How to discriminate between hibernating and stunned myocardium.

AIM: The aim of the present study was to examine if it is possible to discriminate between hibernating and stunned myocardium in vivo by determining the ratio between diastolic and systolic coronary arterial inflow and by measuring oxygen saturation in draining coronary venous blood. METHODS: Experiments were performed in 32 open chest pigs anesthetized with sodium pentobarbital. In 11 pigs hibernation was induced in a part of the left ventricular myocardium by reducing flow in the mid-left anterior descending coronary artery (LAD) to about 60% of baseline flow. In 12 pigs stunning was induced by occluding mid-LAD twice for 10 min with a 30 min interval. In 9 pigs (control group) coronary flow was not manipulated. RESULTS: We found, at comparable degrees of regional dysfunction, that the ratio between diastolic and systolic flow in stunned myocardium remained unaltered, but fell from about 2 to 1 in hibernating myocardium. Furthermore, coronary venous oxygen saturation decreased from about 30% to 17% in blood draining hibernating myocardium, but remained statistically unaltered in blood draining stunned myocardium. CONCLUSION: We conclude that it is possible to discriminate between hibernating and stunned myocardium by measuring phasic coronary arterial blood flow and oxygen saturation in blood draining the region in question. During hibernation only, the diastolic flow component of coronary arterial inflow is reduced and the coronary venous oxygen extraction increased.

Pentobarbital versus medetomidine-ketamine-fentanyl anaesthesia: effects on haemodynamics and the incidence of ischaemia-induced ventricular fibrillation in swine.

The present study was performed to compare haemodynamic variables at baseline and the incidence of ventricular fibrillation during the early phase of ischaemia in swine during pentobarbital or medetomidine-ketamine-fentanyl anaesthesia. Twenty-two swine (mean +/- SD: 29+/- 3 kg) were anaesthetized with sodium pentobarbital (induction with 36 mg/kg intraperitoneally, and maintenance with 5-20 mg/kg/h intravenously [i.v.]) and 6 swine (27+/- 3 kg) were anaesthetized with ketamine and fentanyl (premedicated with medetomidine 0.1 mg/kg and ketamine 10 mg/kg intramuscularly, induction with ketamine 20 mg/kg and fentanyl 0.025 mg/kg i.v., and maintenance with ketamine 20 mg/kg/h and fentanyl 0.025 mg/kg/h i.v.). After a stabilization period of 30 min, the left anterior descending coronary artery (LAD) was occluded for 10 min. Haemodynamic data and occurrence of ventricular fibrillation were recorded. The ischaemic area was measured by fluorescing microspheres. Swine anaesthetized with medetomidine-ketamine-fentanyl had significantly lower heart rate, myocardial contractility, peak left ventricular pressure, arterial blood pressure, aortic blood flow, myocardial blood flow and cardiac index at baseline, than swine anaesthetized with pentobarbital. Whereas none of the swine anaesthetized with pentobarbital fibrillated during the LAD occlusion, ventricular fibrillation occurred in 83% of the animals anaesthetized with medetomidine-ketamine-fentanyl (P< 0.001). No significant difference was found in size of ischaemic area between the two groups. Thus, we show a depression in haemodynamic variables at baseline and a higher incidence of ventricular fibrillation during the early phase of ischaemia in swine anaesthetized with medetomidine-ketamine-fentanyl compared to swine anaesthetized with pentobarbital.

Myocardial extracellular signal regulatory kinases are activated by laser treatment.

AIM: Transmyocardial laser revascularization (TMR) and percutaneous transluminal myocardial laser revascularization (PTMR) have anti-anginal effects on certain groups of patients with ischemic heart disease, possibly by inducing myocardial neoangiogenesis through the mechanical injury. Here we examine the effects of TMR and PTMR on extracellular signal regulatory kinases (ERKs), which have been implicated in the control of neoangiogenesis in vitro. METHODS: Eight pigs were anesthetized with ketamine and fentanyl. In five pigs TMR was performed in the left ventricular anterior wall and PTMR in the posterior wall. Biopsies were taken either after 2 hours, 3, 7, 14, and 30 days. Three pigs served as controls and provided samples for baseline values and time-matched controls at 2 hours and 3 days. ERKs activity was determined by increased phosphorylation of myelin basic protein. Total ERKs protein abundance was determined by Western blot with an antibody against ERK1 and ERK2. RESULTS: It was found that ERKs activity was higher in all samples from the laser treated myocardium than in the control sample at baseline (TMR: >or=1878 pmol Pi x min(-1) mg pr(-1) vs 104 pmol Pi x min(-1) mg pr(-1), respectively, p<0.05. PTMR: >or=346 pmol Pi x min(-1) mg pr(-1) vs 136 pmol Pi min(-1) mg pr(-1), respectively, p<0.05). The time-matched samples showed increased activities of ERKs after laser treatment. The protein level of ERKs in myocardium treated with TMR and PTMR parallelled the data on ERKs activity. CONCLUSIONS: Our data suggest that the ERKs system is activated in the porcine heart by the mechanical injury of TMR and PTMR.

