E Hochhauser

Publications (26)58.26 Total impact

• Article: Conditioned medium from hypoxic cells protects cardiomyocytes against ischemia.

  B Chanyshev, A Shainberg, A Isak, Y Chepurko, E Porat, E Hochhauser
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  ABSTRACT: The hypothesis of the present study is that cardiomyocytes subjected to prolonged ischemia, may release survival factors that will protect new cardiac cells from ischemic stress. We exposed neonatal rat cardiomyocyte primary cultures to hypoxia, collected the supernatant, treated intact cardiac cells by this posthypoxic supernatant, and exposed them to hypoxia. The results show cardioprotection of the treated cells compared with the untreated ones. We named the collected posthypoxic supernatant "conditioned medium" (CM), which acts in a dose-dependent manner to protect new cardiac cells from hypoxia: 100 or 75% of CM diluted in phosphate-buffered saline (PBS) protected cells as if they were not exposed to hypoxia (P < 0.001). When CM was removed from the cells before hypoxia, protection was not observed. CM also protected skeletal muscle cultures from hypoxia, but not cardiac cells against H(2)O(2)-induced cell damage. Finally, CM treatment protected the isolated heart in Langendorff set-up against ischemia. Smaller infarct size (9.9 ± 4.4% vs. 28.3 ± 8.5%, P < 0.05), better Rate Pressure Product (67 ± 11% vs. 48.6 ± 13.4%, P < 0.05) and better rate of contraction and relaxation were observed following ischemia and reperfusion (1341 ± 399 mmHg/s vs. 951 ± 349 mmHg/s, P < 0.05 and 1053 ± 347 mmHg/s vs. 736 ± 314 mmHg/s, P < 0.05). To conclude, there are factors that are released from the heart cells subjected to ischemia/hypoxia that protects cardiomyocytes from ischemic stress.
  Molecular and Cellular Biochemistry 12/2011; 363(1-2):167-78. · 2.06 Impact Factor
• Article: UTP reduces infarct size and improves mice heart function after myocardial infarct via P2Y2 receptor.

  R Cohen, A Shainberg, E Hochhauser, Y Cheporko, A Tobar, E Birk, L Pinhas, J Leipziger, J Don, E Porat
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  ABSTRACT: Pyrimidine nucleotides are signaling molecules, which activate G protein-coupled membrane receptors of the P2Y family. P2Y(2) and P2Y(4) receptors are part of the P2Y family, which is composed of 8 subtypes that have been cloned and functionally defined. We have previously found that uridine-5'-triphosphate (UTP) reduces infarct size and improves cardiac function following myocardial infarct (MI). The aim of the present study was to determine the role of P2Y(2) receptor in cardiac protection following MI using knockout (KO) mice, in vivo and wild type (WT) for controls. In both experimental groups used (WT and P2Y(2)(-/-) receptor KO mice) there were 3 subgroups: sham, MI, and MI+UTP. 24h post MI we performed echocardiography and measured infarct size using triphenyl tetrazolium chloride (TTC) staining on all mice. Fractional shortening (FS) was higher in WT UTP-treated mice than the MI group (44.7±4.08% vs. 33.5±2.7% respectively, p<0.001). However, the FS of P2Y(2)(-/-) receptor KO mice were not affected by UTP treatment (34.7±5.3% vs. 35.9±2.9%). Similar results were obtained with TTC and hematoxylin and eosin stainings. Moreover, troponin T measurements demonstrated reduced myocardial damage in WT mice pretreated with UTP vs. untreated mice (8.8±4.6 vs. 12±3.1 p<0.05). In contrast, P2Y(2)(-/-) receptor KO mice pretreated with UTP did not demonstrate reduced myocardial damage. These results indicate that the P2Y(2) receptor mediates UTP cardioprotection, in vivo.
  Biochemical pharmacology 08/2011; 82(9):1126-33. · 4.25 Impact Factor
• Article: Adenosine A(1) and A (3) receptor agonists reduce hypoxic injury through the involvement of P38 MAPK.

