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There is now good evidence to indicate the onset of myocardial ischemia is accompanied by a decline in intracellular pH which parallels the decrease in tension development. The component of the excitation--contraction coupling system which is responsible for the loss in tension development has not been determined although the contractile proteins are a likely candidate since the calcium sensitivity of tension development and of myofibrillar ATPase are both inhibited by a decrease in pH. However, these studies have utilized normal tissues and the effects of pH compounded with ischemia have not been determined. It is plausible to suggest that there may occur ischemic damage to the excitation--contraction coupling system which would depress function in a manner distinct from that incurred by acidosis. Toya-Oka and Ross have demonstrated a loss in regulatory proteins during regional ischemia, suggesting an effect of ischemia independent of pH. We recently demonstrated, in sarcoplasmic reticulum isolated from ischemic myocardium, a defect in function which could not be accounted for solely on the decrease in pH. It was, therefore, the purpose of this study to determine the effects of decreasing pH on cardiac myofibrillar ATPase activity isolated from hearts which had been subjected to short-term, global normothermic ischemia. This design permits us to answer the following questions: Is there a decrease in myofibrillar ATPase activity in the canine heart following 30 min of normothermic global ischemia? Does acidosis play a contributory role in any observed depression of myofibrillar ATPase activity during ischemia? and Does the ischemic process, independent of acidosis, produce a further depression of myofibrillar ATPase activity?
J Mol Cell Cardiol 1985 May
PMID:The effect of short term normothermic global ischemia and acidosis on cardiac myofibrillar Ca2+-Mg2+ ATPase activity. 316 34

Myocardial ischaemia induces cytosolic acidification, which promotes cardiac damage, dysfunction or arrhythmia. In this study, we investigated the effect of ouabain on the intracellular pH (pHi) in cultured mouse ventricular cells, using 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF). The average resting pHi in myocytes was 7.19. After myocytes were acid-loaded with NH4Cl, the pHi recovered from acidosis to the resting level within a few minutes via amiloride-sensitive Na+/H+ exchange. Ouabain inhibited this pHi recovery dose-dependently with half-maximal inhibition at 3 X 10(-5) M, but did not suppress the ionophore monensin-induced pHi elevation. The inhibition of the pHi recovery from acidosis by ouabain is possibly caused by an inhibition of amiloride-sensitive Na+/H+ exchange, which is secondary to a suppression of Na+ efflux through (Na+, K+) pump. Above results demonstrate the possibility that digitalis promotes intracellular acidosis or inhibits the pHi recovery from acidosis in ischaemic myocardium.
J Mol Cell Cardiol 1988 Jan
PMID:Ouabain inhibits intracellular pH recovery from acidosis in cultured mouse heart cells. 336 75

Carnitine, certain of its derivatives, and the amino acid metabolite, taurine, when administered independently in prior studies have been shown to improve cardiac mechanic and/or metabolism. The purpose of these studies is to test a new compound, propionylcarnitine taurine (PCT), which potentially combines these actions, in a therapeutic trial to preserve function in a setting of myocardial ischemia. In the main protocol, PCT was administered (0.71 mg/kg/min I.V.) to eight extracorporeally perfused, intact, working swine hearts over a 70 min perfusion trial and compared with seven similarly prepared placebo hearts. Left anterior descending (LAD) flows were held at aerobic levels (6.3 +/- 0.3 ml/min/g dry) for 40 min and then reduced acutely by 50% for 30 min. Serum fatty acids (FA) in both groups were augmented to 1.27 +/- 0.5 mumol/ml. Contractility (measured regionally from shortening rates of ultrasonic crystals placed in the LAD circulation); myocardial oxygen consumption (MVO2); and FA oxidation (measured from 14CO2 production rates from labeled palmitate infused into the LAD perfusate) were obtained serially throughout the perfusion trials. Regional contractility was significantly increased in PCT-treated hearts as compared with placebo hearts both during normal and ischemic flows. Treatment appeared to deplete free carnitine stores in both aerobic and ischemic myocardium but failed to modify acyl CoA levels. In seven additional animals PCT was shown to independently stimulate fatty acid oxidation (about 39 delta % increase) at aerobic flows. Lastly in nine separate animals (4 placebo; 5 treatment) prepared and studied identically to those of the main protocol, taurine alone (0.2 mg/kg/min infused IV for 70 min) was without influence in reproducing mechanical benefits. Thus, PCT favorably enhances regional contractility in conditions of myocardial ischemia, presumably by the positive inotropic effects of the propionylcarnitine constituent of the compound.
J Mol Cell Cardiol 1988 Jan
PMID:The effects of propionylcarnitine taurine on cardiac performance in aerobic and ischemic myocardium. 336 80

