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Query: UNIPROT:P06889 (Mol)
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Abdominal aorta constriction was performed in 10-week-old Lewis rats (Aoband). Ten weeks later the hearts were isolated and attached to a non-recirculating perfusion apparatus. The hearts could eject against a diastolic aortic pressure of either 60 or 100 mmHg. The functional recovery was compared with that of hearts of sham-operated (Sham) rats. After 45 min of global ischemia, Sham hearts regained cardiac output up to 75% and 70% of the pre-ischemic levels at 60 and 100 mmHg, respectively. At 60 mmHg Aoband hearts showed a minor recovery of ejection function. However, at 100 mmHg the recovery of Aoband hearts was completely comparable with that of Sham hearts. At 60 mmHg but not at 100 mmHg, the pre-ischemic and post-ischemic coronary flow was lower in Aoband than in Sham hearts (P less than or equal to 0.05). During the initial reperfusion phase Sham hearts, perfused at 60 mmHg, released more degradation products of adenine nucleotides and lactate dehydrogenase (LDH) than Aoband hearts (P less than or equal to 0.05), while the Aoband hearts lost more degradation products and LDH than the Sham hearts later during the reperfusion phase (P less than or equal to 0.05). In the groups perfused at 60 mmHg, higher tissue levels of ATP were found in Sham than in Aoband hearts at the end of the reperfusion period (P less than or equal to 0.05). However, at 100 mmHg comparable levels were found in the Sham and Aoband hearts. It is concluded that the height of the coronary perfusion pressure is of critical importance for the post-ischemic functional recovery of the compensated hypertrophied heart. At sufficiently high perfusion pressure levels, the functional and biochemical recovery of the hypertrophied heart is at least as good as in the non-hypertrophied heart. However, in the hypertrophied heart a coronary perfusion pressure which is too low leads to relative underperfusion during the initial reperfusion period which is associated with severely depressed cardiac performance and delayed wash-out of metabolites and intracellular enzymes.
J Mol Cell Cardiol 1990 Dec
PMID:The effects of global ischemia and reperfusion on compensated hypertrophied rat hearts. 215 Sep 72

Maintenance of low coronary flow (1 ml/min) during 40 or 70 min of anoxia maintained function and prevented Ca2+ overload during reoxygenation in isolated rat hearts. In comparison, recovery from 40 min of global ischemia resulted in only 20% of preischemic function and an increase in end-diastolic pressure (LVEDP) to 39 mmHg. Reperfusion Ca2+ uptake rose from 0.6 to 10.2 mumol/g dry tissue. Intracellular Na+ (Nai+) increased from 13 to 61 mumol/g dry tissue after 40 min of global ischemia, but was unchanged in hearts with low flow anoxia. When glucose and pyruvate were omitted from buffer used for anoxic perfusion, recovery was only 15% of preanoxic values, LVEDP rose to 32 mmHg, and reperfusion Ca2+ uptake was 7.2 mumol/g dry. In addition, Nai+ increased (47.4 mumol/g dry tissue) and ATP was depleted (1.0 mumol/g dry tissue) in the absence of substrate. In anoxic hearts supplied substrate, Nai+ stayed low (12 mumol/g dry tissue) and ATP was preserved (11.6 mumol/g dry tissue). Addition of ouabain (100 or 200 microM) and provision of zero-K+ buffer increased Nai+ and resulted in impaired functional recovery, increased LVEDP, and greater reperfusion Ca2+ uptake. These interventions also decreased energy availability in anoxic hearts. To distinguish between effects of Na+ accumulation and ATP depletion, monensin, a Na+ ionophore, was added during low flow anoxia. Monensin increased Nai+, decreased functional recovery and increased reperfusion Ca2+ uptake in a dose-dependent manner (1-10 microM) without changing ATP content. These results suggested that reduction of Nai+ accumulation by maintenance of Na+, K+ pump activity was the major mechanism of the beneficial effects of low coronary flow on reperfusion injury.
J Mol Cell Cardiol 1990 Jan
PMID:Na+ accumulation increases Ca2+ overload and impairs function in anoxic rat heart. 215 54