[Three cardiac mysteries--stunning, hibernation and ischemic preconditioning]. / Tre kardiale mysterier--stunning, hibernering og iskemisk prekondisjonering.

BACKGROUND: Cardiovascular research has led to the identification of three new and important phenomena: myocardial stunning, myocardial hibernation, and ischaemic preconditioning. Myocardial stunning is characterised by transient contractile dysfunction that persists after reperfusion despite the absence of irreversible damage and despite restoration of normal or near normal coronary blood flow. Myocardial hibernation is a condition of sustained reduction of contractile function in hypoperfused but viable myocardium, which recovers completely upon reperfusion. Ischaemic preconditioning refers to a phenomenon by which one or more brief periods of myocardial ischaemia increases the ischaemic tolerance against infarction by endogenous adaptive mechanisms. MATERIAL AND METHODS: Current relevant literature obtained through PubMed search is reviewed with emphasis on occurrence of the phenomena, the therapeutic potential, and the underlying mechanisms. RESULTS: Several observations indicate that myocardial stunning, myocardial hibernation, and ischaemic preconditioning may occur in patients with coronary heart disease. Actually, an increasing amount of evidence indicates that these phenomena are of major importance with regard to myocardial ischaemic tolerance. The mechanisms underlying these phenomena are, however, not yet clarified. INTERPRETATION: A better understanding of the mechanisms underlying myocardial stunning, myocardial hibernation, and ischaemic preconditioning may provide a rational basis for development of therapeutic interventions that increase myocardial ischaemic tolerance.

Technetium 99m single positron emission computed tomography scanning for assessing mandible invasion in oral cavity cancer.

OBJECTIVES: To study the accuracy of single positron emission computed tomography (SPECT) scanning and compare its results to clinical examination, Panorex, and computed tomography (CT) scanning with respect to determining mandibular invasion by oral cavity and oropharyngeal cancer, and to define the role of SPECT scanning in the preoperative assessment of oromandibular cancer. STUDY DESIGN: Prospective study of 38 patients who underwent technetium 99m SPECT scanning as part of their preoperative clinical assessment for cancer at risk of invading the mandible. All patients underwent partial or segmental mandibulectomy as part of their surgical management. METHODS: A data protocol was used to tabulate patient demographics, tumor characteristics and results of preoperative tests as patients were enrolled into the study. Following surgical treatment, these data were correlated with histopathological findings. Detailed analysis was performed to assess the tabulated data. RESULTS: The SPECT scanning demonstrated an 87% overall accuracy in predicting bone invasion compared with 71% for clinical examination, CT scanning, and Panorex x-rays. The SPECT scanning was significantly more sensitive (95%) than either CT scans (55%) or Panorex x-rays (50%). Notably SPECT scanning demonstrated a considerable improvement in specificity (72%) compared with conventional radionuclide scanning. Although not as specific as CT scanning or plain films, SPECT scanning was significantly more effective in ruling out disease than was clinical examination. CONCLUSIONS: Preoperative SPECT scanning used in combination with clinical examination, CT scanning, and Panorex x-rays to assess patients at risk for mandible involvement by oral cavity cancer can improve the accuracy of predicting bone invasion and help in appropriate treatment planning so as to safely reduce the proportion of disease-free jaws resected.

Effects on infarct size and on arrhythmias by controlling reflow after myocardial ischaemia in pigs.

