raffinose and diacetylmonoxime

Right heart dysfunction is a major cause for early morbidity and mortality after heart transplantation. Experiments were designed to evaluate the influence of the calcium-desensitizing drug 2,3-butanedione 2-monoxime (BDM) on right heart function in a porcine model of heart transplantation.. Donor hearts of domestic pigs were arrested with BDM in Krebs solution (n = 7) and with BDM in Bretschneider's histidine-tryptophan-ketoglutarate (HTK) solution (n = 6). There were 2 control groups: University of Wisconsin (UW, n = 6) and HTK (n = 6). An isovolumic model was used in which the right ventricular volume was precisely controlled in vivo with an intracavitary high-compliance balloon. After 4 hours of ischemia, hearts were transplanted into recipients. After 1 and 2 hours of reperfusion, the right ventricular balloon volume was increased in 10-mL increments until right ventricular failure occurred and the developed pressures were recorded.. Maximal right ventricular developed pressures were significantly different after 2 hours of reperfusion (UW: 35 +/- 13 mm Hg; HTK: 47 +/- 8 mm Hg; Krebs+BDM: 49 +/- 9 mm Hg; HTK+BDM: 50 +/- 6 mm Hg; P =.04). Hearts subjected to BDM could be loaded with a significantly increased volume after 1 hour and after 2 hours (UW: 57 +/- 10 mL vs HTK: 43 +/- 8 mL vs Krebs+BDM: 70 +/- 10 mL vs HTK+BDM: 67 +/- 15 mL; P =.002). Postischemic right ventricular enddiastolic compliance was significantly increased in groups treated with BDM after 1 hour (P =.02) and after 2 hours (P =.039).. The drug BDM significantly improves right ventricular function in a heart transplantation model. The increase in volume load and developed right ventricular pressure achieved by BDM application would translate into a decreased risk of right ventricular failure after clinical transplantation.

Topics: Adenosine; Allopurinol; Animals; Calcium; Creatine Kinase; Creatine Kinase, MB Form; Diacetyl; Glucose; Glutathione; Heart Transplantation; Insulin; Isoenzymes; Isotonic Solutions; Lactic Acid; Mannitol; Myocardium; Organ Preservation; Organ Preservation Solutions; Potassium Chloride; Procaine; Raffinose; Swine; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Pressure

A limitation to fully using lung transplantation for patients with end-stage lung diseases is short, safe preservation time (4 to 6 hours). Our goal is to extend this to 24 hours or more, which would greatly improve clinical lung transplantation.. We used the isolated perfused rat lung to test how two preservation solutions (low potassium dextran and University of Wisconsin solution) affected quality of lungs after 6, 12, and 24 hours of preservation. Also, we tested modifications of the University of Wisconsin solution, including reversing the ratio of Na/K, the addition of 1.5 mmol/L calcium, and the combination of calcium and butanedione monoxime, agents that improve cardiac preservation. After preservation at 4 degrees C, lungs were reperfused at 37 degrees C with a physiologically balanced solution. Pulmonary artery flow rate, airway peak inspiratory pressure, and tissue edema were used to assess degree of preservation and reperfusion injury.. Low potassium dextran solution gave poor preservation (decreased pulmonary artery flow, tissue edema) after 12 hours of cold storage. There were no differences between regular and reversed Na/K ratio University of Wisconsin solutions at 12 or 24 hours of preservation. Addition of calcium had no beneficial effect on lung preservation. However, University of Wisconsin solution with calcium and butanedione monoxime gave excellent 24-hour cold storage, with pulmonary artery flow rate, tissue edema, and airway peak inspiratory pressure equal to control (0 hours of preservation) lungs.. The University of Wisconsin solution appears capable of lung preservation for up to 24 hours if modified to contain calcium and butanedione monoxime. The mechanism of action of butanedione monoxime may be related to the suppression of smooth muscle contraction resulting in vasodilation of the cold-stored lung on reperfusion.

