Ventricular Lactate Research Articles

Adding Bupivacaine to High-potassium Cardioplegia Improves Function and Reduces Cellular Damage of Rat Isolated Hearts after Prolonged, Cold Storage

Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone. After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 microm bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4 degrees C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured. All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline. Adding bupivacaine to a depolarizing cardioplegia solution reduces cell damage and improves cardiac function after prolonged storage. Metabolic inhibition may contribute to this phenomenon, which is not entirely explained by sodium channel blockade.

Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts

Adenosine deaminase (ADA) may be multifunctional, regulating adenosine levels and adenosine receptor (AR) agonism, and potentially modifying AR functionality. Herein we assess effects of ADA (and A1AR) deficiency on AR-mediated responses and ischaemic tolerance. Normoxic function and responses to 20 or 25 min ischaemia and 45 min reperfusion were studied in isolated hearts from wild-type mice and from mice deficient in ADA and/or A1ARs. Neither ADA or A1AR deficiency significantly modified basal contractility, although ADA deficiency reduced resting heart rate (an effect abrogated by A1AR deficiency). Bradycardia and vasodilation in response to AR agonism (2-chloroadenosine) were unaltered by ADA deficiency, while A1AR deficiency eliminated the heart rate response. Adenosine efflux increased 10- to 20-fold with ADA deficiency (at the expense of inosine). Deletion of ADA improved outcome from 25 min ischaemia, reducing ventricular diastolic pressure (by 45%; 21+/-4 vs. 38+/-3mm Hg) and lactate dehydrogenase (LDH) efflux (by 40%; 0.12+/-0.01 vs. 0.21+/-0.02 U/g/min ischaemia), and enhancing pressure development (by 35%; 89+/-6 vs. 66+/-5mm Hg). Similar protection was evident after 20 min ischaemia, and was mimicked by the ADA inhibitor EHNA (5 microM). Deletion of ADA also enhanced tolerance in A1AR deficient hearts, though effects on diastolic pressure were eliminated. Deficiency of ADA does not alter sensitivities of cardiovascular A1 or A2ARs (despite markedly elevated [adenosine]), but significantly improves ischaemic tolerance. Conversely, A1AR deficiency impairs ischaemic tolerance. Effects of ADA deficiency on diastolic pressure appear solely A1AR-dependent while other ARs or processes additionally contribute to improved contractile recovery and reduced cell death.

Dichloroacetate causes toxic neuropathy in MELAS

To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). High levels of ventricular lactate, the brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS. The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety. During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms. DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.

Physiological Measures Associated with Marathon Running Performance in High-Level Male and Female Homogeneous Groups

The study tested the hypothesis that physiological measurements can predict marathon running performance in a top-level homogeneous group of males and females. Ten male, performance: 2:12:04, coefficient of variation (CV)=2.33%, and 8 female marathon runners, performance: 2:34:53, CV=4.54%, performed an increment test on the treadmill (starting speed, 8 km.h-1; increments, 2 km.h-1; increment duration, 3 min to exhaustion). The heart rate (HR), VO2 and the lactate concentrations were measured at the end of each exercise level. During the recovery time, HR and lactate were measured. Furthermore, echocardiographic, anthropometric and haematologic measurements were made. The results of a stepwise multiple regression analysis using marathon time as the dependent variable yielded R2=0.983 for the male group and R2=0.984 for the female group. The model for the male group used the independent variables lactate value at 10 km.h-1, left ventricular telediastolic diameter (LVD) and lactate value at 22 km.h-1. The model for the female group used the independent variables subscapular skinfold, serum ferritin and sum of six skinfolds. Our study demonstrates that in males and females, physiological parameters can explain the variance in marathon time among elite homogeneous groups.