Part of the myocardial damage after an ischaemic period might be related to the reperfusion conditions. Many abrupt changes occurring in the heart during reperfusion may add to the damage during the preceding ischaemic period, and increase in infarct size. In this study we tested the hypothesis that infarct size and occurrence of ventricular arrhythmias might be reduced by restricting reflow after an ischaemic period. Seventeen pigs underwent 45 min of total occlusion of the left anterior descending coronary artery with an hydraulic occluder. In the intervention group reperfusion was restricted to 50% of baseline during the first minute, to 100% during the next minute, kept constant for 1 min, and thereafter allowed to increase by 50% of baseline flow every minute until free reflow. In the control group reflow was not restricted. Arrhythmias were recorded. After 2.5 h of reperfusion the heart was excised. Infarct size was measured by using triphenyltetrazolium chloride (delineation of necrosis), fluorescent microspheres (delineation of area at risk) and planimetry. No reduction in infarct size (% of area at risk) was found between the intervention group and the control group (75.9 +/- 5.3% vs. 72.4 +/- 4.3%). The incidence of ventricular arrhythmias and ventricular fibrillation were not found to be different between the groups during reperfusion. Hemodynamic parameters were not significantly different between the two groups. Our data indicate that no substantial protection against myocardial infarct or ventricular arrhythmias could be achieved by controlling reflow using the present protocol after a period of myocardial ischaemia in pigs. Accordingly, our data do not support the notion that control of reflow may be beneficial when treating coronary artery occlusion with percutaneous coronary angioplasty (PCA).

Transmyocardial laser treatment reduces ischemia-induced ventricular fibrillation during the early phase (1a) after coronary artery occlusion in open chest anesthetized pigs.

INTRODUCTION: It has previously been shown that transmyocardial revascularization with laser (TMR) prior to coronary artery occlusion decreases the occurrence of ischemia-induced arrhythmias. The aim of the present study was to determine the effects of TMR on ventricular fibrillation and other arrhythmias during the early (1a) and late phase (1b) of ischemia in pigs. METHODS: In six pigs TMR was performed in the anterior wall of the left ventricle 60 minutes prior to occlusion of the proximal LAD. Six other pigs were subjected to coronary occlusion without preceding TMR and served as controls. RESULTS: During the 30 min period with LAD occlusion ventricular fibrillation occurred 22 times in 5 of 6 control animals (20 episodes in phase la, 2 in phase 1b), whereas none of the animals subjected to TMR prior to the coronary artery occlusion developed ventricular fibrillation (p<0.01). The total number of premature beats per animal was lower during the early phase (la) after LAD occlusion in the TMR group than in the control group (18+/-13 vs 248+/-82, p<0.05). CONCLUSIONS: TMR prior to occlusion of LAD reduced the occurrence of early phase (la) ischemia-induced ventricular fibrillation and premature beats. This anti-fibrillatory effect might explain the improved survival observed in experimental studies after TMR prior to coronary artery occlusion found by others.

Importance of heart rate for acute hibernation in isolated blood-perfused piglet hearts.

BACKGROUND: Hibernating myocardium may benefit from revascularization. There are several experimental models for acute hibernation. In intact hearts low-flow ischemia causes time-dependent metabolic alterations, termed "metabolic adaptation". In isolated heart preparations metabolic responses to low-flow ischemia vary, and signs of metabolic adaptation are not consistently found. In isolated hearts global ischemia may cause bradycardia unless the hearts are paced. We hypothesized that the lack of consistent metabolic adaptation to low-flow ischemia in isolated hearts might be due to bradycardia during ischemia. In this study we investigated the influence of heart rate on metabolism and function in an isolated heart preparation. METHODS: Isolated blood-perfused piglet hearts were subjected to 120 min 10% flow. In groups A (n=9) and B (n=4) hearts were not paced during ischemia, in groups C (n=5) and D (n=5) hearts were paced at pre-ischemic heart rate during ischemia. RESULTS: Without pacing, heart rate declined to approximately 1/3 during ischemia and anaerobic metabolism showed a slight decline over time. With pacing, production of protons, pCO2 and lactate showed a bell-shaped curve which peaked at 20-25 min of ischemia, followed by a subsequent decline towards the end of ischemia (overall p < 0.001 for all). However, reperfusion revealed impaired recovery of function in paced hearts compared to non-paced hearts (53 +/- 7% vs 77 +/- 4%, p < 0.05) concomitant with higher release of creatine kinase (455 +/- 93 IU/100 g vs 106 +/- 13 IU/100 g, p < 0.01). CONCLUSIONS: When heart rate is allowed to decline during low-flow ischemia in isolated piglet hearts, signs of metabolic adaptation are not evident. When hearts are paced during ischemia time-dependent alterations in anaerobic metabolism occur, resembling observations seen in intact beating hearts. However, paced hearts also show indications of increased cellular injury, indicating that in paced hearts the metabolic consequences are mostly due to increased irreversible cell injury. Thus, the model for acute hibernation with 10% flow in isolated blood-perfused piglet hearts are critically dependent on bradycardia during ischemia.

Microembolization in pigs: effects on coronary blood flow and myocardial ischemic tolerance.

