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The present study evaluates the activity of the Na/H antiport during cold ischemia and aims to determine its influence on cellular sodium. pH and volumes. Cellular parameters; volumes, sodium, pH and high energy phosphates, were measured by multinuclear NMR spectroscopy in rat hearts during 12 h of storage at 4 degrees C and reperfusion, along with functional parameters. Cell volumes were measured by 1H and 59Co NMR using the extracellular marker cobalticyanide, pH and energetics by 31P NMR and sodium compartmental distribution by 23Na NMR spectroscopy using the shift reagent Dy(TTHA)-3. Three storage solutions were applied: Krebs-Henseleit (containing 144 mM sodium, KH), a solution supplemented with 0.20 mM amiloride (KH-ami) and a solution containing 23 mM sodium and 242 mM mannitol (KH-man). Inhibition of the Na/H antiport with amiloride reduced the cellular sodium accumulation by 56%. The end-ischemic concentrations were 45 mM (KH-ami) and 77 mM (KH). Amiloride also reduced the extent of cell swelling by 53% from an end-ischemic volume of 3.56 ml/gdw (KH) to 2.97 ml/gdw (KH-ami), however cell swelling persisted in both groups at reperfusion (33% increase in cell water). The molar ratio of sodium and water cellular accumulation was constant: Na/H2O approximately 3.7 x 10(-3) throughout the whole storage period. Inhibition of the antiport was protective for the high energy phosphates during ischemia and reperfusion. In KH-ami the pH acidified after 6 h of storage to an end-ischemic value of 6.35 (pH = 6.50 in KH): this difference persisted after 60 min of reperfusion, pH = 6.98 in KH-ami and pH = 7.1 in KH. Storage in the low-sodium solution was disadvantageous for the high energy phosphates during ischemia and reperfusion with a recovery of pH to 6.92 when reperfused with KH. Hearts stored with amiloride or mannitol solution failed to resume contraction at reperfusion. It is concluded: (a) the antiport is active at 4 degrees C; (b) during ischemia it mediates sodium influx and contributes to cell swelling with minor effects on the cytosolic pH; (c) at reperfusion the antiport is active it participates in the extrusion of excess protons, but has a minor impact on sodium and water homeostasis; (d) inhibition of the antiport does not protect the cardiac muscle at low temperatures.
J Mol Cell Cardiol 1996 Mar
PMID:The relation between cellular sodium, pH and volumes and the activity of Na/H antiport during hypothermic ischemia: multinuclear NMR studies of rat hearts. 901 42

The long-range goal of this research is to establish an in vitro system that will permit pertubation of mammalian heart development and in situ examination of the cellular and molecular events underlying cardiac morphogenesis. Rat embryos at 9.5-11.5 days of gestation were placed in culture bottles containing rat serum and Tyrode's solution. Embryos cultured for 24 and 48 h were compared to age-matched in vivo controls for morphological score, morphometric analysis of heart development, and confocal and electron microscopic analysis of myofiber pattern formation. Morphological scores indicated that embryos cultured for 24 h from day 9.5 to 10.5 had essentially normal development when compared to age-matched embryos allowed to develop in vivo. Development of embryos maintained for 48 h in culture was slightly delayed at 66-68% of age matched in vivo embryos. Analysis of hearts from embryos allowed to develop 9.5-11.5 days in vivo plus 24 and 48 h in culture showed that the ventricular thickness and height, as well as the truncal, atrial and ventricular diameters were equivalent to those of hearts from age-matched in vivo controls. Hearts from embryos allowed to develop from 11.5-12.5 days in vitro and cultured for 24 and 48 h had smaller left ventricular and atrial dimensions than controls. Cardiac myofibrillogenesis and myofibrillar pattern formation in embryos cultured from 9.5 days of in vivo development for 48 h were also normal. These studies indicate that the rat whole embryo culture system is a useful model to study several critical periods in mammalian heart development.
J Mol Cell Cardiol 1997 Jan
PMID:Analysis of heart development in cultured rat embryos. 904 51