  D Leshem-Lev, E Hochhauser, B Chanyshev, A Isak, A Shainberg
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  ABSTRACT: Activation of either the A(1) adenosine receptor (A(1)R) or the A(3) adenosine receptor (A(3)R), by their specific agonists CCPA and Cl-IB-MECA, respectively, protects cardiac cells in culture against ischemic injury. Yet the full protective mechanism remains unclear. In this study, we therefore examined the involvement of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK) phosphorylation in this protective intracellular signaling mechanism. Furthermore, we investigated whether p38 MAPK phosphorylation occurs upstream or downstream from the opening of mitochondrial ATP-sensitive potassium (K(ATP)) channels. The role of p38 MAPK activation in the intracellular signaling process was studied in cultured cardiomyocytes subjected to hypoxia, that were pretreated with CCPA or Cl-IB-MECA or diazoxide (a mitochondrial K(ATP) channel opener) with and without SB203580 (a specific inhibitor of phosphorylated p38 MAPK). Cardiomyocytes were also pretreated with anisomycin (p38 MAPK activator) with and without 5-hydroxy decanoic acid (5HD) (a mitochondrial K(ATP) channel blocker). SB203580 together with the CCPA, Cl-IB-MECA or diazoxide abrogated the protection against hypoxia as shown by the level of ATP, lactate dehydrogenase (LDH) release, and propidium iodide (PI) staining. Anisomycin protected the cardiomyocytes against ischemic injury and this protection was abrogated by SB203580 but not by 5HD. Conclusions Activation of A(1)R or A(3)R by CCPA or Cl-IB-MECA, respectively, protects cardiomyocytes from hypoxia via phosphorylation of p38 MAPK, which is located downstream from the mitochondrial K(ATP) channel opening. Elucidating the signaling pathway by which adenosine receptor agonists protect cardiomyocytes from hypoxic damage, will facilitate the development of anti ischemic drugs.
  Molecular and Cellular Biochemistry 12/2010; 345(1-2):153-60. · 2.06 Impact Factor
• Article: Bax deficiency reduces infarct size and improves long-term function after myocardial infarction.

  E Hochhauser, Y Cheporko, N Yasovich, L Pinchas, D Offen, Y Barhum, H Pannet, A Tobar, B A Vidne, E Birk
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  ABSTRACT: We have previously found that, following myocardial ischemia/reperfusion injury, isolated hearts from bax gene knockout mice [Bax(-/-)] exhibited higher cardioprotection than the wild-type. We here explore the effect of Bax(-/-), following myocardial infarction (MI) in vivo. Homozygotic Bax(-/-) and matched wild-type were studied. Mice underwent surgical ligation of the left anterior descending coronary artery (LAD). The progressive increase in left-ventricular end diastolic diameter, end systolic diameter, in Bax(-/-) was significantly smaller than in Bax(+/+) at 28 d following MI (p < 0.03) as seen by echocardiography. Concomitantly, fractional shortening was higher (35 +/- 4.1% and 27 +/- 2.5%, p < 0.001) and infarct size was smaller in Bax(-/-) compared to the wild-type at 28 days following MI (24 +/- 3.7 % and 37 +/- 3.3%, p < 0.001). Creatine kinase and lactate dehydrogenase release in serum were lower in Bax(-/-) than in Bax(+/+) 24 h following MI. Caspase 3 activity was elevated at 2 h after MI only in the wild-type, but reduced to baseline values at 1 and 28 d post-MI. Bax knockout mice hearts demonstrated reduced infarct size and improved myocardial function following permanent coronary artery occlusion. The Bax gene appears to play a significant role in the post-MI response that should be further investigated.
  Cell Biochemistry and Biophysics 01/2007; 47(1):11-20. · 3.74 Impact Factor
• Article: Cathepsin B inactivation attenuates the apoptotic injury induced by ischemia/reperfusion of mouse liver.