The myocardial energy requirements of the noradrenergic nerve terminal to retain its transmitter during acute myocardial ischemia were examined in the isolated perfused rat heart. In hearts perfused with glucose as exogenous substrate no increased release of noradrenaline (NA) could be detected during ischemia. In contrast, an increased efflux of NA was seen from glucose-perfused hearts when the glycolytic pathway was inhibited with 0.5 mM iodacetic acid. Accordingly, induction of ischemia in glycogen-depleted hearts (in the absence of exogenous substrate) or in hearts perfused with either lactate, pyruvate or acetate was also associated with a marked efflux of NA. However, no efflux was detected from glycogen-depleted hearts when glucose was present during the ischemic period. Uncoupling of oxidative metabolism with 0.1 mM 2.4-dinitrophenol did not cause any increased loss of NA during ischemia. In conclusion, these results demonstrate that severe restriction in coronary flow is accompanied by increased release of myocardial NA. Furthermore, maintainance of anaerobic glycolysis is of crucial importance for retention of the noradrenergic transmitter during ischemic conditions.
J Mol Cell Cardiol 1988 Mar
PMID:A crucial role of ongoing anaerobic glycolysis in attenuating acute ischemia-induced release of myocardial noradrenaline. 339 56

Depolarization of resting membrane potential during acute myocardial ischemia is strongly correlated with the accumulation of extracellular potassium ([K+]e). Also, diastolic currents of injury flowing across the ischemic border that occur as a result of local differences in resting membrane potentials cause changes in the TQ-segments of unipolar, DC-coupled, extracellular electrograms. Further, the changes in [K+]e and TQ-segment potentials during acute ischemia and reperfusion follow a similar time course. For these reasons, a predictable relationship between [K+]e and TQ potentials might be expected to exist. If found, easily obtainable local TQ potential measurements could serve as an index of the resting membrane depolarization induced by [K+]e accumulation and, by extension, as an index of ischemic injury. We measured local [K+]e and TQ potentials from 30 mid-myocardial sites in central and marginal ischemic zones in 2 isolated, Langendorff-perfused porcine hearts during a single, 10-min ligation of the left anterior descending coronary artery. In general, we found a linear relationship between [K+]e and TQ potential for both ischemic zones when data was taken as a whole, but the slopes (S) and correlation coefficients (R) were markedly different between the two locations (-2.24 vs -1.28 and -0.73 vs -0.51 for central and marginal zones, respectively). Further, we found a time dependent change in both S and R that was biphasic. Both were low during the first minutes, attained their maximum values at 4 mins, and then fell during the remainder of the occlusion. We conclude, therefore, that local TQ potentials cannot be used as an index of the severity of ischemic changes.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1987 Oct
PMID:Relationship between extracellular potassium accumulation and local TQ-segment potential during acute myocardial ischemia in the porcine. 343 53