Vanadium compounds have been shown to cause a variety of biological and metabolic effects including inhibition of certain enzymes, alteration of contractile function, and as an insulin like regulator of glucose metabolism. However, the influence of vanadium on metabolic and ionic changes in hearts remains to be understood. In this study we have examined the influence of vanadate on glucose metabolism and sodium transport in isolated perfused rat hearts. Hearts were perfused with 10 mM glucose and varying vanadate concentrations (0.7-100 microM) while changes in high energy phosphates (ATP and phosphocreatine (PCr)), intracellular pH, and intracellular sodium were monitored using 31P and 23Na NMR spectroscopy. Tissue lactate, glycogen, and (Na+, K+)-ATPase activity were also measured using biochemical assays. Under baseline conditions, vanadate increased tissue glycogen levels two fold and reduced (Na+, K+)-ATPase activity. Significant decreases in ATP and PCr were observed in the presence of vanadate, with little change in intracellular pH. These changes under baseline conditions were less severe when the hearts were perfused with glucose, palmitate and beta-hydroxybutyrate. During ischemia vanadate did not limit the rise in intracellular sodium, but slowed sodium recovery on reperfusion. The presence of vanadate during ischemia resulted in attenuation of acidosis, and reduced lactate accumulation. Reperfusion in the presence of vanadate resulted in a slower ATP recovery, while intracellular pH and PCr recovery was not affected. These results indicate that vanadate alters glucose utilization and (Na+, K+)-ATPase activity and thereby influences the response of the myocardium to an ischemic insult.
Mol Cell Biochem 1997 May
PMID:Influence of vanadate on glycolysis, intracellular sodium, and pH in perfused rat hearts. 914 18

It is not yet known if the alterations in myocardial glucose metabolism and the exaggerated left ventricular dysfunction that occur during reperfusion in hypertrophied hearts are reversible. Thus, we studied isolated working hearts from aortic-banded (n = 29) and sham-operated control (n = 32) male Sprague-Dawley rats with or without enalapril maleate treatment (25.6 +/- 0.8 mg/kg per day, p.o.) to determine the effect of regression of cardiac hypertrophy on myocardial glucose metabolism and post-ischemic heart function. Hearts were perfused with buffer containing 1.2 mM palmitate, 11 mM [5-3H]/[U-14C]-glucose, 0.5 mM lactate and 100 microU/ml insulin. Glucose metabolism [rates of glycolysis (3H2O production) and rates of oxidation (14CO2 production) of exogenous glucose] and heart function (heart rate x peak systolic pressure) were measured during 30 min pre-ischemic perfusion and 60 min of reperfusion following 20 min of global, no-flow ischemia. Hearts from untreated aortic-banded rats were hypertrophied, being 27.6 +/- 1.8% larger than hearts from untreated control rats. Enalapril treatment caused regression of cardiac hypertrophy that normalized heart weight in aortic-banded rats. Rates of glycolysis of exogenous glucose in hearts from untreated aortic-banded rats were accelerated compared to rates in hearts from untreated control rats during pre-ischemic perfusion (4391 +/- 97 v 2652 +/- 69 nmol glucose/min per g dry wt, respectively, P < 0.05) and reperfusion (2402 +/- 58 v 1597 +/- 88 nmol glucose/min per g dry wt. respectively, P < 0.05). In contrast, rates of glycolysis of exogenous glucose in hearts from enalapril-treated aortic-banded rats were normalized before and after ischemia. Rates of glycolysis of exogenous glucose in hearts of control rats were not affected by enalapril treatment. Oxidation of exogenous glucose was not different among groups either before or after ischemia. Function of hearts from untreated aortic-banded rats at the end of reperfusion was significantly less than that of hearts from untreated control rats (23.9 +/- 2.6 v 32.2 +/- 0.7 mmHg x beats per min/1000, respectively, P < 0.05). As with myocardial glucose metabolism function of hearts from aortic-banded rats treated with enalapril was normalized during reperfusion. Thus, pharmacologically induced regression of pressure-overload cardiac hypertrophy normalizes glucose metabolism as well as left ventricular function during reperfusion.
J Mol Cell Cardiol 1997 Mar
PMID:Regression of cardiac hypertrophy normalizes glucose metabolism and left ventricular function during reperfusion. 915 55