  Z Ben-Ari, E Mor, D Azarov, J Sulkes, R Tor, Y Cheporko, E Hochhauser, O Pappo
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  ABSTRACT: A major mechanism underlying warm ischemia/reperfusion (I/R) injury during liver transplantation is the activation of the caspase chain, which leads to apoptosis. Recently, it was demonstrated that the release of cathepsin B, a cysteine protease, from the cytosol in liver injury induces mitochondrial release of cytochrome c and the activation of caspase-3 and -9, thereby leading to apoptosis. The aim of this study was to ascertain if cathepsin B inactivation attenuates the apoptotic injury due to I/R in mouse liver. A model of segmental (70%) hepatic ischemia was used. Eighteen mice were anesthetized and randomly divided into three groups: (1) Control group: sham operation (laparotomy); (2) Ischemic group: midline laparotomy followed by occlusion of all structures in the portal triad to the left and median lobes for 60 min (ischemic period); (3) Study group: like group 2, but with intraperitoneal administration of a pharmacological inhibitor of cathepsin B (4 mg/100 g) 30 min before induction of ischemia. Serum liver enzyme levels were measured by biochemical analysis, and intrahepatic caspase-3 activity was measured by fluorometric assay; apoptotic cells were identified by morphological criteria, the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) fluorometric assay, and immunohistochemistry for caspase-3. Showed that at 6 h of reperfusion, there was a statistically significant reduction in liver enzyme levels in the animals pretreated with cathepsin B inhibitor (p<0.05). On fluorometric assay, caspase-3 activity was significantly decreased in group 3 compared to group 2 (p<0.0001). The reduction in postischemic apoptotic hepatic injury in the cathepsin B inhibitor -treated group was confirmed morphologically, by the significantly fewer apoptotic hepatocyte cells detected (p<0.05); immunohistochemically, by the significantly weaker activation of caspase-3 compared to the ischemic group (p<0.05); and by the TUNEL assay (p<0.05). The administration of cathepsin B inhibitor before induction of ischemia can attenuate postischemic hepatocyte apoptosis and thereby minimize liver damage. Apoptotic hepatic injury seems to be mediated through caspase-3 activity. These findings have important implications for the potential use of cathepsin B inhibitors in I/R injury during liver transplantation.
  APOPTOSIS 12/2005; 10(6):1261-9. · 4.79 Impact Factor
• Article: Effect of adenosine A2A receptor agonist (CGS) on ischemia/reperfusion injury in isolated rat liver.

  Z Ben-Ari, O Pappo, J Sulkes, Y Cheporko, B A Vidne, E Hochhauser
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  ABSTRACT: Ischemia/reperfusion injury during liver transplantation is a major cause of primary nonfunctioning graft for which there is no effective treatment other than retransplantation. Adenosine prevents ischemia-reperfusion-induced hepatic injury via its A2A receptors. The aim of this study was to investigate the role of A2A receptor agonist on apoptotic ischemia/reperfusion-induced hepatic injury in rats. Isolated rat livers within University of Wisconsin solution were randomly divided into four groups: (1) continuous perfusion of Krebs-Henseleit solution through the portal vein for 165 minutes (control); (2) 30-minute perfusion followed by 120 minutes of ischemia and 15 minutes of reperfusion; (3) like group 2, but with the administration of CGS 21680, an A2A receptor agonist, 30 microg/100 ml, for 1 minute before ischemia; (4) like group 3, but with administration of SCH 58261, an A2A receptor antagonist. Serum liver enzyme levels were measured by biochemical analysis, and intrahepatic caspase-3 activity was measured by fluorometric assay; apoptotic cells were identified by morphological criteria, the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) fluorometric assay, and immunohistochemistry for caspase-3. Results showed that at 1 minute of reperfusion, there was a statistically significant reduction in liver enzyme levels in the animals pretreated with CGS (p < 0.05). On fluorometric assay, caspase-3 activity was significantly decreased in group 3 compared to group 2 (p < 0.0002). The reduction in postischemic apoptotic hepatic injury in the CGS-treated group was confirmed morphologically, by the significantly fewer apoptotic hepatocyte cells detected (p < 0.05); immunohistochemically, by the significantly weaker activation of caspase-3 compared to the ischemic group (p < 0.05); and by the TUNEL assay (p < 0.05). In conclusion, the administration of A2A receptor agonist before induction of ischemia can attenuate postischemic apoptotic hepatic injury and thereby minimize liver injury. Apoptotic hepatic injury seems to be mediated through caspase-3 activity.
  APOPTOSIS 11/2005; 10(5):955-62. · 4.79 Impact Factor
• Article: TPEN attenuates hepatic apoptotic ischemia/ reperfusion injury and remote early cardiac dysfunction.

