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Query: UNIPROT:P06889 (Mol)
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We studied the effects of the potent Na/H exchange inhibitor methylisobutyl amiloride (MIA, 1 microM) on post-ischemic ventricular recovery and energy metabolic status in spontaneously contracting, isolated rat and guinea-pig hearts subjected to 45 min zero-flow ischemia followed by reperfusion. For both species, MIA was added either 15 min prior to ischemia and was present throughout reperfusion or was added at the time of reperfusion only. In control rat hearts, force recovery after 30 min of reperfusion was 25.6 +/- 6.0% of the pre-ischemic value whereas in hearts pre-treated with MIA recovery was enhanced to 55.4 +/- 9% (P < 0.05). Elevation of resting tension during the first 20 min of reperfusion was also significantly reduced by MIA pre-treatment. When MIA was added at the time of reperfusion only, recovery was generally lower than that seen with MIA pre-treatment although significantly higher values were seen through much of the reperfusion period. In rat hearts, MIA reduced the time required for return to sustained contractile recovery particularly in those hearts where the drug was added prior to ischemia (control, 11.4 +/- 2.7 min; MIA, 2.6 +/- 0.5 min, P < 0.05). Similar effects of MIA pre-treatment were seen in guinea-pig hearts in terms of contractile recovery, time to recovery and reduction in resting tension although MIA addition at the time of reperfusion was without beneficial effect either on the magnitude of contractile recovery or time required for restoration of function. In guinea-pig hearts, recovery of function was accompanied by substantial bradycardia. However, maintenance of ventricular rate through electrical pacing exerted no significant influence on the protective effects of MIA pre-treatment. There was no effect of MIA on energy metabolites in reperfused rat hearts or paced guinea-pig hearts, although in spontaneously contracting guinea-pig hearts improved recovery of function was associated with significantly higher levels of high energy phosphates. No effects of tissue metabolites were seen in ischemic non-reperfused hearts irrespective of treatment. The protective effects of MIA were not related to diminished release of creatine kinase during reperfusion. Our results demonstrate marked protective effects of MIA, on the reperfused rat and guinea-pig myocardium. These studies also demonstrate, for the first time, that the effects of amiloride analogues are not species specific and further support the concept that Na/H exchange inhibition may represent an effective therapeutic approach for the protection of reperfused cardiac tissue.
J Mol Cell Cardiol 1993 Aug
PMID:Protective effects of the potent Na/H exchange inhibitor methylisobutyl amiloride against post-ischemic contractile dysfunction in rat and guinea-pig hearts. 826 64

Glycolysis normally provides only a small fraction of myocardial ATP production, but ATP from glycolysis may be preferentially used to support membrane activities such as ion pumping. Since ion homeostasis is disturbed during ischemia, glycolysis may be particularly important in the recovery of postischemic myocardium. This hypothesis was investigated in isovolumic, isolated rabbit hearts, perfused with 16 mM glucose, 5 mM pyruvate or 5 mM acetate. Global left ventricular function (rate-pressure product, RPP) and unidirectional ATP synthesis rate (P(i)-->ATP flux, 31P NMR) were measured before and after 20 min global ischemia. Control hearts with intact glycolysis were compared with hearts which had glycolysis inhibited by iodoacetate (150 microM), 2-deoxyglucose (10 mM) or prior glycogen depletion. In normal hearts, inhibition of glycolysis had no effect on function when pyruvate or acetate was present as as a carbon substrate. In post-ischemic hearts, reperfusion with glucose (n = 7) resulted in moderate recovery of function to about 65% of pre-ischemic levels after 1 h reperfusion. Administration of iodoacetate at the onset of reperfusion to hearts receiving pyruvate or acetate resulted in much worse functional recovery and a marked rise in left ventricular end-diastolic pressure (LVEDP). With pyruvate (n = 7), RPP recovered to 27% of pre-ischemic levels, while mean LVEDP increased to 34 mmHg (vs 16 mmHg with glucose); with acetate (n = 6), RPP returned to 31% of pre-ischemic levels, while mean LVEDP rose to 32 mmHg. The ratio of P(i)-->ATP flux to atoms of oxygen consumed (P:O ratio) was 2.14 +/- 0.36 in hearts reperfused with iodoacetate and pyruvate, consistent with partial mitochondrial uncoupling. However, if inhibition of glycolysis with iodoacetate was delayed until after 30 min reperfusion, recovery of hearts reperfused with pyruvate was similar to hearts perfused with glucose, and there was no evidence of mitochondrial uncoupling (P:O ratio = 2.95 +/- 0.33). Inhibition of glycolysis during reperfusion with 2-deoxyglucose yielded results similar to reperfusion with iodoacetate. The worst recovery was observed in hearts with combined glycolytic inhibition by pre-ischemic glycogen depletion and iodoacetate during reperfusion (RPP = 13% of pre-ischemic levels). These findings indicate that glycolysis plays a crucial role during early reperfusion in the functional and metabolic recovery of post-ischemic myocardium.
J Mol Cell Cardiol 1993 Mar
PMID:The functional recovery of post-ischemic myocardium requires glycolysis during early reperfusion. 851 Jan 69