Post-ischemic contractile dysfunction in the heart may be due to oxygen-derived free radicals catalyzed by low molecular weight iron (lmw Fe), which is thought to accumulate during ischemia and reperfusion. We tested the hypothesis that functional preconditioning with transient ischemia in the rat heart may be due to decreasing the myocardial lmw Fe pool, and consequently free radicals during ischemia or reperfusion. Hearts were preconditioned with two 5-min episodes of ischemia followed by 5 min of reperfusion. The lmw Fe pool of pre-ischemic hearts was 172 +/- 13pmol/mg protein. After 40 min of prolonged ischemia, the lmw Fe contents were 176 +/- 25 and 127 +/- 13 pmol/mg for non-conditioned and preconditioned hearts, respectively (P=N.S.). After 10 min of reperfusion, the lmw Fe contents were 246 +/- 26 and 228 +/- 23 pmol/mg protein, respectively (P=N.S.). We next tested the ability of deferoxamine, an iron chelator, to mimic functional preconditioning. The percentage recoveries of heart rate x developed pressure after 40 min of ischemia and 30 min of reperfusion were 38 +/- 6 and 25 +/- 5 for non-conditioned and deferoxamine-treated hearts, respectively (P=N.S.). We further tested the hypothesis by determining if iron-overloading by dietary enhancement and weekly iron injections would exacerbate post-ischemic contractile dysfunction and attenuate functional preconditioning with ischemia. The total iron contents of the high iron and normal groups were 10.3 +/- 0.6 and 4.4 +/- 0.2 nmol/mg protein (P<0.001). Percentage recoveries of heart rate x developed pressure were 36 +/- 6 and 33 +/- 5 for non-conditioned hearts in the high iron and normal iron groups, respectively (P=N.S.). Percentage recoveries of heart rate x developed pressure were 58 +/- 5 and 68 +/- 6 for ischemically preconditioned hearts in the high and normal iron groups, respectively (P= N.S.). The results suggest that functional preconditioning in the rat heart is not due to attenuation lmw Fe accumulation.
J Mol Cell Cardiol 1997 Apr
PMID:Role of low molecular weight iron in functional preconditioning of the isolated rat heart. 916 Aug 61

Abnormalities in the gene for Duchenne muscular dystrophy produce skeletal and myocardial changes, by impairing dystrophin production in patients with Duchenne and Becker muscular dystrophy. However, it is not known whether myocardial dystrophin may be altered in patients with other heart diseases. To investigate whether changes in myocardial dystrophin may be induced by acute myocardial injury, the immunostaining patterns of myocardial dystrophin were examined, together with those of myocardial actin, in rats with isoproterenol-induced myocardial damage. Hearts were excised at 6, 12, 24 and 48 h, and 1 and 4 weeks after the subcutaneous administration of 100 mg/kg of isoproterenol. Frozen serial sections were prepared for haematoxylin and eosin staining, and for immunostaining for dystrophin and actin. The immunostaining patterns of actin were used as an indicator of cell injury. The myocardial cells observed were classified into four types, according to staining pattern: normal for both actin and dystrophin (Type 1): normal for actin, but abnormal for dystrophin (Type 2); abnormal for actin, but normal for dystrophin (Type 3); and abnormal for both actin and dsytrophin (Type 4). The percentage of myocardial cells with abnormal staining (Types 2, 3 and 4) at 6, 12, 24 and 48 h after isoproterenol injection was 22.4, 12.6, 16.0 and 2.4%, respectively; most cells were Types 3 and 4. One week after injection or later, no Type 3 or 4 cells were detected, while the percentages of Type 2 cells were 2.7% for 1 week and 2.2% for 4 weeks, significantly higher than the corresponding value in the control group. In conclusion, changes in myocardial dystrophin may occur in isoproterenol-induced myocardial injury in rats.
J Mol Cell Cardiol 1997 Apr
PMID:Abnormal immunostaining for dystrophin in isoproterenol-induced acute myocardial injury in rats: evidence for change in dystrophin in the absence of genetic defect. 916 Aug 73