  E Hochhauser, Z Ben-Ari, O Pappo, Y Chepurko, B A Vidne
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  ABSTRACT: The release of cardioactive substances during hepatic ischemia/reperfusion injury generates toxic free radicals that inflict hepatic and remote cardiac damage. The aim of the study was to determine whether TPEN, a potent iron chelator, ameliorates the apoptotic hepatic and cardiac function injuries. Three groups of isolated rat livers were studied: (1) continuously perfused with Krebs-Henseleit solution; (2) subjected to 120 min of ischemia and 15 min of reperfusion; (3) as in group 2, with TPEN administered prior to ischemia. Isolated hearts were perfused for 65 min with the effluent of the reperfused livers. Results showed that TPEN administration reduced the release of norepinephrine, epinephrine, dopamine, prostaglandin E2 and angiotensin II, decreased intrahepatic caspase-3 activity, and decreased the mean hepatocyte apoptotic index (TUNEL assay) (p = 0.001). Perfusion with post-ischemic hepatic effluent caused a transient 15-min increase in left ventricular contraction and coronary flow (p < 0.05), followed by a decrease in cardiac function at one hour. TPEN reduced the transient elevation in left ventricular contraction p < 0.05), but did not prevent the subsequent decrease in cardiac function. In conclusion, TPEN attenuates post-ischemic apoptotic hepatic injury by modulating caspase-3-like activity and reduces the cardioactive substances released from the liver.
  APOPTOSIS 02/2005; 10(1):53-62. · 4.79 Impact Factor
• Article: Effects of vasoactive substances released from ischemic reperfused liver on the isolated rat heart.

  E Hochhauser, I Alterman, A Weinbroum, Y Barak, D Harell, A Raz, A Erman, B Vidne
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  ABSTRACT: Cardiovascular dysfunction frequently occurs after major vascular surgery or liver transplantation. To evaluate the effects on myocardial activity of vasoactive agents released from ischemic-reperfused liver. Isolated rat livers were perfused with Krebs-Henseleit solution (KH), propranolol 10(-5) M, losartan 2x10(-5) M and indomethacin 10(-5) M, then made globally ischemic for 120 min (37 degrees C) and reperfused. Isolated hearts from other rats were stabilized with KH and reperfused for 15 min with the perfusate exiting the livers. Livers were disconnected, and the hearts continued to be recirculated with the accumulated liver and heart effluent for an additional 50 min. Enzyme leakage, different vasoactive substances, left ventricular developed pressure (LVP) and coronary flow were measured during the experimental protocol. Hepatic release of adrenaline, noradrenaline, angiotensin II, prostaglandin E(2) and thromboxane B(2) was significantly increased in the liver effluent following ischemia. When this effluent was directed to the heart, LVP was significantly raised in the first 10 min of reperfusion (137+/-5%) followed by marked decreased (46+/-6%) during the following 65 min of myocardial reperfusion. In the ischemic-reperfused drug-treated groups, the initial positive effect on LVP was milder than in controls (propranolol 112+/-12%, losartan 111+/-11%, indomethacin 113+/-9%) and the final LVP was lower (propranolol 29+/-6%, losartan 27+/-7% [P<0.05 versus ischemic control], indomethacin 46 +/-12%). During the initial phase of reperfusion, vasoactive substances released in the hepatic effluent potentiated LVP of the hearts exposed to this effluent. When the three inhibitory drugs were added to KH, this initial augmentation was not sustained. Propranolol and losartan, but not indomethacin, further depressed LVP. Vasoactive substances released from ischemic reperfused livers directly influenced heart function.
  Experimental and clinical cardiology 01/2001; 6(1):29-34. · 0.58 Impact Factor
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  Available from: Avi A Weinbroum

  Article: The influence of aprotinin on myocardial function after liver ischemia-reperfusion.

  O Madhala-Givon, E Hochhauser, A Weinbroum, Y Barak, T Krasnov, S Lelcuk, D Harell, B Vidne
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  ABSTRACT: The beneficial effect of aprotinin, a naturally occurring protease inhibitor, on preservation of organs such as the liver, kidney and lung has been documented. To explore the effects of hepatic ischemia and reperfusion on both liver and myocardial function, using a dual isolated perfused organ model with and without aprotinin. Isolated rat livers were stabilized for 30 minutes with oxygenated modified Krebs-Henseleit solution at 37 degrees C. Livers were then perfused continuously with KH or KH + aprotinin 10(6) KIU/L for an additional 135 min. Livers of two other groups were made globally ischemic for 120 min, then perfused for 15 min with KH or with KH + aprotinin. Isolated hearts (Langendorff preparation) were stabilized for 30 min and then reperfused with KH or KH + aprotinin exiting the liver for 15 min. The liver's circuit was disconnected, and hearts were re-circulated with the accumulated liver + heart effluent for an additional 50 min. In the ischemia and ischemia + aprotinin groups, portal vein pressure (1 and 15 min reperfusion) was 331 +/- 99% and 339 +/- 61% vs. 308 +/- 81% and 193 +/- 35% of baseline, respectively (P < 0.03 vs. ischemia). There were no other differences in the enzyme leakage between aprotinin-treated or untreated ischemic livers. Left ventricular pressure was stable in the controls. However, LV pressure in groups perfused with ischemic liver effluent declined within 65 min reperfusion, whether aprotinin treated or not (84 +/- 8% and 73 +/- 5% of baseline, respectively, P < 0.004 only for ischemia vs. control). When aprotinin was used, LV pressure was inclined to be higher while liver portal vein pressure was lower, thus providing protection against liver and heart reperfusion injury.
  The Israel Medical Association journal: IMAJ 06/2000; 2(6):450-4. · 1.02 Impact Factor
• Article: Multiple organ dysfunction after remote circulatory arrest: common pathway of radical oxygen species?