Dronedarone Administration Prevents Body Weight Gain and Increases Tolerance of the Heart to Ischemic Stress: A Possible Involvement of Thyroid Hormone Receptor α1

Hypothyroid heart displays a phenotype of cardioprotection against ischemia and this study investigated whether administration of dronedarone, an amiodarone-like compound that has been shown to preferentially antagonize thyroid hormone binding to thyroid hormone receptor alpha1 (TRalpha1), results in a similar effect. Dronedarone was given in Wistar rats (90 mg/kg, once daily (od) for 2 weeks) (DRON), while untreated animals served as controls (CONT). Hypothyroidism (HYPO) was induced by propylthiouracil administration. Isolated rat hearts were perfused in Langendorff mode and subjected to 20 minutes of zero-flow global ischemia (I) followed by 45 minutes of reperfusion (R). 3,5,3' Triiodothyronine remained unchanged while body weight and food intake were reduced. alpha-Myosin heavy chain (alpha-MHC) decreased in DRON while beta-myosin heavy chain (beta-MHC) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) expression (SERCA) was similar to CONT. In HYPO, alpha-MHC and SERCA were decreased while beta-MHC was increased. Myocardial glycogen content was increased in both DRON and HYPO. In DRON, resting heart rate and contractility were reduced and ischemic contracture was significantly suppressed while postischemic left ventricular end-diastolic pressure and lactate dehydrogenase release (IU/L min) after I/R were significantly decreased. In conclusion, dronedarone treatment results in cardioprotection by selectively mimicking hypothyroidism. This is accompanied by a reduction in body weight because of the suppression of food intake. TRs might prove novel pharmacologic targets for the treatment of cardiovascular illnesses.

Cerebral lactic acidosis correlates with neurological impairment in MELAS

To evaluate the role of chronic cerebral lactic acidosis in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).The authors studied 91 individuals from 34 families with MELAS and the A3243G point mutation and 15 individuals from two families with myoclonus epilepsy and ragged red fibers (MERRF) and the A8344G mutation. Subjects were divided into four groups. Paternal relatives were studied as controls (Group 1). The maternally related subjects were divided clinically into three groups: asymptomatic (no clinical evidence of neurologic disease) (Group 2), oligosymptomatic (neurologic symptoms but without the full clinical picture of MELAS or MERRF) (Group 3), and symptomatic (fulfilling MELAS or MERRF criteria) (Group 4). The authors performed a standardized neurologic examination, neuropsychological testing, MRS, and leukocyte DNA analysis in all subjects.The symptomatic and oligosymptomatic MELAS subjects had significantly higher ventricular lactate than the other groups. There was a significant correlation between degree of neuropsychological and neurologic impairment and cerebral lactic acidosis as estimated by ventricular MRS lactate levels.High levels of ventricular lactate, the brain spectroscopic signature of MELAS, are associated with more severe neurologic impairment.

Acute effects of 17beta-estradiol on myocardial pH, Na+, and Ca2+ and ischemia-reperfusion injury.

Evidence suggests that 1) ischemia-reperfusion injury is due largely to cytosolic Ca(2+) accumulation resulting from functional coupling of Na(+)/Ca(2+) exchange (NCE) with stimulated Na(+)/H(+) exchange (NHE1) and 2) 17beta-estradiol (E2) stimulates release of NO, which inhibits NHE1. Thus we tested the hypothesis that acute E2 limits myocardial Na(+) and therefore Ca(2+) accumulation, thereby limiting ischemia-reperfusion injury. NMR was used to measure cytosolic pH (pH(i)), Na(+) (Na(i)(+)), and calcium concentration ([Ca(2+)](i)) in Krebs-Henseleit (KH)-perfused hearts from ovariectomized rats (OVX). Left ventricular developed pressure (LVDP) and lactate dehydrogenase (LDH) release were also measured. Control ischemia-reperfusion was 20 min of baseline perfusion, 40 min of global ischemia, and 40 min of reperfusion. The E2 protocol was identical, except that 1 nM E2 was included in the perfusate before ischemia and during reperfusion. E2 significantly limited the changes in pH(i), Na(i)(+), and [Ca(2+)](i) during ischemia (P < 0.05). In control OVX vs. OVX+E2, pH(i) fell from 6.93 +/- 0.03 to 5.98 +/- 0.04 vs. 6.96 +/- 0.04 to 6.68 +/- 0.07; Na(i)(+) rose from 25 +/- 6 to 109 +/- 14 meq/kg dry wt vs. 25 +/- 1 to 76 +/- 3; [Ca(2+)](i) changed from 365 +/- 69 to 1,248 +/- 180 nM vs. 293 +/- 66 to 202 +/- 64 nM. E2 also improved recovery of LVDP and diminished release of LDH during reperfusion. Effects of E2 were diminished by 1 microM N(omega)-nitro-L-arginine methyl ester. Thus the data are consistent with the hypothesis. However, E2 limitation of increases in [Ca(2+)](i) is greater than can be accounted for by the thermodynamic effect of reduced Na(i)(+) accumulation on NCE.