The presence of left ventricular hypertrophy (LVH) is associated with an increased incidence of arrhythmias. Our previous study on hypertrophied rat hearts has demonstrated that regression of LVH prevents ischemia-induced lethal arrhythmias. To elucidate the underlying mechanism of the reduced incidence of arrhythmias in regression of LVH, we examined electrophysiological properties of both hypertrophied and regressed left ventricular cells. Hearts from spontaneously hypertensive rats (SHR) were used as LVH, and those from Wistar-Kyoto rats (WKY) served as control. SHR with regression of LVH (REG) was produced by captopril treatment. Action potentials and membrane currents of subendocardial left ventricular cells were compared by the whole-cell patch-clamp techniques. Although the membrane capacitance of SHR cells was significantly greater than that of WKY cells, that of REG cells was normalized to the control level. Prolonged action potential duration (APD) and reduced density of transient outward current (ito) in SHR cells was normalized by LVH regression (APD at 75% repolarization (ms) and ito density at +60 mV (pA/pF): WKY 36.1 +/- 4.2, 11.9 +/- 1.3, SHR 73.1 +/- 12.9, 5.2 +/- 0.7, REG 29.5 +/- 3.9, 10.4 +/- 2.0, P = 0.015, P = 0.001 v WKY). No significant differences were observed in the densities of steady-state outward current, inward rectifier current, and L-type Ca2+ current. The restoration of ito density by regression of LVH could normalize the prolonged APD in hypertensive LVH, which may be causally related to the reduced incidence of arrhythmias in LVH regression.
J Mol Cell Cardiol 1997 May
PMID:Restoration of action potential duration and transient outward current by regression of left ventricular hypertrophy. 920 19

ATP sensitive potassium channel (KATP) openers (e.g. cromakalim) are thought to be cardioprotective during ischemia-reperfusion, while KATP blockers (e.g. glibenclamide) may potentiate ischemia-reperfusion damage. We studied cardiac energetics and intracellular pH, by 31P magnetic resonance spectroscopy, during ischemia-reperfusion of buffer perfused, isolated rat hearts in the presence of cromakalim (10 microM) or glibenclamide (1, 10 and 50 microM). Hearts were subjected to 25 min total global ischemia at 36.5 degrees C and reperfused for 45 min. Pre-treatment with cromakalim delayed the time to ischemic contracture (19.3 +/- 1.5 min v 15.3 +/- 0.6 for control, P < 0.05) and significantly improved recovery of function at 45 min reperfusion (84 +/- 11% pre-ischemic rate pressure product (RPP) v 38 +/- 5 for control, P < 0.05). This was accompanied by an attenuation in the loss of ATP during ischemia. Pre-treatment with glibenclamide decreased the time to ischemic contracture: 16.1 +/- 0.8 min. 15.1 +/- 0.7, 12.0 +/- 1.2 (P < 0.01) and 9.5 +/- 0.9 (P < 0.001) for control, 1, 10 and 50 microM glibenclamide respectively. 50 microM glibenclamide significantly improved functional recovery at 45 min reperfusion but 1 and 10 microM were without effect; 24 +/- 6, 22 +/- 4, 29 +/- 4 and 58 +/- 7% (P < 0.05) of pre-ischemic RPP for control, 1, 10 and 50 microM glibenclamide. During ischemia, intracellular ATP was depleted more rapidly in the presence of 50 microM glibenclamide and intracellular acidosis was significantly attenuated (final pH 6.3 v 5.8 for control). 50 microM glibenclamide also decreased tissue lactate content at the end of ischemia (75 +/- 3 mumol/g dry weight v 125 +/- 18 for control, P < 0.05) and this attenuation of lactate accumulation and consequent decreased intracellular acidosis may be responsible for the cardioprotection observed under these conditions. These latter effects are unlikely to be related to glibenclamide's KATP blocking activity. This study demonstrates that blocking of myocardial KATP does not potentiate ischemia-reperfusion injury and, in addition, illustrates the important role played by intracellular acidosis in myocardial ischemia-reperfusion injury.
J Mol Cell Cardiol 1997 Jun
PMID:Effects of cromakalim and glibenclamide on myocardial high energy phosphates and intracellular pH during ischemia-reperfusion: 31P NMR studies. 922 Mar 52