Amiodarone is used extensively for the chronic treatment of life-threatening arrhythmias caused by ischemic heart disease. However, chronic therapy with this agent results in phospholipidosis in various tissues and it has been suggested that the inhibition of lysosomal phospholipase A by this drug contributes to this abnormality. Exogenous amiodarone has been shown to inhibit purified rat liver lysosomal phospholipase A1, as well as acid phospholipase activities of alveolar macrophage homogenates and those of snake venom phospholipase A2 and bacterial phospholipase C. The effects of drug treatment on heart have not been explored. The results described here demonstrate that amiodarone also significantly increases (37%, p less than 0.001) phospholipid content in cat hearts. This increase is proportionately distributed to all major phospholipid classes, with the exception of sphingomyelin which appears to increase more than the others. In addition, the data also show that following amiodarone treatment, the endogenous drug levels in the heart were sufficient to reduce in vitro losses of membrane phospholipid at 37 degrees C by inhibiting a variety of endogenous phospholipases at physiological (7.4), ischemic (6.2) and acidic (5.0) pH values. This protection is more pronounced at acidic pH values than at physiological pH. Endogenous amiodarone also affects myocardial phospholipase activities towards exogenous phosphatidylcholine and again the extent of inhibition is more at acidic pH. These results suggest that amiodarone induces phospholipidosis in the heart by inhibiting phospholipid catabolism and that its antiarrhythmic properties may reside in its ability to modulate alkaline, neutral and acid phospholipase activities in ischemia. To what extent amiodarone metabolites (desethylamiodarone and bis-desethylamiodarone) are involved in these actions remains to be determined.
Mol Cell Biochem 1987 Nov
PMID:Effects of chronic amiodarone treatment on cat myocardial phospholipid content and on in vitro phospholipid catabolism. 345 65

The hypothesis that prostacyclin (PGI2) might have a direct cytoprotective action in ischaemic cardiac tissue was investigated. Myocardial ischaemia was induced in perfused rabbit hearts by ligating the left main coronary artery. Coronary flow, oxygen uptake, and turnover of lactate and purines were measured before and up to 120 min after coronary occlusion. After this, ischaemic tissue was separated from perfused myocardium, and levels of lactate, adenine nucleotides and creatine phosphate were determined in specimens from non ischaemic, ischaemic and border zones. PGI2 (final conc. 10(-7) M) was infused before or 30 min after ligation and the results were compared to those in control hearts. Coronary ligation reduced coronary flow and oxygen consumption by about 50%. The fractional extraction of lactate decreased from 20% to close to zero and purine release increased 5-fold. In the non-ischaemic area the tissue levels of ATP and creatine phosphate were high, with a low content of lactate, but in the ischaemic area the levels of ATP and creatine phosphate were considerably reduced and the content of lactate was high. Although coronary flow and oxygen uptake were elevated after treatment with PGI2, no change in lactate or purine turnover was observed. Neither the weight of the non-perfused myocardium nor the tissue levels of the adenine nucleotides, creatine phosphate and lactate were affected by PGI2 treatment. The data indicate that in this model, in which effects on cardiac work, collateral flow and platelets are eliminated, PGI2 does not limit ischaemic myocardial injury. Hence, the hypothesis of a direct cytoprotective action of PGI2 in ischaemic myocardial tissue was not supported.
J Mol Cell Cardiol 1986 Oct
PMID:Effect of prostacyclin on the severity of ischaemic injury in rabbit hearts subjected to coronary ligation. 353 19

We tested the hypothesis that cultured chick embryo ventricular cells grown in monolayer could be used to study calcium fluxes across the myocardial sarcolemmal membrane during simulated ischemia. A specially adapted anaerobic chamber allowed the exposure of heart cells to profound hypoxia (PO2 less than 1.5 Torr) for prolonged periods of time. Ca2+ flux studies were conducted in this chamber following hypoxia and substrate deprivation to simulate important components of myocardial ischemia. To prove we were measuring cellular rather than interstitial cation contents we conducted 51Cr-EDTA interstitial space marker washout studies and showed that our procedures were sufficient to remove at least 99.7% of the extracellular fluid. The addition of lanthanum (1 mM) to the wash solution reduced nonspecific 45Ca2+ binding to the polystyrene culture plates to less than 0.03% of applied counts, but did not alter 45Ca2+ uptake under normoxic conditions. Following 2 h of hypoxia and substrate deprivation the Ca2+ content of the rapidly exchangeable Ca2+ pool of cultured monocytes increased 282% compared to control values during normoxia. We conclude that cultured chick embryo ventricular cells grown in monolayer are suitable for investigation of cation fluxes during simulated ischemia. Under the conditions studied, lanthanum displaceable Ca2+ did not make a major contribution to Ca2+ influx. The system permitted clear resolution of alterations in Ca2+ flux kinetics under conditions of profound hypoxia.
J Mol Cell Cardiol 1987 Mar
PMID:Calcium flux measurements during hypoxia in cultured heart cells. 359 83