Dual Roles of 5-Hydroxytryptamine in Ischemia-Reperfusion Injury in Isolated Rat Hearts

5-Hydroxytryptamine (5-HT) has been shown to be involved in exacerbating cardiac ischemia-reperfusion injury; however, the role of 5-HT in the injury has yet to be established. This study demonstrates that 5-HT has dual roles in ischemia-reperfusion injury. The role of 5-HT in cardiac ischemia-reperfusion injury was examined in isolated rat hearts perfused with oxygenated Krebs-Henseleit solution. A 30-minute global ischemia and 30-minute reperfusion exacerbated functional cardiac parameters such as left ventricular end-diastolic pressure, coronary flow, heart rate, and total lactate dehydrogenase release. The 5-HT(2A) receptor antagonist sarpogrelate (0.3-1.0 microM) improved cardiac function during ischemia-reperfusion. High-performance liquid chromatography analysis revealed an elevation in the level of 5-HT in the coronary effluent immediately after ischemia, suggesting that 5-HT is released from the ischemic heart and that sarpogrelate protects the heart from ischemia-reperfusion injury by blocking 5-HT(2A) receptors. However, 5-HT (0.3-1.0 microM) applied exogenously unexpectedly improved the cardiac mechanical parameters during ischemia-reperfusion, increased coronary flow, and increased the level of NO in the effluent, which was inhibited by L-N(G)-nitro-arginine methyl ester, a NO synthase blocker. Present results suggest dual roles of 5-HT in ischemia-reperfusion injury. During ischemia, 5HT is released endogenously, constricts coronary smooth muscles via 5-HT(2A) receptors, and aggravates cardiac function. In contrast, 5-HT applied exogenously affects predominantly non-5HT(2A) receptors on the endothelium and induces coronary vasodilatation via endothelial NO production, which is protective against ischemia-reperfusion injury.

Lumbar and ventricular CSF protein, leukocytes, and lactate in suspected bacterial CNS infections.

Protein concentration, leukocyte density, and lactate concentration were studied in 41 pairs of ventricular and lumbar CSF drawn at an interval of less than 24 hours from patients with suspected bacterial CNS infections. The ventriculo-lumbar ratios ranged from 0.003 to 10.2 (median=0.42) for protein and from 0.002 to 53.5 (median=0.17) for leukocytes. The uneven distribution of leukocytes and proteins in the CSF space may produce findings that fail to indicate bacterial CNS infections. Lactate was distributed more homogeneously in the CSF space than protein and leukocytes (ventriculo-lumbar ratio 0.52 to 1.66 [median=0.811).

Nitrous oxide reduces inspired oxygen fraction but does not compromise circulation and oxygenation during hemodilution in pigs.