  A A Weinbroum, E Hochhauser, V Rudick, Y Kluger, E Karchevsky, E Graf, B A Vidne
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  ABSTRACT: Cardiovascular, respiratory, and vascular dysfunction can follow trauma-induced no-flow-reflow states: hemorrhage, blunt trauma, or neurogenic shock. Liver ischemia-reperfusion (IR) induces remote lung damage by means of xanthine oxidase (XO) pro-oxidant activity. This damage was not proven in the heart, neither was the independent role of radical oxygen species (ROS) established in such cases. We investigated whether multiple organ dysfunction after a trauma-like IR is XO and ROS related and whether clinically used ROS scavengers could be beneficial. A controlled, randomized trial in which isolated rat livers, hearts, lungs, and aortic rings were perfused with Krebs-Henseleit solutions. After stabilization, livers were either perfused or made ischemic (2 hours). Then, pairs of liver plus heart, lung, or ring were reperfused in series (15 minutes), and then the second organ circulated alone for 45 minutes. Remote organ protection against the pro-oxidant hepatic-induced toxicity was evaluated by using allopurinol (1 mmol/L, heart), mannitol (0.25 g/kg, lung), or methylene blue (40 mg/kg, ring). IR liver effluents typically contained high lactate dehydrogenase, XO, and uric acid concentrations compared with control organs. IR was associated with doubled lung peak inspiratory pressure and reduced static compliance. Myocardial velocity of contraction and relaxation decreased by one third of baseline, and rings contracted abnormally and responded inadequately to phenylephrine. Wet-weight to dry-weight ratios in the remote organs increased as well. Most remote reperfusion injuries were attenuated by the drugs. Liver no-flow-reflow directly induces myocardial, pulmonary, and vascular dysfunction. These are likely mediated by XO and ROS. The tested drugs protected against these pro-oxidants, even in the presence of circulating XO.
  The Journal of trauma 11/1999; 47(4):691-8. · 2.48 Impact Factor
• Article: Isoflurane and sodium nitroprusside reduce the depressant effects of protamine sulfate on isolated ischemic rat hearts.

  E Hochhauser, P Halpern, V Zolotarsky, T Krasnov, J Sulkes, B Vidne
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  ABSTRACT: The administration of protamine sulfate (protamine) to reverse the action of heparin is associated with adverse reactions. We studied the effects of protamine and isoflurane on isolated, perfused rat hearts previously subjected to cardioplegic ischemia. Hearts were perfused with oxygenated Krebs-Henseleit (KH) solution for 30 min, then subjected to cardioplegic ischemia for 30 min (KCl 16 mEq/L at 31 degrees C) and 5 min reperfusion. Drug exposure lasted 15 min, and the recovery period was 60 min. Test groups were control, protamine (10 microg/mL), isoflurane (1.5%), protamine +/- isoflurane, sodium nitroprusside (SNP) (2.5 ng/mL), and SNP +/- protamine. Left ventricular developed pressure (LVP), coronary flow, and myocardial oxygen consumption were depressed by protamine to 30% +/- 4%, 47% +/- 4%, and 39% +/- 4% of baseline (P < 0.001 versus control), respectively. Isoflurane and SNP afforded partial protection from the effects of protamine: LVP was 57% +/- 5% and 51% +/- 3% of baseline, respectively (P < 0.05 versus protamine alone and control); coronary flow was 70% +/- 6% and 97% +/- 12% of baseline, respectively (P < 0.05 versus protamine alone; P < 0.05 for isoflurane versus control); and O2 consumption was 69% +/- 6% and 88% +/- 15% of baseline, respectively (P < 0.05 versus protamine; P < 0.05 for isoflurane versus control). In this model, protamine-induced myocardial depression and coronary vasoconstriction were less pronounced in the presence of either isoflurane or SNP. Implications: We examined the interactions of isoflurane, sodium nitroprusside, and protamine in a rat heart model and found that both isoflurane and sodium nitroprusside partially protect the heart from the depressant effects of protamine. This finding is significant, as these drugs are often used in heart surgery.
  Anesthesia & Analgesia 05/1999; 88(4):710-6. · 3.29 Impact Factor
• Article: Mediation of Multiple Organ Dysfunction By Radical Oxygen Species Following Remote Circulatory Arrest. Common Mechanism of Action?