The ability of diltiazem and/or desferrioxamine to enhance the recovery of cardiac contractile function during reperfusion after prolonged hypothermic storage was assessed. Isolated rat hearts were arrested with St. Thomas' Hospital Cardioplegic Solution and stored for 10 h at 4 degrees C. Reperfusion in the Langendorff mode was initially carried out with crystalloid perfusate with or without added diltiazem (0.5 mumol/l) and/or desferrioxamine (15, 50, 100, 150 or 250 mumol/l). After 15 min the drugs were discontinued and the hearts were perfused for a further 45 min. Diltiazem reduced leakage of creatine (CK) kinase during the first 15 min of reperfusion from 102 +/- 8 IU/15 min/g dry wt to 67 +/- 9 IU/15 min/g dry wt (P less than 0.05). However, during the subsequent period of diltiazem-free perfusion, CK leakage was similar to control values (131 +/- 24 vs 142 +/- 34 IU/45 min/g dry wt, respectively). After 1 h of reperfusion there was no significant difference in total CK leakage between the diltiazem and the control groups (198 +/- 32 vs 244 +/- 39 IU/60 min/g dry wt, respectively). Desferrioxamine had no effect on CK leakage at any of the doses studied. Diltiazem significantly reduced leakage of enzyme during the initial reperfusion phase when combined with desferrioxamine; however, as with diltiazem alone, this protection was lost after the drug was withdrawn. Post-ischemic contents of adenosine triphosphate and creatine phosphate were similar in all groups as was the final recovery of function, as assessed by left ventricular developed pressure at an end-diastolic pressure of 5 mmHg. In conclusion, neither diltiazem nor desferrioxamine nor both together could be shown to confer benefit during reperfusion after long-term storage.
J Mol Cell Cardiol 1990 Nov
PMID:Diltiazem and/or desferrioxamine administered at the time of reperfusion fail to improve post-ischemic recovery in the isolated rat heart after long-term hypothermic storage. 228 82

To assess the nature of ischemia- and reperfusion-induced lipid changes and their consequences for myocardial function and integrity, Krebs-Henseleit perfused, isolated, working rat hearts were treated with nicotinic acid or mepacrine, putative inhibitors of triacylglycerol and phospholipid hydrolysis, respectively. In non-treated hearts 60 min ischemia resulted in a marked rise in myocardial fatty acid (FA) content. The FA content sharply increased further during 30 min reperfusion. Seven out of 16 (44%) hearts fibrillated continuously during reperfusion. Post-ischemic recovery of cardiac output (CO) of the non-fibrillating hearts amounted to 68 +/- 15% of the preischemic value. Nicotinic acid (10 microM) significantly reduced FA accumulation during ischemia (P less than 0.05), but not during reperfusion (0.05 less than P less than 0.10). Post-ischemic recovery of CO was improved (87 +/- 12%). This was neither associated with preservation of myocardial adenine nucleotide content, nor significant reduction of enzyme release. Mepacrine (1 microM) completely abolished reperfusion arrhythmias and improved recovery of CO (88 +/- 7% of pre-ischemic value). The reduction of FA content in ischemic and reperfused hearts did not reach the level of significance. Enzyme release was not attenuated. At 10 microM, mepacrine completely prevented accumulation of FAs during ischemia and reperfusion, abolished reperfusion-arrhythmias, and reduced enzyme release. No concomitant preservation of adenine nucleotides was observed. In conclusion, nicotinic acid and mepacrine are able to reduce ischemia- and reperfusion-induced changes in myocardial lipid metabolism. In addition, both drugs improve post-ischemic functional recovery. It remains to be established whether these effects are causally related.
J Mol Cell Cardiol 1990 Feb
PMID:Effects of nicotinic acid and mepacrine on fatty acid accumulation and myocardial damage during ischemia and reperfusion. 232 35

The objective of this study was to characterize the effect of prostacyclin (PGI2) on ventricular function following total global ischemia in isolated working rat hearts and to investigate the mechanism of its action. Ischemia was initiated for 10, 15, 20 or 25 min with or without treatment with PGI2. Increasing durations of ischemia resulted in a progressive decline in high energy phosphate (HEP) stores, an elevation in tissue lactate, and incomplete recovery of function with reperfusion. Prostacyclin at either 1 or 10 ng/ml had no effect on HEP levels or total adenine nucleotides, and tissue lactate was not significantly affected by PGI2 in hearts made ischemic for 10 to 20 min, but both PGI2 concentrations significantly elevated lactate levels after 25 min ischemia. Reperfusion recovery of left ventricular function was complete following 10 and 15 min ischemia, but incomplete recovery was evident following 20 min ischemia (77% of pre-ischemic function); and although PGI2 had no direct effect on the function of aerobically perfused hearts, recovery of aortic flow with 1 ng/ml PGI2 after 20 min of ischemia was reduced to approximately 20% (P less than 0.01). This depression in recovery was associated with significantly increased lactate levels during reperfusion. At a concentration of 10 ng/ml PGI2 did not depress ventricular recovery or elevate lactate content after 20 min ischemia. When hearts made ischemic for 20 min were analyzed, a significant negative correlation was found between ventricular recovery (aortic flow rate) and lactate concentration; however, no correlation existed between recovery and ATP levels. After 25 min of ischemia, five of eight (62.5%) untreated hearts demonstrated some degree of ventricular recovery, however, only two of ten hearts studied demonstrated any measurable functional recovery with either PGI2 concentration. This effect of PGI2 to reduce or prevent recovery of ventricular function following either 20 or 25 min of ischemia as well as the corresponding elevation in lactate levels was prevented by treatment with the calcium channel blocker verapamil. This study therefore shows that PGI2 at critical low concentrations can depress left ventricular recovery following total ischemia. This effect of PGI2 becomes more pronounced as ischemia duration is prolonged and is associated with elevated tissue lactate levels. The studies with verapamil suggest that PGI2 may be acting via the slow calcium channel to increase lactate levels and depress ventricular recovery following prolonged periods of ischemia.
J Mol Cell Cardiol 1989 Mar
PMID:Inhibition of post-ischemic ventricular recovery by low concentrations of prostacyclin in isolated working rat hearts: dependency on concentration, ischemia duration, calcium and relationship to myocardial energy metabolism. 266 90