Topics: Adenosine; Allopurinol; Animals; Calcium; Diacetyl; Glutathione; In Vitro Techniques; Insulin; Lung; Male; Muscle Contraction; Organ Preservation; Organ Preservation Solutions; Raffinose; Rats; Rats, Sprague-Dawley; Time Factors; Vasodilation

To minimize decreases in left ventricular (LV) compliance immediately after rat heart transplantation, we tested several different methods of myocardial protection.. Five groups of ACI rat hearts (n = 6 each) were arrested by coronary perfusion with 5 ml of UW (University of Wisconsin), UW-BDM (UW with 2,3-butanedione monoxime), CU (Columbia University), or CU-BDM solution or by LV injection of potassium chloride and Ringer's lactate immersion (KCl/RL). After abdominal isografting and blood reperfusion for 15 min, transplanted hearts (TxH) were arrested and excised. Diastolic LV pressure-volume curves (LVPVCs) were correlated with myocardial water content (MWC). Native hearts (NH) were arrested identically to TxH and maintained at 4 degrees C by immersion. LVPVCs were measured at 15-min intervals for 90 min.. In three of four pressure intervals at Time 0, normalized LV volume (LVV) was smaller (P < 0.05, ANOVA) in KCl/RL native hearts than in the four perfusion groups. LVV decreased significantly in NH after 45-75 min; LVV decreased similarly with time in all groups. In TxH, postarrest LVVs were higher with UW-BDM, CU-BDM, and CU than with UW or KCl/RL (P < 0.05, ANOVA). Expressing LVV of TxH as a percentage of NH, UW-BDM, CU, and CU-BDM provided qualitatively better diastolic properties than KCl/RL and UW.. Thus rat LVPVCs can be improved after heart transplantation with alternative strategies of myocardial protection. KCl arrest decreases LV filling volume in this model and should be avoided.

Topics: Abdomen; Adenosine; Allopurinol; Animals; Blood Pressure; Blood Volume; Diacetyl; Glutathione; Heart Arrest, Induced; Heart Transplantation; Insulin; Isotonic Solutions; Myocardial Reperfusion; Organ Preservation Solutions; Potassium Chloride; Raffinose; Rats; Rats, Inbred ACI; Ringer's Lactate; Transplantation, Heterotopic; Ventricular Function, Left

The optimal temperature for cardiac allograft storage remains controversial. We conjectured that supplementation of the potent cardioprotective agent 2,3-butanedione monoxime with calcium may improve allograft storage and make the precise storage temperature less critical.. Hearts were harvested from Sprague-Dawley rats (250 to 350 g), mounted on a Langendorff apparatus, and instrumented with an intraventricular balloon. Hearts were flushed and stored with either unmodified University of Wisconsin solution (UWS) or UWS supplemented with 10 mmol/L of 2,3-butanedione monoxime and calcium 0.1 mmol/L (BDM). Hearts were then subjected to 12 hours of storage at one of five temperatures (0 degree, 4 degrees, 8 degrees, 12 degrees, or 16 degrees C) in a complete 2 x 5 factorial design (n = 6/group). Data are reported either as a percentage of the prestorage results or as an absolute value (mean +/- standard deviation).. Recovery of developed pressure (p < 0.0001), coronary flow (p < 0.0001), and diastolic volume (p < 0.001) were significantly enhanced, whereas creatine kinase (p < 0.0001) and lactate dehydrogenase release (p < 0.0001) were reduced in the BDM versus the UWS groups. In both the BDM and UWS storage groups, recovery was better at temperatures of 8 degrees C or less than at 12 degrees C or more. The single preferred temperature was 4 degrees C, significantly better than 0 degree C with unmodified UWS, while similar to 0 degree and 8 degrees C with BDM. Adenine nucleotide values were decreased equally in the BDM and UWS hearts, but preservation was enhanced at 0 degree C compared with all warmer temperatures.. We conclude that 4 degrees C is the preferred temperature for prolonged cardiac storage with UWS and that the inclusion of 2,3-butanedione monoxime with calcium 0.1 mmol/L markedly enhances recovery for storage temperatures of 8 degrees C or less.

