Superior 12-hour heart preservation with pinacidil hyperpolarizing solution compared to University of Wisconsin solution.

BACKGROUND: novel donor heart preservation solution was formulated to produce hyperpolarized arrest with the potassium channel opener, pinacidil. The superior cardioprotective efficacy of this solution has been demonstrated previously when compared to University of Wisconsin solution following 4 hours of hypothermic ischemia. This study tested the hypothesis that pinacidil solution may extend preservation time and provide superior cardioprotective efficacy following 12 hours of ischemia. METHODS: Sixteen rabbit hearts were assigned to receive either pinacidil solution or University of Wisconsin solution in a crystalloid-perfused Langendorff model. Thirty minutes of initial perfusion preceded baseline data acquisition. Left ventricle pressure-volume curves were generated by inflating an intra-ventricular latex balloon. Following cardioplegic administration, hearts underwent 12 hours of hypothermic storage. After 60 minutes of reperfusion, post-ischemic data were acquired. RESULTS: Pinacidil solution demonstrated significantly better myocardial preservation compared to University of Wisconsin solution, with better recovery of developed pressure (53.0 +/- 11.1% vs 20.7 +/- 4.3%, p = 0.017, respectively), post-ischemic coronary flow (55.3 +/- 12.6% vs 23.9 +/- 4.3%, p = 0.034), maximum systolic dP/dT (46.4 +/- 8.3% vs 20.2 +/- 5.1%, p = 0.018) and minimum diastolic -dP/dT (65.3 +/- 10.8% vs 20.2 +/- 5.1%, p = 0.002). Diastolic compliance, expressed as baseline/post-ischemic diastolic slope ratios, was also better preserved by pinacidil solution (0.55 +/- 0.09) vs University of Wisconsin solution (0.40 +/- 0.03) (p = 0.135). CONCLUSIONS: A novel pinacidil solution resulted in improved donor heart preservation during 12 hours of hypothermic ischemia compared to the "gold standard," University of Wisconsin solution. Adopting alternative strategies of hyperpolarized arrest may allow extension of preservation time beyond the limits of traditional depolarizing solutions.

Modifications in surgical implantation of the Penn State electric total artificial heart.

BACKGROUND: Two modifications of the surgical implantation protocol for the Penn State Total Artificial Heart (ETAH) were evaluated: Phrenic nerve ischemia was prevented by minimizing dissection and traction; and hemostasis was augmented and ETAH cuff anastomoses reinforced by using fibrin glue. METHODS: Thirteen Holstein calves underwent orthotopic surgical implantation of the Penn State ETAH between February 1998 and August 2000. Mean hemodynamic and laboratory chemistry variables from the first postoperative week were compared between calves receiving the original (n = 7) and modified (n = 6) protocol. RESULTS: Calves assigned to the modified protocol displayed an improvement in the Po2/FiO2 ratio compared to original (419.4 +/- 17.5 vs 336.3 +/- 35.4, respectively; p = 0.05). All additional parameters were equivalent between groups. The percent survival of animals receiving the modified protocol at 2, 4, and 12 weeks was higher than that of animals that underwent the original protocol. Original-protocol calf deaths consisting of hemothorax (n = 3), and respiratory failure (n = 1) were prevented in the modified protocol. CONCLUSIONS: Our results suggest that manipulations in surgical protocol may promote increased survival in calves implanted with the Penn State ETAH.

Mechanisms responsible for cell volume regulation during hyperkalemic cardioplegic arrest.

BACKGROUND: Cardioplegia has been shown to induce significant cell swelling. This study tested the hypothesis that (1) the [K+][Cl-] product of the cardioplegia solution is the main determinant of myocyte swelling, and (2) reperfusion myocyte shrinkage results from a rectifying Cl- conductance. METHODS: Rabbit ventricular myocytes were superfused with 37 degrees C Krebs-Henseleit solution for 10 minutes. Then cells underwent 20 minutes of superfusion with standard St. Thomas' solution ([K+][Cl-] product = 2566 mmol/L2) and two solutions with lower [K+][Cl-] product (1500 and 700 mmol/L2) at 9 degrees C. Cells were then resuperfused with 37 degrees C Krebs-Henseleit solution for 30 minutes. Cell volume was measured by videomicroscopy. RESULTS: Cells superfused with St. Thomas' having [K+][Cl-] products of 2,566, 1,500, and 700 mmol/L2 swelled by 9.18%+/-3.57%, 5.51%+/-1.08%, and 1.49%+/-1.56%, respectively. Reexposure to Krebs-Henseleit solution caused these cells to shrink by 5.79%+/-1.41%, 8.72% +/-3.68%, and 13.46%+/-5.60%, respectively. This shrinkage was blocked by Cl- channel blockers given at the onset of superfusion. CONCLUSIONS: Lowering the [K+][Cl-] product of St. Thomas' solution attenuated myocyte edema. Myocyte shrinkage during reexposure to Krebs-Henseleit solution resulted from the volume-activated Cl- channel.