Coronary microembolization has been reported to increase coronary blood flow (CBF) through adenosine release. Because adenosine may increase ischemic tolerance against infarction, we tested the hypothesis that myocardial microembolization, a common finding in patients with ischemic heart disease, induces cardioprotection. Additionally, because the use of microspheres is a common tool to measure tissue perfusion, the effects of small amounts of microspheres on CBF were examined. Using anesthetized pigs, we measured CBF with a transit time flow probe on the left anterior descending coronary artery (LAD). In six pigs the relationship between the amount of injected microspheres (0-40 x 10(6), 15 micrometer in diameter, left atrial injections) and the effect on CBF was examined. Coronary hyperemia occurred, which was linearly related to the amount of microspheres injected: maximal increase in CBF (%) = 2.8 +/- 1.5 (SE) + (5.8 +/- 0.7 x 10(-7) x number of injected microspheres). Because injection of 40 x 10(6) microspheres induced a long-lasting hyperemic response, which could be blocked by 8-p-sulfophenyl theophylline, ischemic tolerance was examined in five other pigs after two injections, each of 40 x 10(6) microspheres, at a 30-min interval. Six control pigs had no injections. Ischemic tolerance was evaluated by measuring infarct size (tetrazolium stain) as the percentage of area at risk (fluorescent particles) after 45 min of LAD occlusion followed by 2 h of reperfusion. Pretreatment by microspheres increased infarct size from 60 +/- 3% of area at risk in control animals to 84 +/- 6% (P < 0.05). The injection of microspheres induced a significant hyperemic flow response without causing necrosis by itself. We conclude that microembolization, evoking coronary hyperemia, does not improve but reduces myocardial ischemic tolerance against infarction in pigs.

Transmyocardial laser induces coronary hyperemia and reduces ischemia-related arrhythmias, but fails to delay development of myocardial necrosis after coronary artery occlusion in pigs.

BACKGROUND: Several investigators have reported that transmyocardial revascularization (TMR) prior to acute coronary artery occlusion improves regional myocardial function and reduces the infarct size in animals with significant coronary collateral circulation. Whether the protective effect of TMR is due to perfusion through the laser-made channels, increased collateral flow or other mechanisms remains unresolved. The aim of this study was to investigate whether TMR performed prior to acute coronary artery occlusion could offer protection from ischemic injury in the pig, an animal with limited native collateral coronary circulation. METHODS: In one group (n=4), TMR was performed in the anterior wall of the left ventricle 30 minutes prior to occlusion of the proximal LAD for 45 minutes. The other group (n=6) was subjected to transient ischemia of the same duration without previous TMR. Area at risk and infarct size were determined after sacrifice. RESULTS: No significant difference was found in the infarct size between the two groups (69+/-2% in the TMR group versus 62+/-4% in the control group). However, the arrhythmic index during the period of ischemia was significantly lower in the TMR group (1.0+/-0.3 vs 8.3+/-2.2, p<0.001). Blood flow in LAD increased to a maximum of 135+/-6% of baseline level three minutes after the end of the TMR procedure. CONCLUSIONS: TMR failed to reduce the infarct size following acute coronary artery occlusion in the pig, an animal with a small collateral coronary flow capacity, but reduced ischemia-related arrhythmias and increased coronary flow transiently.

Duration of ischaemic preconditioning and importance of size of area at risk in pigs.

An explanation of the preconditioning phenomenon must account for the biology of the phenomenon. Here we provide a more thorough characterization of ischaemic preconditioning (IPC), examining temporal characteristics and the importance of the size of area at risk. IPC was induced by two 10-min LAD occlusions separated by 30 min reperfusion in pentobarbital anaesthetized open-chest pigs. The last brief occlusion was followed by either 30 min, 2 h or 4 h of reperfusion. The degree of protection was evaluated by measuring infarct size after either 45 or 60 min LAD occlusion followed by 2 h of reperfusion. To examine the importance of the size of area at risk, the occlusion site on LAD was varied between pigs. IPC followed by 30 min and 2 h of reperfusion reduced infarct size from 58+/-2% of area at risk to 15+/-4% (P<0.05) and 15+/-6% (P<0.05), respectively, by 45 min of LAD occlusion. After 4 h of reperfusion the infarct size-limiting effect of IPC was still prominent when a test ischaemic period of 45 min was used (47+/-5%vs 13+/-1%P<0.05). IPC was paralleled by an increased incidence of ventricular fibrillation during the early phase of the prolonged LAD occlusion after 30 min, 2 h and 4 h of reperfusion. Although no correlation was found between infarct size (as a percentage of area at risk) and area at risk (as a percentage of ventricular weight) in control pigs, a positive correlation was found between these variables in preconditioned pigs. We conclude that the infarct size-limiting effect of IPC lasts at least 4 h and that it is paralleled by profibrillatory effects in open-chest pigs. Furthermore, the infarct size-limiting effect of IPC depends on the size of area at risk, being most pronounced when area at risk is small.