The use of nitrous oxide (N2O) during hemodilution has been questioned. Nitrous oxide reduces the inspired oxygen fraction (F1O2), depresses myocardial function and may reduce cardiac output (CO) and systemic oxygen delivery (DO2SY). The aim of this study was to evaluate the importance of the effects of nitrous oxide on systemic and myocardial circulation and oxygenation during extreme, acute, normovolemic hemodilution. Ten midazolam-fentanyl-pancuronium anesthetized pigs were exposed to 65% N2O before and after extreme isovolemic hemodilution (hematocrit 33 +/- 1% and 10 +/- 1%, respectively). Systemic and myocardial hemodynamics, oxygen delivery and consumption and blood lactate were measured before (at F1O2 1.0 and 0.35) and during N2O exposure. Hemodilution caused an increase in CO from 137 +/- 43 to 229 +/- 32 ml.kg-1.min-1 (P < 0.01), a decrease in systemic vascular resistance (from 42 +/- 14 to 20 +/- 4 mmHg.L-1.min-1, P < 0.05), a decrease in mean arterial blood pressure (from 119 +/- 19 to 100 +/- 26 mmHg, P < 0.05) and a decrease in DO2SY from 21.1 +/- 6.9 to 13.7 +/- 2.1 ml.kg-1.min-1 (P < 0.01). Cardiac venous blood flow increased by 135% (P < 0.01) and cardiac venous saturation from 25 +/- 6 to 41 +/- 5% (P < 0.05). After hemodilution, changing F1O2 from 1.0 to 0.35 reduced arterial blood oxygen content from 59.4 +/- 3.7 to 52.3 +/- 5.1 ml.L-1 (P < 0.01), mixed venous saturation (SvO2) from 75 +/- 9 to 47 +/- 7% (P < 0.05) and DO2SY from 13.7 +/- 2.1 to 11.9 +/- 2.3 ml.kg-1.min-1 (P < 0.05). Dissolved oxygen at F1O2 = 1.0 and F1O2 = 0.35 constituted 25.4 +/- 3.1% and 10.1 +/- 1.5%, respectively, of systemic oxygen delivery after hemodilution, compared with 10.7 +/- 1.2% and 3.9 +/- 0.5% before hemodilution (P < 0.01). Left ventricular oxygen delivery and consumption were unchanged. Exposure to N2O did not affect mean arterial blood pressure or systemic vascular resistance before or after hemodilution. After hemodilution during N2O-exposure, CO and DO2SY decreased by 9% (P < 0.01 and P < 0.05, respectively), but no changes in SvO2, systemic oxygen uptake or arterial lactate were observed. The effect of N2O on myocardial oxygenation was similar before and after hemodilution; cardiac venous blood flow, left ventricular oxygen delivery and uptake decreased, but no animals showed left ventricular lactate production. Nitrous oxide did not compromise systemic and myocardial circulation and oxygenation during acute normovolemic hemodilution in pigs. Possible adverse effects from the use of nitrous oxide during hemodilution seem to be related to a reduced F1O2, reducing the safety margin for systemic oxygen delivery.

Increased tolerance of the chronically hypoxic immature heart to ischemia. Contribution of the KATP channel.

Hypoxia from birth in immature rabbits increases the tolerance of isolated hearts to ischemia compared with age-matched normoxic rabbits. We determined whether this increased tolerance to ischemia was due to an alteration in the ATP-sensitive potassium (KATP) channel and whether increased KATP channel activation was associated with increases in intracellular lactate. Isolated immature rabbit hearts (7 to 10 days old) were perfused with bicarbonate buffer at 39 degrees C in the Langendorff mode at a constant pressure. Saline-filled latex balloons were placed in the left and right ventricles for measurement of developed pressure. A KATP channel agonist (bimakalim) or a KATP channel antagonist (glibenclamide) was added 15 minutes before a global ischemic period of 18 minutes, followed by 35 minutes of reperfusion. Rabbits raised from birth in hypoxic conditions (FIO2 = 0.12) displayed significantly enhanced recovery of developed pressure. The right ventricle was more tolerant of ischemia than the left ventricle in normoxic and hypoxic hearts. Bimakalim (1 mumol/L) increased the recovery of left ventricular developed pressure in normoxic hearts to values not different from those of hypoxic controls (43 +/- 3% to 67 +/- 5%) and slightly increased developed pressure in hypoxic hearts (67 +/- 5% to 72 +/- 5%). Glibenclamide (3 mumol/L) abolished the cardioprotective effect of hypoxia (67 +/- 5% to 43 +/- 5%). Constant-flow studies indicated that the effects of bimakalim and glibenclamide were independent of their actions on coronary flow. Ventricular lactate and lactate dehydrogenase concentrations were elevated in hypoxic hearts compared with normoxic control hearts. Increased tolerance to ischemia exhibited by chronically hypoxic rabbit hearts is associated with increased activation of the KATP channel. This increased KATP activity may be the result of increased intracellular concentrations of lactate.

Myocardial protection after monophosphoryl lipid A: studies of delayed anti‐ischaemic properties in rabbit heart