Free radical reactions have been suggested to be important events in the mechanism of myocardial injury during ischemia and reperfusion. Most of the in vivo evidence implicating free radical mediated events in the etiology of myocardial injury has been based on intervention studies which document the efficacy of oxygen free radical scavengers in improving function or tissue salvage. We have assayed free fatty acid oxidation products (hydroxy conjugated dienes) derived from myocardial phospholipid as chemical markers of oxidative injury. Biopsies, harvested from canine myocardium subjected to cardiopulmonary bypass with no aortic crossclamp (control), from pre-ischemic, end ischemic (at the end of 45 min of global normothermic ischemia induced by aortic crossclamp) and at 5, 10, 15, 30 and 60 mins of reperfusion were analyzed for hydroxy conjugated dienes using HPLC with structural confirmation by GC-MS. All biopsies were taken from non-necrotic myocardium as indicated by gross tetrazolium staining of myocardial cross sections. Trace levels of hydroxy conjugated dienes could be detected in the preischemic biopsies or control biopsies harvested from hearts subjected to cardiopulmonary bypass with no ischemia. At the end of 45 min ischemia, however, a significant increase in 18:2 and 20:4 hydroxy isomers was detected and confirmed by GC-MS (P less than 0.05 vs. control). After 5 mins of reperfusion a further significant increase in hydroxy conjugated dienes was noted with 18:2, 20:4 and 22:6 isomers being identified (P less than 0.01 vs. end ischemia). By 30 min of reperfusion the concentration of phospholipid oxidation products had returned to pre-ischemic levels. This study presents the first chemically rigorous in vivo evidence for the formation of products of phospholipid oxidation (hydroxy conjugated dienes) during myocardial ischemia and reperfusion and supports the concept of oxygen free radical mediated lipid peroxidation. This study emphasizes the formation of phospholipid oxidation products during ischemia and particularly during the early phase of reperfusion and illustrates the transient nature of these products in myocardial phospholipid.
J Mol Cell Cardiol 1987 Mar
PMID:Conjugated dienes in ischemic and reperfused myocardium: an in vivo chemical signature of oxygen free radical mediated injury. 359 84

The major electrophysiological changes during the first 10 min of myocardial ischemia caused by complete obstruction of a coronary artery are a reduction in membrane potential, a decrease in action potential amplitude and upstroke velocity, and a prolongation of recovery of excitability following an action potential. Conduction velocity in the direction parallel to the long axis of myocardial fibers (VL) and in the transverse direction (VT) in normal myocardium are in the order of 40 cm/s and 20 cm/s respectively. During ischemia, conduction velocity decreases and lowest values for VL are in the order of 20 cm/s, for VT around 10 cm/s, before the ischemic tissue becomes inexcitable. Calculated dimensions of a possible re-entrant circuit in acutely ischemic myocardium (the product of refractory period and conduction velocity) are in the order of 7 to 8 cm. Re-entrant circuits of such dimensions were indeed demonstrated by simultaneous recording of 125 extracellular potentials from the epicardial surface of the ventricles during spontaneously occurring ventricular arrhythmias after coronary occlusion. Previous studies provided evidence that premature ventricular depolarization which initiate re-entry originated in the subendocardium, and the present experiments confirmed this. Destruction of the subendocardium of isolated, Langendorff perfused canine hearts, including the Purkinje system, by intracavitary application of phenol, did not, however, abolish ectopic activity during either ischemia or reperfusion, although the nature of the arrhythmias during ischemia was different from those in intact hearts. Coupling intervals of ectopic beats were longer in phenol-treated hearts than in intact hearts, but the site of origin of initial ectopic beats leading to ventricular tachycardia could not be determined. Re-entrant circuits with revolution times in the order of 340 to 400 ms accounted for the slow tachycardias observed in phenol-treated hearts. In contrast to intact hearts, these tachycardias never degenerated into ventricular fibrillation, indicating that an intact Purkinje system may be a necessary requirement for ventricular fibrillation to occur during acute, regional myocardial ischemia.
J Mol Cell Cardiol 1986 Apr
PMID:Electrophysiological basis for arrhythmias caused by acute ischemia. Role of the subendocardium. 371 46


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