Intracellular pH (pHi) and developed pressure during hypercapnic acidosis were studied in the spontaneously hypertensive rat (SHR) heart and Wistar-Kyoto controls. Developed pressure was determined using a modified Langendorff isovolumic perfusion technique and 31P magnetic resonance spectroscopy was used to determine pHi. In response to acidosis, both developed pressure and pHi first decreased and then partially recovered. In the SHR group, pHi during the early periods of acidosis was significantly higher than in the control group while there was no significant difference in the steady-state pHi. The addition of 5-(N,N)-hexamethylene-amiloride (HMA), a specific inhibitor of Na(+)-H+ exchange, abolished these difference. Furthermore, HMA was found to inhibit recovery in pHi and developed pressure during acidosis in both groups. These results demonstrate that Na(+)-H(+)-exchange in the rat heart plays a major role in pHi regulation and contributes to functional recovery during acidosis. In addition, Na(+)-H(+)-exchange activity, as previously found in other tissues in hypertension, is increased in the SHR heart.
J Mol Cell Cardiol 1995 Aug
PMID:Altered Na(+)- H(+)- exchange activity in the spontaneously hypertensive perfused rat heart. 852 11

It is well known that ischaemic preconditioning delays infarct size during regional ischaemic insults. However, the extent of this protective effect against different ischaemia periods has not been established, and any reduction in stunning has been difficult to demonstrate with regional models. In this study we have investigated ischaemic preconditioning in a buffer-perfused isolated rabbit heart model with a global ischaemic insult, and measured both infarct volume and functional recovery. Experiments were performed with three ischaemia time periods of 15, 20 and 30 min at 37 degrees C. Infarct volume (expressed as a percentage of left ventricular volume) was measured by tetrazolium staining after 2 hours reperfusion, and left ventricular developed pressure with an intraventricular balloon. Hearts preconditioned with 5 min ischaemia and 10 min reperfusion were compared with a control group. In this model, preconditioning resulted in a 57% reduction in infarct volume compared with control hearts (P = 0.02) subjected to 20 min of global ischaemia, but the degree of this infarct delaying effect was dependent on the ischaemia time and was only 37% (P = 0.02) and 11% (N.S.) with a 30 min and 15 min ischaemic challenge respectively. Recovery of post-ischaemic left ventricular developed pressure as a percentage of the pre-ischaemic value correlated very well with infarct volume in control r = -0.82 (P < 0.001) and preconditioned r = -0.78 (P < 0.001) groups, and the slope of the regression lines was similar for both groups. These results demonstrate that the degree of protection produced by preconditioning is not uniform but varies with the length of the ishaemic insult. By measuring both infarct volume and functional recovery we have been able to confirm that any post-ischaemic improvement in global left ventricular function produced by preconditioning is secondary to reduced infarction, and hence that preconditioning does not attenuate stunning.
J Mol Cell Cardiol 1995 Aug
PMID:Ischaemic preconditioning in a model of global ischaemia: infarct size limitation, but no reduction of stunning. 852 25

Over a 10-week period, female Wistar rats received a diet containing various levels of four trace elements (Zn, Cu, Mn, Se), co-factors of antioxidant enzymes (superoxide dismutase SOD, glutathione peroxidase GPx), in order to examine the influence of supplementation or deficiency of these elements (i) on tissue antioxidant enzyme defence systems, and (ii) on the susceptibility of the myocardium to ischemia-reperfusion injury. At the end of the dietary treatment, hearts were perfused at constant flow (11 ml/min) before being subjected to 15 min of total global normothermic ischemia, followed by reperfusion. The effects of the various diets (deficient, standard or supplemented) were estimated by studying functional recovery of various cardiac parameters (left ventricular developed pressure LVDP, dP/dtmax, heart rate x LVDP) as well as ultrastructural tissue characteristics. Furthermore, SOD and GPx activities were measured before ischemia and at the end of the reperfusion period. Results suggest that: (a) the activity of antioxidant enzymes increased or decreased significantly when diet was respectively supplemented with, or deficient in, trace elements, but was not further modified by an ischemia-reperfusion episode: (b) the recovery of cardiac function during reperfusion, and ventricular myocardial ultrastructure were significantly improved under the influence of trace element supplementation when compared to both standard and deficient groups. These results illustrate the protective effect of trace elements which are co-factors of antioxidant enzymes in limiting ischemia-reperfusion induced injury, and suggest a possible use in the field of anti-ischemic therapy.
J Mol Cell Cardiol 1995 Oct
PMID:Effect of dietary antioxidant trace element supply on cardiac tolerance to ischemia-reperfusion in the rat. 857 45