Donor heart preservation with a novel hyperpolarizing solution: superior protection compared with University of Wisconsin solution.

OBJECTIVES: A donor heart preservation solution was designed to use hyperpolarized arrest with the adenosine triphosphate-sensitive potassium-channel opener pinacidil. This solution contained concentrations of potassium, sodium, calcium, magnesium, lactobionate, and the buffer histidine specifically chosen to minimize intracellular calcium accumulation associated with prolonged ischemia. METHODS: Twenty-four rabbit hearts were randomly assigned to receive 1 of 3 preservation solutions in a crystalloid-perfused Langendorff model: (1) prototype solution containing a 0.5 mmol/L concentration of pinacidil, (2) prototype solution without pinacidil as control, and (3) University of Wisconsin solution. Thirty minutes of initial perfusion preceded baseline data acquisition. Data comprised left ventricle pressure-volume curves generated by inflating an intraventricular latex balloon. After cardioplegic administration, hearts underwent 4 hours of hypothermic storage, followed by 60 minutes of reperfusion and postischemic data acquisition. RESULTS: Postischemic developed pressure was better preserved by pinacidil solution (92.4% +/- 4.5%) than by the control (74.9% +/- 3.4%, P =.01) and University of Wisconsin solutions (66.7% +/- 5.1%, P =.001). Diastolic negative dP/dT was better preserved by pinacidil solution (104.4% +/- 10.2%) than by the control (80.2% +/- 4.2%, P =.034) and University of Wisconsin solutions (71.7% +/- 7.0%, P =.015). Diastolic compliance, expressed as baseline/postischemic diastolic slope ratios, was more poorly preserved by University of Wisconsin solution (0.67 +/- 0.07) than by the pinacidil (0.88 +/- 0.05, P =.041) and control solutions (0.87 +/- 0.05, P =.021). Postischemic coronary flow was higher in hearts exposed to pinacidil solution (77.8% +/- 3.0%) than in those exposed to the control (66.8% +/- 2.4%) and University of Wisconsin solutions (70.9% +/- 4.0%, P =.07). CONCLUSIONS: The superiority of the pinacidil solution in this experiment demonstrated that hyperpolarized arrest with potassium-channel openers improves donor heart preservation when administered in a novel histidine-buffered lactobionate-enriched vehicle.

Donor heart preservation with the potassium channel opener pinacidil: comparison with University of Wisconsin and St. Thomas' solution.

BACKGROUND: Hyperpolarized arrest with the potassium channel opener pinacidil has been shown to provide effective myocardial protection during short-term global ischemia. This study tested the hypothesis that pinacidil may provide effective long-term protection for heart transplant preservation. METHODS: Four concentrations of pinacidil (50 microM, 100 microM, 0.5 mM, 1.0 mM) mixed in Krebs-Henseleit solution were compared with University of Wisconsin and St. Thomas' Hospital solutions in a Krebs-Henseleit perfused rabbit Langendorff model (n = 6 for each group). Hearts underwent 4 hours of hypothermic (4 degrees C) storage. Over a wide range of volumes, left ventricular systolic function, diastolic compliance, and coronary flow were measured prior to and following storage. Time to mechanical and electrical arrest, and post-ischemic percent tissue water were also measured. RESULTS: Pinacidil 0.5 mM provided the best preservation of post-ischemic systolic function and coronary flow compared with the other pinacidil concentrations and was statistically equivalent to St. Thomas' solution in terms of post-ischemic systolic, diastolic, and flow properties. However, hearts protected with University of Wisconsin solution had significantly better preservation of systolic function and coronary flow. CONCLUSIONS: This investigation demonstrated that pinacidil in Krebs-Henseleit solution possesses efficacy in long-term donor heart preservation. Pinacidil was equivalent to St. Thomas' solution but inferior to University of Wisconsin solution. Hyperpolarized arrest with potassium channel openers may be a novel strategy to improve donor heart preservation.

Computer-assisted endoscopic coronary artery bypass anastomoses: a chronic animal study.

