Effects of different beta adrenoceptor ligands in mice with permanent occlusion of the left anterior descending coronary artery.

1. We have studied the effects of three betaAR ligands (carvedilol, alprenolol, and ICI-118551) with different pharmacological profiles and negative efficacy at the beta2AR on cardiac in vivo, in vitro, biochemical and gene expression parameters in mice with permanent occlusion of the left anterior descending coronary artery. 2. Cardiac in vivo parameters were determined using Doppler studies. Mitral-wave E peak velocity (EPV) and aortic peak velocity (AoPV) decreased in the first 2 weeks postocclusion. After 3 weeks of drug treatment, EPV was improved in the carvedilol group to preocclusion values; however, a further reduction in EPV in the alprenolol and control permanent occlusion group was measured and there was no change after ICI-118551 treatment. AoPV was unchanged between weeks 2 and 5 in all groups. 3. The left atria were isolated to record isometric tension responses to isoprenaline. Permanent occlusion significantly reduced the maximum isoprenaline response to 30% of control and carvedilol increased the maximum response to isoprenaline significantly to 60%. 4. The biochemical and gene expression studies revealed different effects of the three betaAR ligands. Most notably, carvedilol reduced gene expression of myosin heavy chain beta. 5. These results indicate that chronic treatment with carvedilol is beneficial in a mouse model of myocardial damage resulting from ischaemia. We hypothesise that these beneficial effects of the drug may be because of the negative efficacy at the beta2AR, combined with beta1AR antagonism.

Pyruvate-enriched resuscitation: metabolic support of post-ischemic hindlimb muscle in hypovolemic goats.

Tourniquet-imposed ischemia-reperfusion of extremities generates reactive oxygen and nitrogen species (RONS), which can disrupt intermediary metabolism and ATP production. This study tested the hypothesis that fluid resuscitation with pyruvate, a natural antioxidant and metabolic fuel, ameliorates the deleterious effects of ischemia-reperfusion on intermediary metabolism in skeletal muscle. Anesthetized male goats (∼25 kg) were bled to a mean arterial pressure of 48 ± 1 mmHg and then subjected to 90 min hindlimb ischemia with a tourniquet and femoral crossclamp, followed by 4-h reperfusion. Lactated Ringers (LR) or pyruvate Ringers (PR) was infused intravenous for 90 min, from 30 min ischemia to 30 min reperfusion, to deliver 0.05 mmol kg(-1) min(-1) lactate or pyruvate. Time controls (TC) underwent neither hemorrhage nor hindlimb ischemia. Lipid peroxidation product 8-isoprostane, RONS-sensitive aconitase and creatine kinase activities, antioxidant superoxide dismutase activity, and phosphocreatine phosphorylation potential ([PCr]/[{Cr}{P(i)}]), an index of tissue energy state, were measured in reperfused gastrocnemius at 90 min resuscitation (n = 6 all groups) and 3.5 h post-resuscitation (n = 8 TC, 9 LR, 10 PR). PR more effectively than LR suppressed 8-isoprostane formation, prevented inactivation of aconitase and creatine kinase, doubled superoxide dismutase activity, and augmented [PCr]/([Cr][P(i)]). Pyruvate-enriched Ringer's is metabolically superior to Ringer's lactate for fluid resuscitation of tourniqueted muscle.

Novel Split Chest Tube Improves Post-Surgical Thoracic Drainage.

OBJECTIVE: Conventional, separate mediastinal and pleural tubes are often inefficient at draining thoracic effusions. DESCRIPTION: We developed a Y-shaped chest tube with split ends that divide within the thoracic cavity, permitting separate intrathoracic placement and requiring a single exit port. In this study, thoracic drainage by the split drain vs. that of separate drains was tested. METHODS: After sternotomy, pericardiotomy, and left pleurotomy, pigs were fitted with separate chest drains (n=10) or a split tube prototype (n=9) with internal openings positioned in the mediastinum and in the costo-diaphragmatic recess. Separate series of experiments were conducted to test drainage of D5W or 0.58 M sucrose, an aqueous solution with viscosity approximating that of plasma. One litre of fluid was infused into the thorax, and suction was applied at -20 cm H2O for 30 min. RESULTS: When D5W was infused, the split drain left a residual volume of 53 ± 99 ml (mean value ± SD) vs. 148 ± 120 for the separate drain (P=0.007), representing a drainage efficiency (i.e. drained vol/[drained + residual vol]) of 95 ± 10% vs. 86 ± 12% for the separate drains (P = 0.011). In the second series, the split drain evacuated more 0.58 M sucrose in the first minute (967 ± 129 ml) than the separate drains (680 ± 192 ml, P<0.001). By 30 min, the split drain evacuated a similar volume of sucrose vs. the conventional drain (1089 ± 72 vs. 1056 ± 78 ml; P = 0.5). Residual volume tended to be lower (25 ± 10 vs. 62 ± 72 ml; P = 0.128) and drainage efficiency tended to be higher (98 ± 1 vs. 95 ± 6%; P = 0.111) with the split drain vs. conventional separate drains. CONCLUSION: The split chest tube drained the thoracic cavity at least as effectively as conventional separate tubes. This new device could potentially alleviate postoperative complications.

Pyruvate-fortified resuscitation stabilizes cardiac electrical activity and energy metabolism during hypovolemia.

AIM: To test the hypothesis that fluid resuscitation with Ringer's solution enriched with pyruvate (PR), a physiological antioxidant and energy substrate, affords protection of myocardial metabolism and electrophysiological performance superior to lactated Ringer's (LR) during hypovolemia and hindlimb ischemia-reperfusion. METHODS: Male domestic goats (25-30 kg) were exsanguinated to a mean arterial pressure of 48 ± 1 mmHg. Right hindlimb ischemia was imposed for 90 min by applying a tourniquet and femoral crossclamp. LR or PR, infused iv, delivered 0.05 mmol/kg per minute L-lactate or pyruvate, respectively, from 30 min hindlimb ischemia until 30 min post-ischemia. Time controls (TC) underwent neither hemorrhage, hindlimb ischemia nor resuscitation. Goats were sacrificed and left ventricular myocardium biopsied at 90 min fluid resuscitation (n = 6 per group) or 3.5 h later (n = 9 LR, 10 PR, 8 TC). RESULTS: Myocardial 8-isoprostane content, phosphocreatine phosphorylation potential, creatine kinase activity, and heart rate-adjusted QT interval (QTc) variability were evaluated at 90 min resuscitation and 3.5 h post-resuscitation. PR sharply lowered pro-arrhythmic QTc variability vs LR (P < 0.05); this effect persisted 3.5 h post-resuscitation. PR lowered myocardial 8-isoprostane content, a product of oxidative stress, by 39 and 37% during and 3.5 h after resuscitation, respectively, vs LR. Creatine kinase activity fell 42% post-LR vs TC (P < 0.05), but was stable post-PR (P < 0.02 vs post-LR). PR doubled phosphocreatine phosphorylation potential, a measure of ATP free energy state, vs TC and LR (P < 0.05); this energetic enhancement persisted 3.5 h post-resuscitation. CONCLUSION: By augmenting myocardial energy state and protecting creatine kinase activity, pyruvate-enriched resuscitation stabilized cardiac electrical function during central hypovolemia and hindlimb ischemia-reperfusion.