To identify proteins that interact in vivo with muscle components we have used a genetic approach based on the isolation of suppressors of mutant alleles of known muscle components. We have applied this system to the case of troponin I (TnI) in Drosophila and its mutant allele heldup2 (hdp2). This mutation causes an alanine to valine substitution at position 116 after a single nucleotide change in a constitutive exon. Among the isolated suppressors, one of them results from a second site mutation at the TnI gene itself. Muscles endowed with TnI mutated at both sites support nearly normal myofibrillar structure, perform notably well in wing beating and flight tests, and isolated muscle fibers produce active force. We show that the structural and functional recovery in this suppressor does not result from a change in the stoichiometric ratio of TnI isoforms. The second site suppression is due to a leucine to phenylalanine change within a heptameric leucine string motif adjacent to the actin binding domain of TnI. These data evidence a structural and functional role for the heptameric leucine string that is most noticeable, if not specific, in the indirect flight muscle.
Mol Biol Cell 1995 Nov
PMID:Functional recovery of troponin I in a Drosophila heldup mutant after a second site mutation. 858 47

The combination of vitamin E supplementation with dihydrolipoic acid perfusion synergistically improves cardiac functional recovery during post-ischemic reperfusion or post-hypoxic reoxygenation of the rat heart. To elucidate the mechanism of this effect, isolated rat hearts were perfused using a working heart system. In hearts perfused with a buffer containing dihydrolipoic acid, ATP levels were significantly higher than those of hearts perfused without addition of dihydrolipoic acid during 90 min of reoxygenation following 30 min of hypoxia. Cardiac tissue glutathione status measured in hearts after perfusion experiments showed significant elevation of reduced glutathione in vitamin E supplemented normoxic rat hearts without hypoxia. Significant elevation of oxidized glutathione was observed in dihydrolipoic acid perfused heart after hypoxia-reoxygenation. It is concluded that vitamin E and dihydrolipoic acid exert separate and synergistic effects in the protection of the hypoxic-reoxygenated heart.
Biochem Mol Biol Int 1995 Oct
PMID:The influence of vitamin E and dihydrolipoic acid on cardiac energy and glutathione status under hypoxia-reoxygenation. 859

The induction of heat shock proteins in the myocardium has been suggested as a possible intervention to allow for enhanced cardioprotection. We examined the cardioprotective effects of Hsp 70 induction in a clinically relevant model, in which a brief period of retrograde hyperthermic perfusion (42 degrees C) was applied for 15 min, only 5 min prior to global ischemia and reperfusion in the isolated perfused rat heart. Our results indicate that in retrograde hyperthermic perfused hearts (n = 17) there was enhanced dP/dT, end diastolic pressure, and peak developed pressure during normothermic reperfusion following 15 min of global ischemia when compared to control hearts perfused at 37 degrees C (n = 18). Northern analysis indicated Hsp 70 mRNA, in retrograde hyperthermic perfused hearts, was increased 9.0 +/- 0./70-fold (P < 0.001) by 30 min and 9.1 +/- 0.45-fold (P < 0.001) by 60 min of normothermic reperfusion. Western analysis revealed that the Hsp, heat inducible 72 kD protein was increased 1.74 +/- 0.35-fold (P < 0.001) by 30 min and 1.79 +/- 0.31-fold at 60 min of normothermic reperfusion when compared to no ischemia hearts. Our results demonstrate that the use of 15 min of retrograde hyperthermic perfusion, only 5 min prior to global ischemia and reperfusion, provide for enhanced myocardial functional recovery. Enhanced myocardial functional recovery was associated with the accumulation of Hsp 70 mRNA and the Hsp 72 kD protein.
J Mol Cell Cardiol 1996 Feb
PMID:A brief period of retrograde hyperthermic perfusion enhances myocardial protection from global ischemia: association with accumulation of Hsp 70 mRNA and protein. 872 56

