakalim. Cromakalim increased coronary flow (14 +/- 0.4 in controls versus 21 +/- 0.6 ml/min/g in cromakalim-treated hearts, p < 0.05). This effect was not reduced by coadministration of tedisamil (20 +/- 0.9 ml/min/g in hearts cotreated with both drugs). Tedisamil alone had no significant effect on coronary flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Mechanisms of antifibrillatory effect of acidic reperfusion: role of perfusate bicarbonate concentration.

Transient (2 min) acidic (pH 6.6) reperfusion with low [HCO3-] solution suppresses reperfusion-induced ventricular fibrillation (VF) in the isolated rat heart. Using this preparation, we tested whether the effect was mediated by the high [H+] or the low [HCO3-] of perfusate. Left and right coronary beds were independently perfused with HCO3(-)-containing (25.0 mmol/l) solution at pH 7.4. Regional ischemia was then induced by stopping flow to the left coronary bed for 10 min. Hearts were subsequently assigned to four groups (n = 12 hearts/group), and the left coronary bed was reperfused with either HCO3(-)-containing (25.0 or 4.0 mmol/l) or HCO3(-)-free (5.0 mmol/l HEPES) solution, at pH 7.4 throughout (control reperfusion) or at pH 6.6 for the first 2 min and at pH 7.4 from 2 to 5 min (acidic reperfusion). Regardless of the buffer, controls exhibited a high (92 and 100%) incidence of VF; this was reduced to 42% in both of the acidic reperfusion groups (P < 0.05). There were no intergroup differences in heart rate, coronary flow, or size of ischemic zone. Thus high [H+], rather than low [HCO3-], appears to mediate the antifibrillatory effect of transient acidic reperfusion.

Animals↗
PubMed1993

Early and late effects of leukopenic reperfusion on the recovery of cardiac contractile function. Studies in the transplanted and isolated blood-perfused rat heart.

BACKGROUND: Since there is considerable evidence that leukocytes contribute to tissue injury during ischemia and reperfusion, the present study was designed to: (1) determine whether reperfusion in vivo with leukopenic blood affords protection in a model of reversible hypothermic ischemia, (2) determine the duration of any protection, (3) characterize the relation between protection and duration of leukopenic perfusion, and (4) assess the effect of leukopenic reperfusion on myocardial glutathione content. METHODS AND RESULTS: Rat hearts (n = 12 per group) were excised, immediately arrested with an infusion (2 minutes at 4 degrees C) of St Thomas' cardioplegic solution, and subjected to 4 hours of global ischemia (4 degrees C). The hearts were then transplanted (1 hour additional ischemic time) into the abdomen of saline-treated or leukopenic recipients. Leukopenia was induced by intraperitoneal administration of mustine hydrochloride (2 mg/kg) 3 days before study. Hearts were then reperfused in situ for 1, 4, or 24 hours, after which they were excised and either processed for histological examination (n = 4 per group) or perfused aerobically with bicarbonate buffer for 20 minutes, and contractile function was assessed (n = 8 per group); at the end of this period, some hearts (n = 5 per group) were taken for metabolite analysis. After 1 hour of reperfusion, contractile function in the saline-treated control group was significantly reduced compared with aerobic controls that had not been subjected to ischemia (left ventricular developed pressure [LVDP], 108 +/- 5 vs 126 +/- 3 mm Hg at an end-diastolic pressure of 12 mm Hg; P < .05). However, in the hearts with leukopenic reperfusion, LVDP (119 +/- 2 mm Hg) was similar to that of aerobic controls. This benefit, however, was lost after 4 and 24 hours of reperfusion. Cardiac compliance was not influenced by leukopenia. Coronary flow recovered significantly better in the leukopenic hearts during the first 4 hours of reperfusion (11.8 +/- 0.5 vs 9.3 +/- 0.4 mL/min at 1 hour and 10.0 +/- 0.5 vs 8.0 +/- 0.4 mL/min at 4 hours, P < .05), but again this benefit was lost after 24 hours of reperfusion. The myocardial contents of reduced and oxidized glutathione after 1, 4, and 24 hours of reperfusion were similar in saline-treated and leukocyte-depleted animals. In additional studies, the period of ischemia was extended to 8 hours, and similar results were obtained, with improved recovery of contractile function and coronary flow but not cardiac compliance in the leukopenic group after 1 hour of reperfusion. In further studies with the isolated blood-perfused rat heart, ischemia was induced for 8 hours; this was followed first by reperfusion for 0, 2, 10, 30, or 60 minutes with leukopenic blood and then by perfusion with blood from saline-treated animals for 60, 58, 50, 30, or 0 minutes, respectively. Reperfusion with leukopenic blood for 2 minutes did not improve the recovery of LVDP (106 +/- 7 vs 96 +/- 10 mm Hg in controls; NS) but when continued for 10, 30, or 60 minutes resulted in significant improvements (137 +/- 5, 138 +/- 3, and 150 +/- 10 mm Hg, respectively). Although coronary flow tended to be greater in all leukopenic groups, by the end of 60 minutes of reperfusion, only those hearts reperfused with leukopenic blood for the entire reperfusion period showed a significant improvement (3.4 +/- 0.3 vs 2.5 +/- 0.2 mL/min in controls; P < .05). Histological studies revealed no intravascular aggregation of leukocytes or features of myocyte necrosis. CONCLUSIONS: Reperfusion with leukopenic blood accelerated the rate of recovery of cardiac function after reversible myocardial injury but did not lead to a sustained increase in the eventual extent of recovery. Reperfusion with leukopenic blood for the first 10 minutes of reflow is sufficient to obtain this benefit.