1. Monophosphoryl lipid A (MLA) is a non-pyrogenic derivative of Salmonella lipopolysaccharide. Administration of this agent at high doses to rats and at low doses to dogs was previously shown to confer marked protection against ischaemia-reperfusion 24 h later, although the cellular mechanisms of this delayed protection are obscure. We hypothesized that MLA pretreatment causes the induction of the 70 kDa cytoprotective stress protein HSP70i in the myocardium. If this were the case, protection against ischaemia-reperfusion injury would be observed both in vitro and in vivo. 2. Rabbits were pretreated with MLA 0.035 mg kg-1, i.v. or vehicle solution. For the in vitro study, hearts were isolated 24 h later and Langendorff-perfused with Krebs-Henseleit buffer at 37 degrees C. Global ischaemia was induced for 20 min followed by 120 min reperfusion. Recovery of post-ischaemic left ventricular function and lactate dehydrogenase efflux was similar in MLA and vehicle pretreated hearts and there was no significant difference in the percentage of infarction of the left ventricle determined by triphenyltetrazolium staining (MLA 22.4 +/- 5.2%, vehicle 24.8 +/- 5.1%). 3. When 30 min regional ischaemia and 120 min reperfusion was instituted in pentobarbitone-anaesthetized rabbits 24 h after pretreatment with MLA or vehicle, the percentage infarction within the risk zone was reduced from 42.6 +/- 5.7% in vehicle pretreated animals to 19.6 +/- 4.4% in MLA pretreated animals (P < 0.01). 4. Determination of myocardial HSP70i content by Western blot analysis showed that MLA treatment did not increase HSP70i immunoreactivity. 5. We conclude that MLA at this dose confers protection only against ischaemia-reperfusion injury in vivo and that this protection is not related to induction of HSP70i. Because protection was observed only in vivo it seems possible that the delayed protection conferred by MLA is mediated by effects on humoral or blood-borne factors.

Alleviation of contractile dysfunction in ischemic hearts by slowly inactivating Na+ current blockers

We hypothesized that the slowly inactivating component of Na+ current, which is an integral part of the Na+ window current, is a major pathway for Na+ loading during myocardial ischemia. The putative protective effects of tetrodotoxin (TTX) and R-56865, at concentrations that selectively blocked the Na+ window current, as assessed by action potential plateau shortening without affecting maximum upstroke velocity (Vmax), were examined in isolated Langendorff-perfused guinea pig hearts subjected to 50 min of normothermic global ischemia and 60 min of reperfusion. In papillary muscles, TTX reduced action potential duration at > or = 10 nM but reduced Vmax only at > or = 1 microM. R-56865 (10 nM-10 microM) failed to affect Vmax but concentration dependently reduced action potential duration. Ischemia-induced cardiac dysfunction, including increases in left ventricular end-diastolic pressure and lactate dehydrogenase and creatine phosphokinase release at reperfusion, was attenuated by TTX and R-56865 (0.1-320 nM). Ischemic contracture (increase in left ventricular end-diastolic pressure) was abolished by drug concentrations as low as 1 nM, whereas higher concentrations (> 10 nM) of TTX and R-56865 were required to restore systolic function at reperfusion. TTX and R-56865 had little or no effect on hemodynamic variables. Evidence is provided of pronounced and direct cardioprotective effects of low concentrations of R-56865 and TTX in cardiac muscle during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxic preconditioning preserves antioxidant reserve in the working rat heart

The aim was to examine whether intracellular antioxidants play a role in myocardial preservation following hypoxic preconditioning. Isolated working rat hearts were subjected to 30 min ischaemia and 30 min reperfusion. Control hearts were compared to hearts preconditioned with 10 min hypoxia. Left ventricular function and lactate dehydrogenase (LDH) release were measured in each group. Ascorbate dependent (ADAR) and thiol dependent (TDAR) components of the endogenous myocardial antioxidant reserve were assessed using electron spin resonance spectroscopy. a Hypoxic preconditioning had no effect on left ventricular function after 10 min reoxygenation. During reperfusion, the hypoxically preconditioned hearts had a significantly increased survival rate, aortic flow, developed pressure, and dP/dtmax, and a reduced lactate dehydrogenase release, compared to non-preconditioned controls (P < 0.05). Preconditioned hearts also had significantly higher preservation of baseline ADAR (79%) and TDAR (96%) compared with control hearts, (70%) and (77%), respectively (P < 0.05). Hypoxic preconditioning enhances functional recovery and reduces cell necrosis following global ischaemia in the working rat heart. This phenomenon may, in part, be mediated through enhanced ascorbate and thiol components of the antioxidant reserve.