Quantitative Evaluation of Relationship between Cardiac Energy Metabolism and Post-ischemic Recovery of Contractile Function. Mechanisms of ischemic damage were studied by defining the relationships between post-ischemic work recovery and tissue ATP levels in isolated rat hearts as well as mitochondrial respiration rates in skinned myofibrils. Pre-ischemic levels of ATP were reduced by 2-deoxyglucose treatment and assessed using 31P-NMR. A 70% fall of ATP was not associated with decreased functional recovery. Mitochondrial respiration was assessed without mitochondrial isolation in skinned cardiac fibers in physiological salt solution using a novel method developed by Veksler et al. Maximal rates of mitochondrial respiration were not changed after 35 min of normothermic ischemia using St. Thomas's Hospital cardioplegic solution followed by 30 min of aerobic reperfusion. Only a reversible increase in the rate of basal respiration and a decrease in creatine-stimulated oxygen uptake were observed. Thus, mitochondrial oxidative phosphorylation, as assessed in skinned myofibrils, was tolerant to an ischemic period which induced permanent depression of contractile function along with alterations in metabolite distribution. As a result, tissue level of ATP and rates of mitochondrial respiration provided an estimate of ischemic damage only in cases where damage reached a very severe extent.
J Mol Cell Cardiol 1989 Feb
PMID:Quantitative evaluation of relationship between cardiac energy metabolism and post-ischemic recovery of contractile function. 273 31

Reperfusion of isolated rabbit heart after 60 min of ischaemia resulted in poor recovery of mechanical function, release of reduced (GSH) and oxidized glutathione (GSSG), reduction of tissue GSH/GSSG ratio and shift of cellular thiol redox state toward oxidation, suggesting the occurrence of oxidative stress. Pretreatment of the isolated heart with propionyl-L-carnitine (10(-7) M) improved the functional recovery of the myocardium, reduced GSH and GSSG release and attenuated the accumulation of tissue GSSG. This effect was specific for propionyl-L-carnitine as L-carnitine and propionic acid did not modify myocardial damage.
Mol Cell Biochem
PMID:Protective effect of propionyl-L-carnitine against ischaemia and reperfusion-damage. 277 35

The effect of the carnitine palmitoyltransferase 1 (CPT 1) inhibitor, Etomoxir, on glucose oxidation rates was determined in ischemic hearts reperfused in the presence of fatty acids. Isolated working rat hearts were perfused with 11 mM (14C)-glucose and 1.2 mM palmitate at a 15 cm H2O preload, 80 mm Hg afterload. Hearts were subjected to either 60 min aerobic perfusion, or 15 min work followed by 25 min global ischemia then 60 min of aerobic reperfusion. Steady state glucose oxidation rates in reperfused ischemic hearts were not significantly different from non-ischemic hearts. If 10(-9) M Etomoxir was added immediately prior to reperfusion no significant change in glucose oxidation occurred. Addition of 10(-8) M and 10(-6) M Etomoxir, however, significantly increased glucose oxidation. Etomoxir also significantly improved recovery of mechanical function at a concentration of 10(-8) M or greater. As we previously reported, no significant improvement of function was seen when 10(-9) M Etomoxir was added to the perfusate (Lopaschuk GD et al., Circ Res 63: 1036-1043, 1988). Long chain acylcarnitine levels were significantly reduced in the presence of both 10(-9) M and 10(-8) M Etomoxir. These data demonstrate that the beneficial effect of Etomoxir on reperfusion recovery of ischemic hearts is not due to a lowering of long chain acylcarnitine levels. Etomoxir may improve recovery of function by overcoming fatty acid inhibition of glucose oxidation.
Mol Cell Biochem
PMID:Glucose oxidation is stimulated in reperfused ischemic hearts with the carnitine palmitoyltransferase 1 inhibitor, Etomoxir. 277 37