  A Weinbroum, E Hochhauser, Y Kluger, B Vidne, V Rudick
  The Journal of Trauma and Acute Care Surgery. 11/1998; 45(6):1117.
• Article: Direct induction of acute lung and myocardial dysfunction by liver ischemia and reperfusion.

  A A Weinbroum, E Hochhauser, V Rudick, Y Kluger, P Sorkine, E Karchevsky, E Graf, P Boher, R Flaishon, D Fjodorov, D Niv, B A Vidne
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  ABSTRACT: To investigate whether liver ischemia and reperfusion (IR) directly affect functions of remote organs. Cardiovascular and respiratory dysfunction follows hemorrhage, spinal shock, or trauma as a result of no-flow-reflow phenomena. Hepatic IR induces remote organ damage probably by xanthine oxidase and oxygen species. Isolated rat livers, lungs, and hearts were perfused with Krebs-Henseleit solutions. After stabilization, livers were either perfused or made ischemic. Then, livers and hearts or livers and lungs were reperfused in series, and the liver was disconnected and the second organ continued to perfuse with the accumulated effluents. Ischemic and reperfused liver effluent contained high lactate dehydrogenase and uric acid concentrations compared with controls; xanthine oxidase increased 60 to 100 times. Ischemic and reperfused lung peak inspiratory pressure almost doubled; airway static compliance halved; myocardial contractility decreased to 70% of baseline; wet weight-to-dry weight ratios of lungs and livers increased. Ischemic and reperfused liver can directly induce myocardial and pulmonary dysfunction, presumably by oxidant-induced injury.
  The Journal of trauma 11/1997; 43(4):627-33; discussion 633-5. · 2.48 Impact Factor
• Article: The isolated post ischaemic rat heart is more vulnerable to protamine sulphate than the non-ischaemic heart.

  P Halpern, E Hochhauser, A Puzhevsky, V Rudick, P Sorkine, B Vidine
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  ABSTRACT: Protamine sulphate is currently used for the reversal of heparin anticoagulation but is known to cause direct myocardial depression. The purpose of this study was to compare the effects of protamine sulphate on the isolated heart with and without cardioplegic ischaemia. Isolated rat hearts (Langendorff preparation) were electrically paced at 300 beats/min and perfused with Krebs-Henseleit solution. Five groups were tested: (1) control: no ischaemia, no protamine; (2) no ischaemia, protamine; (3) no ischaemia, protamine (time-matched control to groups 4 and 5); (4) control: ischaemia, no protamine; and (5) ischaemia, protamine. Protamine sulphate was infused for 15 min at 10 microg/ml. In groups 4 and 5, cardioplegic ischemia was maintained for 30 min at 30 degrees C before protamine exposure. Protamine decreased myocardial performance in a time- and dose-dependent manner. Protamine depressed mean (s.d.) myocardial left ventricular pressure in both non-ischaemic hearts (groups 2 and 3, to 49(4)% and 50(4)% from baseline, respectively) and post ischaemic hearts (group 5, to 28(8%). Mean (s.d.) left ventricular-developed pressure only partially recovered after protamine in post-ischaemic hearts (to 55(13)% of baseline) compared with full recovery of the non-ischaemic group. Protamine depressed coronary flow to 70(5)% and 74(8)% in non-ischaemic hearts (groups 2 and 3, respectively) and to 58(7)% in group 5. Coronary flow recovered completely at the end of the experiments in all protamine-treated groups. In conclusion, isolated rat hearts subjected to cardioplegic ischaemia are more vulnerable to protamine than are non-ischaemic hearts.
  Cardiovascular Surgery 05/1997; 5(2):235-40.
• Article: Role of protease inhibition in myocardial preservation following ischemia and reperfusion.