Direct relationship between ischaemic burden and myocardial release of products of lipid peroxidation in patients undergoing percutaneous transluminal coronary angioplasty

Recent studies have shown that free radical activity is increased in humans during percutaneous transluminal coronary angioplasty. These studies, however, have failed to localize the site of free radical activity or to demonstrate a relationship between ischaemic burden and free radical production. The relationship between ischaemic burden and subsequent lipid peroxidation was studied during 16 inflations in eight patients undergoing angioplasty to anterior descending artery lesions. Two inflations 15 min apart were studied in each patient, one using a conventional (occlusive) balloon and one using the ACS Rx 'perfusion' balloon. The severity of the ischaemic insult associated with each inflation was assessed by contrast ventriculography, change in left ventricular end-diastolic pressure and myocardial lactate release 30 s after balloon deflation. Plasma levels of lipid peroxidation products were assessed by analysis of thiobarbituric-acid-reactive substances. A direct relationship was observed between the ischaemic burden and the myocardial release of lipid peroxidation products over the first 4 min after balloon deflation (F = 5.6; P < 0.006). In each patient, one of the inflations was associated with a greater degree of ischaemia. Left ventricular ejection fraction was lower (P < 0.001) and left ventricular end-diastolic pressure was higher (P < 0.002) during the 'ischaemic' inflations. Myocardial release of lipid peroxidation products was significantly higher after the 'ischaemic' balloon inflation (F = 7.65; P < 0.009). Brief periods of human myocardial ischaemia result in myocardial release of lipid peroxidation products in direct proportion to the severity of the preceding ischaemic insult.

Intracoronary infusion of bradykinin: effects on noradrenaline overflow following reperfusion of ischemic myocardium in the anesthetized dog.

The aim of this study was to investigate the effects of intracoronary bradykinin (BK) infusion on noradrenaline release and ventricular arrhythmias induced by coronary occlusion and reperfusion in the anesthetized dog. 14 anesthetized adult mongrel dogs of either sex underwent a 60 min occlusion of the left anterior descending coronary artery (LAD) followed by a 30-min reperfusion period. BK (1 ng.kg-1.min-1, n = 7), or its vehicle (Lactate Ringer, n = 7), infusions just distal to the left coronary ostium started 15 min before the LAD occlusion and were maintained throughout the experimental period. An epicardial vein, running parallel to the LAD was cannulated to enable the biochemical determinations. The effects of BK on ventricular arrhythmias, cardiac noradrenaline and lactate releases and creatine kinase activity were assessed. BK significantly reduced the amount of noradrenaline released at reperfusion by ischemic myocardium (from 82.1 +/- 31.7 to 11.9 +/- 9.6 ng.min-1), as well as plasma creatine kinase activity at 30 min of reperfusion. This is accompanied by a significant reduction in the incidence of reperfusion-induced sustained ventricular tachycardia. This suggests that the protective effect of bradykinin against reperfusion-induced sustained ventricular tachycardia could be associated with a reduction in cardiac noradrenaline release.

The safety of simultaneous arterial and coronary sinus perfusion: experimental background and initial clinical results.

Concern over myocardial damage from simultaneous arterial (antegrade) and coronary sinus (retrograde) perfusion has led to alternating between these delivery routes to maximize their individual benefits. Based upon predominant retrograde drainage via Thebesian veins, this study: (1) confirms experimentally the safety of simultaneous arterial and coronary sinus perfusion; and (2) reports initial clinical application of this combined strategy in 155 consecutive patients. Five mini-pigs (25 to 30 kg) underwent 1 hour of aortic clamping with simultaneous aortic and coronary sinus perfusion at 200 mL/min with normal blood (37 degrees C) before and after 30 minutes of perfusion with either warm (37 degrees C) or cold (4 degrees C) blood cardioplegia. Coronary sinus pressure was always less than 30 mmHg. There was no right or left ventricular edema, lactate production, or lipid peroxidation as transmyocardial and myocardial conjugated dienes were unaltered, and postbypass recovered left ventricular end-systolic elastance (conductance catheter) and preload recruitable stroke work index 101% +/- 3% and 109% +/- 90%, respectively. CLINICAL: Simultaneous arterial/coronary sinus perfusion was used in 155 consecutive high risk patients (New York Heart Association Class III to IV) undergoing isolated coronary artery bypass grafting (CABG) (n = 109) and CABG+valve replacement/repair or aneurysm (n = 46). Included were 16 patients in cardiogenic shock and 24 undergoing reoperation. Mean aortic clamping time averaged 90 +/- 4 minutes (range 30 to 207), with 3.5 +/- 0.1 grafts per patient; all anastomoses were performed with the aorta clamped. Cold intermittent blood cardioplegia was used for distal anastomoses and valve implantation/repair in 123 patients, and warm continuous blood cardioplegia was used in 32 patients. Following a warm cardioplegic reperfusate, all patients received warm noncardioplegic blood perfusion simultaneously via grafts and coronary sinus. Coronary sinus pressure was always less than 40 mmHg. Of 18 patients requiring postoperative mechanical circulatory support (IABP), 16 had IABP placed preoperatively for cardiogenic shock. There were three postoperative myocardial infarctions (2%), and six patients died (3.9% mortality). These experimental and clinical findings overcome perceived concerns about myocardial damage from simultaneous arterial and coronary sinus perfusion, and suggest this approach may add to the armamentarium of cardioprotective strategies.