Topics: Adenosine; Allopurinol; Animals; Cardioplegic Solutions; Diacetyl; Glutathione; Insulin; Organ Preservation; Organ Preservation Solutions; Raffinose; Rats; Rats, Sprague-Dawley; Temperature; Time Factors

The purpose of this study was to compare the effects of the University of Wisconsin solution plus butanedione monoxime, the University of Wisconsin solution without butanedione monoxime, and saline on the preservation of muscle tissue. Forty-nine rat hindlimbs were amputated and replanted. The study population was subdivided into four groups according to flushing solution, storage, and replantation protocols. The limbs of the control group (n = 12) were flushed with 20 ml University of Wisconsin solution and immediately replanted onto the same rat. In the remaining three groups, the limbs were immersed in solution, stored in a refrigerator at 4 degrees C for 24 hours, and then replanted onto a fresh rat. The limbs in the no flushout group (n = 7) were placed into storage in cold saline solution without being flushed. The limbs in the University of Wisconsin solution group (n = 17) were flushed with 20 ml of University of Wisconsin solution prior to storage, and those in the University of Wisconsin solution plus butanedione monoxime group (n = 13) were flushed with 20 ml University of Wisconsin solution plus 20 mM butanedione monoxime. Limb survival rate was 100 percent for the control and University of Wisconsin solution plus butanedione monoxime groups, 87 percent for the University of Wisconsin solution group, and 71 percent for the no flushout group. Seven days after replantation, ATP levels were 71 percent of control in the University of Wisconsin solution plus butanedione monoxime group, 33 percent in the University of Wisconsin solution group, and 29 percent in the no flushout group. Tissue K+/Na+ ratio showed that the University of Wisconsin solution plus butanedione monoxime group maintained electrolyte balance, whereas the balance was significantly lowered in University of Wisconsin solution and no flushout groups. The University of Wisconsin solution plus butanedione monoxime limbs did not exhibit cell swelling, whereas total tissue water values for the University of Wisconsin solution and no flushout groups increased significantly. Serum creatinine kinase, measured 24 hours after replantation, was 120 percent of control in the University of Wisconsin solution plus butanedione monoxime group, 550 percent in the University of Wisconsin solution group, and 772 percent in the no flushout group. Limbs in the University of Wisconsin solution plus butanedione monoxime group had more flexible ankle joints and pliable muscle (i.e., less contracture) tha

Topics: Adenine Nucleotides; Adenosine; Allopurinol; Animals; Cholinesterase Reactivators; Cold Temperature; Creatine Kinase; Diacetyl; Glutathione; Hindlimb; Insulin; Male; Muscle, Skeletal; Organ Preservation Solutions; Potassium; Raffinose; Rats; Rats, Inbred Lew; Replantation; Sodium; Time Factors

Currently, for clinical heart preservation with University of Wisconsin (UW) solution the ischemic time is limited to 8 h. The reliable preservation of the heart for 24 h or more would have a dramatic impact on the existing practice of cardiac transplantation. We showed previously [J. Thorac. Cardiovasc. Surg. 107; 764-775 (1994)] that experimentally preservation could be extended to 24-30 h by preventing ischemic contracture of the heart with 2, 3-butanedione monoxime (BDM) in the UW solution (UWBDM). This resulted in nearly 100% return of function as tested in the isolated crystalloid-reperfused rabbit heart in the nonworking Langendorff preparation. We have confirmed these results and now have measured the function of hearts stored in UWBDM for 2, 4, 12, and 24 h using the isolated working rabbit heart model. Preservation in UWBDM solution resulted in a biphasic decrease of cardiac output. In the hearts preserved for 2-12 h the decrease of function averaged 20-35% upon reperfusion, and the differences at 2, 4, or 12 h were not significant (analysis of variance p > 0.05). A more pronounced decrease of 64% was obtained after 24 h of cold storage. Hearts preserved for 24 h without BDM were practically nonfunctional. The release of enzymes (creatine kinase and lactate dehydrogenase) followed biphasic pattern similar to that of cardiac output: a small release between 2 and 12 h and larger, significant losses at 24 h. Although we originally proposed that hearts preserved with UWBDM for 24 h were well preserved (Langendorff model), we now show that poor function was obtained at 24 h. The difference was that in this study we used a more rigorous, isolated working rabbit heart model to test the function of the preserved heart, and this may be a better test of preservation quality.