Animals↗
PubMed1993

Brain death-induced cardiac contractile dysfunction and long-term cardiac preservation. Rat heart studies of the effects of hypophysectomy.

BACKGROUND: Ischemic brain death induces cardiac contractile dysfunction, which may exclude the heart as a donor organ for transplantation; the mechanism is unknown. Since cerebral ischemia might alter pituitary function, we investigated the influence of hypophysectomy on basal contractile function, brain death-induced contractile malfunction, and the tolerance of the heart to hypothermic ischemic storage. METHODS AND RESULTS: Rats were hypophysectomized and maintained for 5 days; during this time, left ventricular developed pressure (LVDP) fell to 70% of its control value (92 +/- 8 versus 132 +/- 6 mm Hg, P < .05). Diastolic function of isolated blood-perfused hearts 5 days after hypophysectomy was severely impaired (left ventricular volume at 12 mm Hg of end-diastolic pressure was 141 +/- 20 versus 250 +/- 30 microL in sham-operated control rats; P < .05). Brain death in nonhypophysectomized rats resulted in a transient increase in mean arterial pressure (from 112 +/- 4 to 180 +/- 7 mm Hg within the first 30 seconds) followed by a rapid decline to less than 50% of the control value (54 +/- 3 mm Hg after 5 minutes, P < .05). Changes in cardiac function were comparable (cardiac index fell from 34 +/- 2 to 17 +/- 1 mL/min per 100 g body weight, and stroke volume index fell from 82 +/- 5 to 41 +/- 4 microL per beat per 100 g body weight within 10 minutes; P < .05). Brain death in hypophysectomized rats resulted in a similar (but attenuated) biphasic response with arterial pressure (already reduced to 82 +/- 9 mm Hg as a consequence of hypophysectomy) transiently increasing to 144 +/- 9 mm Hg after 30 seconds and then falling to 52 +/- 5 mm Hg by 5 minutes. Finally, we assessed the effects of coincident hypophysectomy and brain death on the ability of the heart to recover from 6 hours of hypothermic (4 degrees C) ischemic storage. Brain death alone had no effect on the postischemic recovery of LVDP (133 +/- 14 versus 129 +/- 12 mm Hg at 8 mm Hg of end-diastolic pressure in the non-brain death group). LVDP in hearts from hypophysectomized rats with brain death recovered to only 84 +/- 13 mm Hg; however, this was virtually identical to the LVDP in hearts from hypophysectomized rats that had not been subjected to brain death (83 +/- 5 mm Hg) or had not even been exposed to hypothermic ischemia (83 +/- 10 mm Hg). CONCLUSIONS: Hypophysectomy induces a deterioration of cardiac function that becomes apparent after 2 days. However, it does not exacerbate the cardiac dysfunction induced by brain death. Hearts from hypophysectomized animals, with or without brain death, recovered less well after prolonged hypothermic storage; nevertheless, the hearts recovered to preischemic levels, indicating that, although hypophysectomy impairs cardiac contractile function, it does not adversely influence the tolerance of the heart to hypothermic ischemia. Pituitary function may be an important factor in determining cardiac function without influencing resistance to ischemia or responses to brain injury.

Animals↗
PubMed1993

Thromboxane A2 mediates pulmonary hypertension after cardiopulmonary bypass in the rabbit.

Clinically, it is well established that cardiopulmonary bypass results in pulmonary dysfunction. Using a recently developed preparation for cardiopulmonary bypass in the rabbit, we have been able to mimic a similar, but more severe, condition. We found that, despite normal histologic structure of the myocardium, hearts could not be weaned from bypass because of a serious increase in pulmonary vascular resistance. Histologic studies of the lungs showed severe intravascular neutrophil aggregation and marked vasoconstriction. To identify the nature and origin of the mediator responsible for the changes in the pulmonary vasculature, we subjected groups of rabbits (n = 4 per group) to bypass with cooling to 18 degrees C, circulatory arrest for 1 hour, and rewarming on bypass to 33 degrees C. Pulmonary vascular resistance was measured at the same temperature before and after bypass. Four groups were studied: group I were untreated controls; group II received the cyclooxygenase inhibitor, indomethacin (0.2 mg/kg intravenously), before operation; group III received the thromboxane A2 synthetase inhibitor, Dazmegral (5 mg/kg intravenously), before operation together with the thromboxane A2 receptor blocker GR 32191B (2 mg/kg per 30 minutes intravenously); and group IV were treated with mustine hydrochloride (1.75 mg/kg intravenously) 3 days before the experiment to deplete the neutrophils by 90%. During circulatory arrest, the heart was protected with an initial infusion (10 ml at 4 degrees C over 1 minute) of St. Thomas' Hospital cardioplegic solution. At the end of the experiment, the heart and lungs were histologically examined. In the control group, a significant increase (+395% when compared with the value recorded before bypass) in pulmonary vascular resistance was observed after bypass. However, in none of the treated groups did pulmonary vascular resistance increase significantly (percentage changes in groups II, III, and IV were -24%, 0%, and +33%, respectively). Pulmonary histologic characteristics were normal in all treated groups, and all animals were successfully weaned from bypass. These results indicate that the increase in pulmonary vascular resistance that arises as a consequence of bypass in rabbits is primarily a result of the production of thromboxane A2, a process in which the neutrophil plays a pivotal role.

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