Intracoronary propofol does not decrease myocardial contractile function in the dog

The intravenous administration of propofol is associated with a considerable decrease in arterial blood pressure. The present study was undertaken to test the hypothesis that myocardial function is not affected by propofol and therefore does not contribute to the hypotensive effect of this anaesthetic agent. Propofol was administered in anaesthetized, open-chest dogs by direct arterial infusion into the left anterior descending coronary artery (LAD). Mean arterial blood pressure, heart rate, left ventricular pressure, dP/dt, regional lactate and oxygen extraction, as well as coronary blood flow were measured. Diastolic function was determined by calculation of the time constant of isovolumetric relaxation from the left ventricular pressure measurement and dP/dt. Contractility was evaluated by measuring regional systolic shortening in an area of the myocardium supplied by the LAD. This was compared with systolic shortening in the distribution of the circumflex (CIRC) artery and with the effects obtained with the intracoronary administration of thiopentone. Intracoronary infusions of propofol and thiopentone did not produce any change in systemic arterial blood pressure, heart rate, or left ventricular end diastolic pressure. Propofol, at a concentration of 5 or 10 micrograms.ml-1 did not decrease systolic shortening in the area perfused by the LAD while thiopentone (40 micrograms.ml-1) reduced systolic shortening by 33% (P < or = 0.05). Neither drug had an effect on systolic shortening in the CIRC area, LAD blood flow or diastolic function. The results of this study suggest that propofol does not have an effect on myocardial contractility. The hypotension associated with the intravascular administration of propofol is more likely due to either a direct vascular or a central effect.

Influence of ATP-sensitive potassium channel blocker on hypoxia-induced damage of isolated guinea pig heart

1. 1. Isolated guinea pig hearts were perfused under constant flow conditions with Krebs-Henseleit buffer. Hearts were subjected to 15 min of hypoxia followed by reoxygenation in the presence and in the absence of 100 μm glyburide, an ATP-sensitive potassium channel blocker. Heart rate, left ventricular pressure and lactate dehydrogenase (LDH) release were measured at 5 min intervals. 2. 2. Small decreases in heart rate and left ventricular pressure were observed during glyburide infusion with hypoxia, however LDH release, which was used as an index of cellular damage, was dramatically elevated. 3. 3. Neither glyburide, nor the vehicle in which it was dissolved, appeared to produce myocardial damage under normoxic conditions. 4. 4. It is concluded that ATP-sensitive potassium channels are important in the protection of the myocardium during hypoxia in isolated guinea pig hearts perfused under constant flow conditions.

Time course of CSF lactate level in subarachnoid haemorrhage. Correlation with clinical grading and prognosis.

Cisternal and/or ventricular cerebrospinal fluid (CSF) and arterial blood lactate and acid-base balance were measured serially in 38 patients with aneurysmal subarachnoid haemorrhage (SAH). Based on daily clinical assessment, the patients and accordingly the samples were divided into two groups according to the grading of the World Federation of Neurosurgical Societies (W.F.N.S.). In cisternal CSF, samples of Grade III-V showed significantly higher lactic acidosis than those of Grade I-II. The time course of lactate and pH in poor prognosis groups had a significant tendency of lactic acidosis, especially on the 5th, 6th, 7th day after SAH. Ventricular CSF lactate increased even without CSF acidosis in Groups III-V. Measurement of CSF lactate, especially from the cisterna magna is useful as an indicator of prognosis and changes of intracranial environment following SAH.