Topics: Adenosine; Adenosine Triphosphate; Allopurinol; Animals; Cardiac Output; Cold Temperature; Diacetyl; Evaluation Studies as Topic; Glutathione; Heart; In Vitro Techniques; Insulin; Models, Biological; Organ Preservation; Organ Preservation Solutions; Rabbits; Raffinose; Time Factors

The University of Wisconsin solution modified with 2,3-butanedione monoxime and calcium experimentally extends the limits of ischemic preservation of the heart. This study evaluates other characteristics of this modified solution that may further enhance preservation: osmolarity, Mg2+ concentration ([Mg2+]), and pH. Rabbit hearts were flushed with the modified University of Wisconsin solution and stored for 40 hours at 4 degrees C. Maximal left ventricular developed pressure (LVDP), left ventricular end-diastolic volume (LVEDV), maximum rate of increase of left ventricular pressure (dP/dt), heart rate, and coronary flow were measured during 60 minutes of isolated crystalloid reperfusion with an isovolumic left ventricular balloon at constant end-diastolic pressure. Creatine kinase release and myocardial adenine nucleotide content were measured at completion of reperfusion. Solution osmolarity was tested at 357, 327, 297, and 277 mOsm/L by reducing K+, Na+, and lactobionate concentrations. [Mg2+] was assessed at 5 and 16 mmol/L. Solution pH was studied at 7.0, 7.4, and 7.8. A control group of hearts was flushed and immediately reperfused to establish baseline function. Hearts stored in either hypertonic (357 mOsm/L) or hypotonic (277 mOsm/L) solutions functioned poorly, reaching 58% and 50% of control LVDP (p < 0.001), 49% (p < 0.01), and 58% (p = not significant) of LVEDV, 56% and 49% of +dP/dt (p < 0.001), respectively, and released substantially more creatine kinase (p < 0.001 versus control).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Allopurinol; Animals; Calcium; Cardioplegic Solutions; Chromogenic Compounds; Creatine Kinase; Diacetyl; Glutathione; Heart Transplantation; Hydrogen-Ion Concentration; Insulin; Magnesium; Myocardial Contraction; Myocardium; Organ Preservation; Organ Preservation Solutions; Osmolar Concentration; Rabbits; Raffinose; Time Factors; Ventricular Function

The University of Wisconsin solution is an effective preservative for cold storage of the cardiac allograft. In an earlier study we showed that addition of calcium and 2,3-butanedione monoxime, a reversible inhibitor of myocardial contracture, further improved preservation of the rabbit heart. In this study we investigated the following: (1) the effects of different concentrations of 2,3-butanedione monoxime and calcium on function of the preserved rabbit heart, (2) how heart preservation is affected when 2,3-butanedione monoxime and calcium are added to the St. Thomas' Hospital and Stanford solutions, and (3) how 2,3-butanedione monoxime and calcium, at optimal concentrations in University of Wisconsin solution, affect hearts preserved up to 48 hours. Rabbit hearts were flushed with preservative and stored at 4 degrees C for 24, 30, 40, or 48 hours. Myocardial function was assessed during 60 minutes of isolated reperfusion, and myocardial adenine nucleotide content was measured after completion of reperfusion. Three concentrations of 2,3-butanedione monoxime (15, 30, and 60 mmol/L) in the University of Wisconsin solution were studied in hearts preserved for 30 hours. Storage with 2,3-butanedione monoxime at 30 mmol/L resulted in significantly better left ventricular developed pressure (p < 0.01), left ventricular end-diastolic volume (p < 0.01), rate of left ventricular pressure rise (p < 0.01), coronary flow (p < 0.05), rate-pressure product (p < 0.001), and adenine nucleotide regeneration (p < 0.05) than with 60 mmol/L, although function was not significantly different when the osmolarity of the solutions was equalized. There was significant reduction in end-diastolic volume (p < 0.05) and adenine nucleotide recovery (p < 0.01) when 2,3-butanedione monoxime was lowered to 15 mmol/L. Decreasing the calcium concentration from 1.0 to 0.1 mmol/L also had a deleterious effect on myocardial function (p < 0.05). The addition of 30 mmol/L 2,3-butanedione monoxime and 1.0 mmol/L calcium to the St. Thomas' or Stanford solutions improved preservation of the heart when compared with the unmodified solutions, but to a lesser degree than with the modified University of Wisconsin solution. After 24 to 48 hours of storage in University of Wisconsin solution containing 30 mmol/L 2,3-butanedione monoxime and 1.0 mmol/L calcium, there was substantial improvement in developed pressure (p < 0.001), end-diastolic volume (p < 0.05), and rate pressure product (p < 0.001), alt