  J Gurevitch, Y Paz, J Barak, M Matsa, A Kramer, D Pevni, E Hochhauser, V Yakirevich
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  ABSTRACT: Aprotinin, a naturally occurring protease inhibitor, in concentrations of 10(6) KIU/L was found to have no effect on myocardial performance in normally perfused isolated rat hearts, before ischemia. Given during the preischemic period, the drug had a significant protective effect on the reperfused hearts, following cardioplegic ischemia: better contractility upon reperfusion (p < 0.011), faster decline of the ischemic contracture, higher coronary flow (p < 0.025), lower AV-difference (p < 0.05), and lower CPK levels (p < 0.01).
  The Journal of cardiovascular surgery 01/1995; 35(6 Suppl 1):95-8. · 1.56 Impact Factor
• Article: Aprotinin improves myocardial recovery after ischemia and reperfusion. Effects of the drug on isolated rat hearts.

  J Gurevitch, J Barak, E Hochhauser, Y Paz, V Yakirevich
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  ABSTRACT: The effects of aprotinin, a protease inhibitor, on the ischemic and nonischemic isolated rat heart was investigated with the use of the modified Langendorff model. During phase I of the study, hearts were perfused with either low-dose aprotinin (10(5) KIU/L), high-dose aprotinin (10(6) KIU/L), or normal saline solution added to modified Krebs-Henseleit solution. No statistically significant differences in contraction amplitude, contractility, coronary flow, and wet/dry heart weight ratio were observed among the three groups of hearts. In phase II, hearts were exposed to a 40-minute period of global ischemia at 31 degrees C. Ischemic arrest was induced by warm cardioplegia. Before ischemia and during cardioplegia, hearts were perfused with either aprotinin 10(6) KIU/L (n = 10) or normal saline solution (n = 10) for 30 minutes. On reperfusion, recovery of hearts treated with aprotinin was significantly better than that of control hearts, as reflected by better contractility (analysis of variance, p = 0.011), higher coronary flow (p < 0.025), and lower creatine kinase levels (p < 0.05). No statistically significant differences in contraction amplitude were observed between the two groups. When the effect of ischemia within each group of hearts was analyzed, the preserving effect of aprotinin was even more pronounced. In the control group, ischemia caused a decrease in contractility (p < 0.025) and a decrease in oxygen consumption (p = 0.006); by contrast, in the aprotinin group the preischemic values were maintained. Accordingly, we conclude that aprotinin at concentrations up to 10(6) KIU/L has no deleterious effect on normally perfused hearts and has a significant protective effect on the ischemic heart when used in high doses in the preischemic period.
  Journal of Thoracic and Cardiovascular Surgery 07/1994; 108(1):109-18. · 3.41 Impact Factor
• Article: Ro 5-4864 has a negative inotropic effect on human atrial muscle strips that is not antagonized by PK 11195.

  E Shany, E Hochhauser, P Halpern, B Vidne, M Gavish, E Geller, A Hasharoni, Y Barak, V Yakirevich
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  ABSTRACT: The effects of Ro 5-4864, a peripheral benzodiazepine receptor agonist (9 x 10(-6) M and 9 x 10(-5) M) and of PK 11195, a peripheral benzodiazepine receptor antagonist (3 x 10(-6) M and 3 x 10(-5) M), alone or together, on contraction parameters of human atrial muscle strips were studied. Atrial muscle strips were obtained from patients undergoing cardiac surgery. The strips were suspended in Krebs-Henseleit solution at 36.8 +/- 0.2 degrees C, connected to an isometric force transducer and then stimulated at 15 V above threshold and paced at 1.5 Hz. Ro 5-4864 at its higher concentration, alone or mixed with PK 11195 at both concentrations, depressed the contraction amplitude to 80% of the control value (P < 0.05). In conclusion, Ro 5-4864 had a small but significant depressant effect on the contraction amplitude of human atrial strips. Surprisingly, this effect was not reversed by the peripheral benzodiazepine receptor antagonist PK 11195.
  European Journal of Pharmacology 04/1994; 253(3):231-6. · 2.52 Impact Factor
• Article: The effect of vitamin D3 deficiency on the isolated chick heart: hemodynamic, P-31 NMR and membrane studies.