To examine the intracellular signaling mechanism of NO in ischemic myocardium, isolated working rat hearts were made ischemic for 30 min followed by 30 min of reperfusion. A separate group of hearts were pre-perfused with 3 mM L-arginine in the presence or absence of 650 microM of protoporphyrin, a heme oxygenase inhibitor for 10 min prior to ischemia. The release of NO was monitored using an on-line amperometric sensor placed into the right atrium. The aortic flow and developed pressure were examined to determine the effects of L-arginine on ischemic/reperfusion injury. Induction for the expression of heme oxygenase was studied by Northern hybridization. For signal transduction experiments, sarcolemmal membranes were radiolabeled by perfusing the isolated hearts with [3H] myoinositol and [14C] arachidonic acid. Biopsies were processed to determine the isotopic incorporation into various phosphoinositols as well as phosphatidic acid and diacylglycerol. cGMP was assayed by radioimmunoassay and SOD content was determined by enzymatic analysis. The release of NO was diminished following ischemia and reperfusion and was augmented by L-arginine. L-arginine reduced ischemic/reperfusion injury as evidenced by the enhanced myocardial functional recovery. Protoporphyrin modulated the effects of L-arginine. cGMP, which was remained unaffected by ischemia and reperfusion, was stimulated significantly after L-arginine treatment. The NO-mediated augmentation of cGMP was reduced by protoporphyrin suggesting that part of the effects may be mediated by CO generated through the heme oxygenase pathway. Reperfusion of ischemic myocardium resulted in significant accumulation of radiolabeled inositol phosphate, inositol bisphosphate, and inositol triphosphate. Isotopic incorporation of [3H] inositol into phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-bisphosphate was increased significantly during reperfusion. Reperfusion of the ischemic heart prelabeled with [14C] arachidonic acid resulted in modest increases in [14C] diacylglycerol and [14C] phosphatidic acid. Pretreatment of the heart with L-arginine significantly reversed this enhanced phosphodiesteratic breakdown during ischemia and early reperfusion. However, at the end of the reperfusion the inhibitory effect of L-arginine on the phosphodiesterases seems to be reduced. In L-arginine treated hearts, SOD activity was progressively decreased with the duration of reperfusion time. The results suggests for the first time that NO plays a significant role in transmembrane signaling in the ischemic myocardium. This signaling appears to be on- and off- nature, and linked with SOD content of the tissue. The signaling is transmitted via cGMP and opposes the effects of phosphodiesterases by inhibiting the ischemia/reperfusion-induced phosphodiesteratic breakdown. Our results also suggest that NO activates heme oxygenase which further stimulates the production of cGMP presumably by CO signaling. Thus, NO not only potentiates cGMP mediated intracellular signaling, it also functions as a retrograde messenger for CO signaling in heart.
Mol Cell Biochem
PMID:Nitric oxide--a retrograde messenger for carbon monoxide signaling in ischemic heart. 873 31

In the adult heart an increase in extracellular [Ca2+] can contribute to the severity of ischemic injury. While experimental studies have suggested that the immature heart is more resistant to ischemia than the mature heart, the reasons for this are unclear. In this study, we determined the effects of increasing perfusate [Ca2+] from 1.25 to 2.5 mM on reperfusion recovery of mechanical function and energy substrate metabolism following ischemia. Isolated bi-ventricular working hearts from 2-week-old rabbits were subjected to a 55-min period of global ischemia followed by 40 min of aerobic reperfusion. Perfusate contained 11 mM glucose, 0.5 mM lactate, and 1.2 mM palmitate, containing either: (i) 1.25 mM Ca2+ throughout the perfusion period (n = 22), (ii) 1.25 mM Ca2+ prior to and during ischemia and 2.5 mM Ca2+ following ischemia (n = 19), or (iii) 2.5 mM Ca2+ throughout the perfusion period (n = 18). In hearts perfused with 1.25 mM Ca2+ throughout, a 57% recovery of preischemic function was seen following ischemia. If [Ca2+] was increased to 2.5 mM during reperfusion a significant improvement of function was seen (hearts recovered 127% of preischemic function). A concentration of 2.5 mM Ca2+ throughout the perfusion resulted in an increase in both pre- and post-ischemic function compared to hearts perfused with 1.25 mM Ca2+ throughout. In both experimental groups reperfused with 2.5 mM Ca2+ a greater than 200% increase in both glucose and lactate oxidation was seen during reperfusion. Fatty acid oxidation rates also returned to pre-ischemic levels in both groups reperfused with 2.5 mM Ca2+, while rates returned to only 53% in hearts reperfused with 1.25 mM Ca2+. As a result, increasing [Ca2+] from 1.25 to 2.5 mM resulted in a 100% increase in ATP production rates during reperfusion. In conclusion, this study demonstrates that increasing [Ca2+] significantly improves post-ischemic recovery of function in isolated bi-ventricular working immature rabbit hearts subjected to a 55-min period of ischemia. The beneficial effects of Ca2+ in these immature hearts may be due to both a direct inotropic effect and a marked increase in carbohydrate oxidation and ATP production during reperfusion.
J Mol Cell Cardiol 1996 Jul
PMID:Calcium improves mechanical function and carbohydrate metabolism following ischemia in isolated Bi-ventricular working hearts from immature rabbits. 884 37


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