Although several studies have demonstrated that nitric oxide appears to be cardioprotective and endothelin-1 (ET-1) deleterious in myocardial ischemia/reperfusion injury, their interactions in the intact heart are unknown. Therefore, coronary effluent and interstitial fluid ("transudate") levels of ET-1 and cyclic GMP, an indirect measure of nitric oxide production, were determined simultaneously in normoxic and reperfused hearts and compared with myocardial and coronary function. Rat hearts were buffer-perfused at 9 ml/min/g heart wet weight for 45 min (baseline), followed either by another 45 min of perfusion (normoxia), or 15 min of total global ischemia and 30 min reperfusion. Hearts received, from 42-90 min, either vehicle, the inhibitor of nitric oxide formation NG-nitro-L-arginine (L-NNA; 200 micromol/l), the nitric oxide donor S-nitroso-N-acetyl-DL-penicillamine (SNAP; 200 micromol/l), or the ET receptor antagonist PD 142893 (200 nmol/l). Both mediators were released preferentially into the vascular lumen which resulted in similar luminal and interstitial concentrations of cyclic GMP, but three-fold higher levels of ET-1 in tissue because of the higher effluent than transudate flow rate. L-NNA increased the release of ET-1 and worsened coronary function, whereas SNAP had opposite effects. On reperfusion, considerable functional impairment was observed, although levels of cyclic GMP both in the vascular and tissue compartment were not reduced, but even increased. Reperfusion functional impairment was aggravated after inhibiting the synthesis of nitric oxide, whereas SNAP restored cardiac and coronary function close to pre-ischemic level. Deterioration of function corresponded with an increased level, and improvement with a decreased level of intersitial ET-1 at the onset of reperfusion. PD 142893 was similarly cardioprotective as SNAP both in normoxia and reperfusion. These results suggest that in reperfusion, cardiac function is depressed, despite increased rather than decreased endogenous nitric oxide production, largely due to the prevalence of the deleterious effects of ET-1 which are overcome by antagonism of ET receptors or exogenous nitric oxide supplied by SNAP.
J Mol Cell Cardiol 1997 Sep
PMID:Interaction of nitric oxide and endothelin-1 in ischemia/reperfusion injury of rat heart. 929 60

This study was designed to test the hypothesis that activation of myocardial pyruvate dehydrogenase (PDH) would improve recovery of heart function after brief, severe hemorrhagic shock. Pentobarbital-anesthetized rats were instrumented to monitor arterial blood pressure and right ventricular pressures. Rats were hemorrhaged via femoral artery to 25-30 mmHg mean arterial pressure (MAP) for 60 min, followed by retransfusion of shed blood with either 1.0 cc saline with no dichloroacetate (-DCA) or 1.0 cc saline containing 150 mg/kg sodium dichloroacetate (+DCA). Rats were observed for 3 h after retransfusion. Hearts were freeze-clamped in situ for analysis of adenosine triphosphate (ATP), creatine phosphate (CrP), lactate and pyruvate content as well as PDH activity (PDHa) and total PDH activity (PDHt). Three h after retransfusion, the rate pressure product (RPP=HRxPSP) was 23 000+/-2733 with no DCA treatment v 36 2769 mmHg/min with DCA treatment (P<0.05, ANOVA). Treatment with DCA also increased myocardial tissue content of high energy phosphates (ATP=10.1+/-1.1 and CrP=5.8+/-1.0 micromol/g weight-DCA, v 15.1+/-0.9 and 14.7+/-1.0 micromol/g dry weight+DCA, P<0.05, both measurements). DCA administration also significantly reduced myocardial lactate contents (14.6+/-2.7 micromol/g dry weight-DCA v 5.9+/-1.0+DCA). Hemorrhagic shock did not change PDHa or PDHt compared to hearts obtained during the pre-hemorrhage period. Retransfusion with DCA significantly increased PDHa activity (6.8+/-1.1 micromol/g dry weight/min-DCA v 29.7+/-2.0 micromol/g dry weight/min+DCA). PDHt was not different between controls and DCA-treated groups. These data indicate that activation of myocardial PDH by adding DCA to retransfused blood improved heart function and metabolism after severe hemorrhagic shock.
J Mol Cell Cardiol 1997 Sep
PMID:Activation of pyruvate dehydrogenase improves heart function and metabolism after hemorrhagic shock. 929 69


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