  E Hochhauser, T Kushnir, G Navon, M Rehavi, J Barak, S Edelstein, B Vidne
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  ABSTRACT: The purpose of this study was to investigate whether vitamin D3 deficiency affects the cardiac function of chick hearts directly or whether the influence is secondary through the hormone's effect on serum calcium levels. To this end, three experimental groups were studied: (a) the control group of vitamin D3 supplemented chicks, Ds, (b) vitamin D3 deficient chicks, Dd, and (c) vitamin D3 supplemented hypocalcemic chicks raised on decreased calcium levels, Dh. The three groups were compared by checking hemodynamic, metabolic and membrane parameters. Total and ionized serum calcium concentrations in the Dh and Dd groups were found to be lower than in the Ds group. Perfusion of the isolated hearts with solutions containing various calcium concentrations (1, 1.5 and 2.5 mM) induced enhanced contractility levels, the magnitude of which was dependent on the difference between the in vivo and perfusate calcium levels. Thus, the inotropic effect was similar and more enhanced for the two hypocalcemic groups. The differences in hemodynamic behaviour could not be explained by variations in the levels of the high energy compounds and acidity, since similar ATP, creatine phosphate and intracellular pH levels were detected for both Ds and Dd groups. However, membrane studies revealed an increase in the number of slow calcium channels for the two hypocalcemic groups and this may be the possible mechanism for the differences in the contractile activity. In conclusion, our study strongly suggests that the effects of vitamin D3 on the heart is mediated only indirectly through its effect on serum calcium levels.
  Journal of Molecular and Cellular Cardiology 02/1993; 25(1):93-102. · 5.17 Impact Factor
• Article: The effects of halothane, enflurane and isoflurane on the isolated rat heart recovering from cardioplegic arrest.

  D Ogorek, E Hochhauser, E Geller, B Vidne, P Halpern, Y Barak, V Yakirevich
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  ABSTRACT: The direct cardiac effects of volatile anesthetics following cardioplegic ischemia were investigated in isolated, paced rat hearts. In one series of experiments, the hearts were perfused with oxygenated Krebs Henseleit solution for a 15-minute stabilization period and then the effect of the volatile anesthetic was tested. In another series of experiments, after the stabilization period, the hearts were subjected to cardioplegic (KCl 20mEq/L) ischemia at 30 degrees C for 30 minutes and then the effect of the volatile anesthetic was tested. Halothane, enflurane or isoflurane was introduced to the Krebs Henseleit solution at 0.7 and 1.4 minimal alveolar concentration. All the volatile anesthetics decreased myocardial contractility in a dose dependent manner both before and after cardioplegic arrest. Halothane decreased coronary flow, while isoflurane and enflurane increased coronary flow in both the cardioplegic and non-cardioplegic hearts. The influence of the anesthetics was transient and ceased once they were withdrawn. Ischemic cardioplegia did not affect the response to volatile anesthetics.
  Cardioscience 10/1992; 3(3):173-7.
• Article: Mechanical, biochemical, and structural effects of vitamin D deficiency on the chick heart.

  E Hochhauser, J Barak, T Kushnir, G Navon, M S Meyer, S Edelstein, M B Ben Bassat, B A Vidne
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  ABSTRACT: The effects of vitamin D deprivation on the chick heart were investigated from three aspects: cardiac contractility (+/- dP/dT), intracellular high-energy phosphorus compounds, and structural differences. Four-week-old vitamin D-deficient chicks were divided into four groups: Group A served as the normal group and received subcutaneous injections of cholecalciferol; Groups B and C were vitamin D-deficient hearts but perfused differently; Group D received daily subcutaneous injections of 5 micrograms of 1,25(OH)2D3. When the isolated spontaneously beating hearts (modified Langendorff preparation) were perfused with Krebs-Henseleit (KH) solution containing a calcium concentration of 2.5mM, the myocardial contractility of the vitamin D-deficient hearts was significantly increased when compared with group A. After the isolated heart had beaten for one hour, the myocardial contractility in the vitamin D-deficient hearts was found to decline to significantly lower values. Presacrifice administration of 1,25(OH)2D3 improved cardiac performance. Vitamin D deficiency resulted in an enhanced rate of decline of the intracellular high-energy phosphorus compounds. No differences were found in the microscopic study. These observations suggest that vitamin D has a role in cardiac function.
  Angiology 05/1989; 40(4 Pt 1):300-8. · 1.51 Impact Factor