BACKGROUND: With traditional instruments, endoscopic coronary artery bypass grafting (ECABG) has not been possible. This study was designed to determine the feasibility of using a robotically-assisted microsurgical system to perform ECABG in a chronic animal model. METHODS: Nine calves were placed on cardiopulmonary bypass after harvesting the left internal mammary artery (LIMA). Subxiphoid endoscopic ports (2 instrument, 1 camera) were placed, and a robotic system was used to perform ECABG between the LIMA and left anterior descending coronary artery. LIMA graft flow (LIMAQ) was measured. Animals were sacrificed at 1 month, and hearts underwent angiographic and histologic analyses. RESULTS: Acute graft patency was 89% (8/9). Two animals died suddenly within the first 48 hours. There was no significant difference in mean acute and chronic (n = 6) LIMAQ (40.9+/-4.7 and 38.5+/-5.0 ml/min, respectively). Survivors had an angiographic patency rate of 100% (6/6), confirmed by histology. CONCLUSIONS: This study shows that ECABG is feasible in a chronic animal model with excellent results.

Convulsive effects of systemic administration of the delta opioid agonist BW373U86 in mice.

A systemically active, nonpeptidic delta receptor-selective agonist, (+-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl) -3- hydroxybenzyl)-N,N-diethylbenzamide (BW373U86), produced a brief, nonlethal convulsion in mice. The behavioral pattern of convulsion produced by pentylenetetrazol was similar to that produced by systemic administration of BW373U86. Although several episodes of convulsion occurred with pentylenetetrazol, BWB373U86 produced a single, brief episode. Naltrexone (10.0 and 100 mg/kg) and naltrindole (1.0, 3.2 and 10.0 mg/kg), but not midazolam (0.32 mg/kg), produced dose-dependent rightward shifts in the potency of BW373U86 to induce a convulsion. A dose of 3.2 mg/kg of midazolam completely eliminated convulsions induced by BW373U86. Midazolam (0.32 and 3.2 mg/kg), but not naltrindole (3.2 and 32.0 mg/kg), produced parallel rightward shifts in the pentylenetrazol dose-effect curve. Pretreatment with a single injection of BW373U86 (3.2, 10.0, 32.0 or 100 mg/kg) produced a dose-related reduction in the capacity of BW373U86 to induce a second convulsion. Recovery of sensitivity to BW373U86 did not return to control levels for up to 2 weeks after pretreatment with a single injection of 32.0 mg/kg of BW373U86. Naltrindole (3.2 mg/kg) administered within 1 hr, but not at 2 hr, after a pretreatment dose of 10.0 mg/kg of BW373U86 prevented the refractoriness (tolerance) induced by the single dose of BW373U86. These data suggest that the convulsions as well as the tolerance induced by BW373U86 were initiated through delta opioid receptors.

The discriminative stimulus effects of clozapine in pigeons: involvement of 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors.

Pigeons were trained to discriminate i.m. injections of the atypical antipsychotic clozapine (1.0 mg/kg) from saline in a two-key operant procedure. In substitution tests, compounds that shared antagonistic action at 5-hydroxytryptamine (5-HT)1C and 5-HT2 receptors produced discriminative stimulus effects similar to clozapine: cyproheptadine, metergoline, mianserin, pizotifen and fluperlapine. 5-HT antagonists selective for 5-HT2 vs. 5-HT1C receptors (e.g., ketanserin, pirenperone, risperidone and methiothepin) failed to produce substantial clozapine-appropriate responding. Other serotonergic compounds failed to produce substantial clozapine-appropriate responding: the 5-HT3 antagonist, ondansetron; the 5-HT1A agonists, (+-)-8-hydroxy-2-(di-n-propylamino)tetralin and BMY 14802; the 5-HT1A/1B agonist, RU24969; the 5-HT1A partial agonist, NAN190; the 5-HT1C/2 antagonist, mesulergine; the 5-HT1 agonist, I-5-hydroxytryptophane; and the 5-HT1C/2 agonist, quipazine. Other reference compounds such as the typical antipsychotics, chlorpromazine and thioridazine; the selective dopamine D-2 antagonists, droperidol and sulpiride; the dopamine D-1 antagonist, SCH 23390; the antimuscarinics, atropine and scopolamine; the antihistamines, pyrilamine and diphenhydramine; the alpha-1 antagonist, prazosin; and the antidepressants, imipramine and chloromipramine also failed to produce clozapine-appropriate responding. Promethazine, cinanserin and amitriptyline produced only partial generalization to the clozapine cue. The results suggest that blockade of both 5-HT2 and/or 5-HT1C receptors is important in the pharmacological mediation of the discriminative stimulus effects of clozapine. Blockade of 5-HT2 receptors appears not to be sufficient to produce clozapine-like discriminative stimulus effects. The precise role of 5-HT1C receptors in the clozapine discriminative stimulus is unclear due to the lack of compounds selective for this receptor.(ABSTRACT TRUNCATED AT 250 WORDS)