alpha 2-Adrenergic receptors are present on human erythroleukemia (HEL) cells, both on the cell surface and in a sequestered compartment. In the current study we show that benextramine, a hydrophilic irreversible antagonist, can be used to investigate alpha 2-adrenergic receptor compartmentation in these cells. In membranes prepared from HEL cells, benextramine competed for all alpha 2-adrenergic receptors ( [3H]yohimbine sites). In intact cells, at 4 degrees, benextramine exhibited a biphasic competition curve for alpha 2-adrenergic receptors, with EC50 values of approximately 10 microM and greater than 1 mM for the high and low affinity components, respectively. We propose that the alpha 2-adrenergic receptors preferentially blocked by benextramine are those on the surface of the cell, whereas those with low affinity are sequestered receptors because: 1) only epinephrine-accessible sites [i.e., cell surface sites; McKernan et al., Mol. Pharmacol. 32:258-265 (1987)] are removed by prior treatment of cells with benextramine, 2) a preparation enriched with surface membranes is also enriched in receptors with a high affinity for benextramine; and 3) after blockade of cell surface receptors (54 +/- 6% of total sites, n = 7) by benextramine, the ability of the alpha 2-adrenergic agonists epinephrine and UK-14,304 to inhibit forskolin-stimulated cAMP accumulation is lost. The latter result implies that only cell surface and not sequestered receptors are functionally coupled to adenylate cyclase. The return of receptors from the sequestered compartment to the cell surface and the recovery of alpha 2-adrenergic receptor function were measured after HEL cells were treated with benextramine (50 microM for 1 hr at 4 degrees). The recovery of receptor binding (t1/2 = 25 min) was somewhat slower than the recovery of function (t1/2 approximately 8 min). This is consistent with the existence of "spare receptors" and also suggests that the sequestered compartment of alpha 2-adrenergic receptors can rapidly exchange with those on the surface. When all alpha 2-adrenergic receptors were blocked by incubation of HEL cells with benextramine for 1 hr at 37 degrees, repopulation of surface and sequestered receptors was much slower (t1/2 = 9 hr for recovery of total receptors). Surface receptors recovered even more slowly than did total cellular receptors consistent with the idea that alpha 2-adrenergic receptors must traverse through intracellular locations before insertion into the cell surface.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1988 Jan
PMID:Selective blockade and recovery of cell surface alpha 2-adrenergic receptors in human erythroleukemia (HEL) cells. Studies with the irreversible antagonist benextramine. 282 99

The time-dependent recovery of gonadotropin-releasing hormone (GnRH) responsiveness in desensitized gonadotropes was examined under conditions of altered membrane fluidity and GnRH exposure. Cultured pituitary cells were treated for 3 h with GnRH (10(-9) M; to provoke homologous desensitization) or vehicle alone (controls). When cells were washed and immediately rechallenged for 3 h with GnRH, gonadotrope responsiveness (assessed by luteinizing hormone (LH) release) was significantly lower in GnRH-pretreated cells than controls. If gonadotropes were allowed to recover in medium alone, membrane fluidity agents 2-(2-methoxyethoxy)-ethyl-8-(cis-2-n-octylcyclopropyl)-octanoate (A2C; 10(-4) M) or cis-vaccenic acid (CVA; 0.5 mM) or a low dose of GnRH (10(-10) M) for up to 48 h prior to rechallenging with GnRH, responsiveness in all cases was significantly lower in GnRH-pretreated cells than controls. However, if cells were treated with either A2C or CVA in the presence of GnRH (10(-10) M) during the recovery period, gonadotrope responsiveness to a subsequent challenge with GnRH was partially restored by 24 h; by 48 h no differences in the LH secretory response to GnRH was detected between GnRH-pretreated cells and controls. The possibility that restoration of the GnRH receptor-linked Ca2+ channel is associated with recovery of the desensitized gonadotrope was also examined. Identical protocols to those described above were used except that the functional integrity of the Ca2+ channel was assessed by measuring LH release in response to increasing doses of maitotoxin (MTX; a specific Ca2+ channel activator). Again, GnRH-pretreated cells were significantly less responsive to MTX than controls when allowed to recover for 48 h in medium alone, A2C (10(-4) M) or GnRH (10(-10) M). However, allowing cells to recover for 48 h under a condition of increased membrane fluidity and basal GnRH levels completely restored the MTX-stimulated LH secretory response in GnRH-pretreated gonadotropes. Taken together, these studies suggest that the physical state of the gonadotrope plasma membrane together with the appropriate hormonal milieu provide an important environment for the gonadotrope to recover from desensitization. Additionally, our results suggest that functional recovery of the GnRH-linked Ca2+ channel may play a requisite role in restoring GnRH responsiveness to the desensitized gonadotrope.
Mol Cell Endocrinol 1988 Sep
PMID:Restoration of the LH secretory response in desensitized gonadotropes. 284 35


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