Topics: Adenosine; Allopurinol; Animals; Bicarbonates; Calcium; Calcium Chloride; Cardioplegic Solutions; Diacetyl; Glutathione; Heart Transplantation; Insulin; Magnesium; Myocardial Contraction; Organ Preservation; Organ Preservation Solutions; Osmolar Concentration; Potassium Chloride; Rabbits; Raffinose; Sodium Chloride; Time Factors

Topics: Adenosine; Allopurinol; Animals; Cardiac Output; Diacetyl; Dobutamine; Glutathione; Heart; Insulin; Myocardial Reperfusion; Organ Preservation; Organ Preservation Solutions; Rabbits; Raffinose

Topics: Adenosine; Adenosine Triphosphate; Allopurinol; Analysis of Variance; Animals; Calcium; Cholinesterase Reactivators; Cold Temperature; Diacetyl; Diastole; Glutathione; Heart; Insulin; Organ Preservation; Organ Preservation Solutions; Rabbits; Raffinose; Solutions; Stroke Volume; Systole

Contracture of the arrested myocardium during prolonged storage of the heart results in both systolic and diastolic dysfunction, and is a major limitation to extended preservation. We studied the effects of a reversible contractile inhibitor, 2,3-butanedione monoxime (BDM), on myocardial ischemic tolerance. Isolated rabbit hearts were flushed with University of Wisconsin (UW) solution with and without 30 mmol/L BDM and 1 mmol/L CaCl, stored at 4 degrees C for 24 hours, and subsequently reperfused for 60 minutes. Left ventricular pressure-volume relationships and adenine nucleotide content were determined before reperfusion. Left ventricular systolic pressure, diastolic volume, and adenine nucleotide content were measured after reperfusion. Hearts stored in UW solution underwent contracture and adenosine triphosphate (ATP) depletion during storage, and exhibited systolic dysfunction, impaired diastolic relaxation, and poor ATP regeneration upon reperfusion. The addition of calcium worsened contracture and ATP depletion (p < 0.005) and slightly improved function and ATP regeneration (p = not significant). Hearts stored in the presence of BDM experience no contracture during storage; ATP was preserved (10.7 versus 15.7 nmol/mg; p < 0.05), and left ventricular systolic pressure and ATP content recovered to 74% and 93% of control on reperfusion, respectively (p < 0.005). Left ventricular diastolic volume remained depressed, however, although less than with UW solution (0.87 versus 0.45 mL; p < 0.001). When both BDM and calcium were included in the UW solution, calcium-stimulated ATP hydrolysis and contracture were prevented, left ventricular systolic pressure returned to 87% of control, and left ventricular diastolic volume and ATP content returned to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenine Nucleotides; Adenosine; Allopurinol; Animals; Calcium Chloride; Compliance; Coronary Circulation; Diacetyl; Glutathione; Heart Rate; Heart Ventricles; In Vitro Techniques; Insulin; Myocardial Ischemia; Myocardium; Organ Preservation; Organ Preservation Solutions; Rabbits; Raffinose; Solutions