A new approach to normalize myocardial temperature in the open-chest pig model.

To prevent unphysiological temperature fluctuations in the myocardium in the open-chest model, we constructed a thermocage. Five pigs under pentobarbital sodium anesthesia underwent repetitive left anterior descending (LAD) coronary artery occlusions. Myocardial temperature was measured without any thoracic temperature-controlling device and in the presence of either a heating lamp or the thermocage. Without any thoracic temperature-controlling device, the temperature at 5-mm myocardial depth was 1.28 +/- 0.33 degrees C below the intra-abdominal temperature (P < 0.05). During a proximal 5-min LAD occlusion, myocardial temperature decreased by 1.86 +/- 1.02 degrees C in the ischemic area (P < 0.05). Both the heating lamp and the thermocage abolished the difference between intra-abdominal and myocardial temperatures and prevented the decrease in myocardial temperature during ischemia. Only the thermocage minimized myocardial temperature fluctuations due to air currents and prevented epicardial exsiccation. We conclude that either a thermocage or a heating lamp may be used to normalize myocardial temperature in the open-chest pig model. However, the thermocage is superior to the lamp in minimizing temperature fluctuations and preventing epicardial exsiccation.

Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial.

PURPOSE: To evaluate the effectiveness and safety of samarium-153 (153Sm) lexidronam (EDTMP) in a double-blind, placebo-controlled study. PATIENTS AND METHODS: Patients with painful bone metastases secondary to a variety of primary malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia. RESULTS: One hundred eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg of active drug had significant reductions in pain during each of the first 4 weeks in both patient-rated and physician-rated evaluations. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg, of active drug. A significant correlation (P = .01) was observed between reductions in opioid analgesic use and pain scores only for those patients who received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity. CONCLUSION: A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded.

Characterization of metabolic responses to low-flow ischemia in intact pig hearts and isolated blood-perfused neonatal pig hearts.

UNLABELLED: There are different well established experimental models of low-flow ischemia. We examined metabolic variables during reduced coronary blood flow (CBF) in intact pig hearts and isolated neonatal pig hearts, producing similar degrees of postischemic dysfunction without infarction. The isolated hearts were perfused with red blood cell enriched buffer. In eight open-chest pigs mid-LAD flow was reduced to 70% for 60 min, followed by 120 min reperfusion. Myocardial segment lengths were recorded and regional coronary venous blood was sampled. In isolated piglet hearts CBF was reduced to 50% (n = 4), 25% (n = 4), and 10% (n = 17). Only when flow was reduced to 10% did hearts show signs of anaerobic metabolism. Mechanical function was recorded by a balloon in the left ventricle and coronary venous blood was sampled. Intact pig hearts showed release of protons, CO2, and lactate which peaked after 5-10 min of ischemia and thereafter stabilized at reduced levels. In contrast, in isolated neonatal hearts exposed to 10% CBF releases of protons, CO2, and lactate were stable during ischemia with no adaptational changes over time. In a separate group (n = 4), repetitive biopsies revealed no adaptational changes over time for adenosine triphosphate and creatine phosphate during 10% CBF. Contractile function was stably reduced during ischemia in both models. CONCLUSION: During reduced CBF "metabolic adaptation" occurs in intact pig hearts. In contrast, this feature is not present in isolated blood-perfused piglet hearts. The mechanisms responsible for these differences are uncertain. However, differences in metabolism between adult and neonatal hearts and different loading conditions during ischemia might contribute.

Improved haemodynamics with increased compression-decompression rates during ACD-CPR in pigs.

The haemodynamic effects of variations in the compression-decompression frequency, 60, 90 and 120 min(-1) during ACD-CPR, were tested in a randomized cross-over design during ventricular fibrillation (VF) in 12 anaesthetized pigs (17-22 kg) using an automatic hydraulic chest compression-decompression device. There were significant increases with increasing frequency for mean (+/- S.D.) carotid blood flow (17 +/- 5, 25 +/- 9 and 36 +/- 12 ml min(-1), transit time flow probe), cerebral blood flow (17 +/- 7, 30 +/- 17 and 40 +/- 13 ml min(-1) 100 g(-1), radionuclide microspheres) and mean aortic pressure (34 +/- 8, 37 +/- 10 and 43 +/- 7 mmHg), respectively. Myocardial blood flow (radionuclide microspheres) and diastolic coronary perfusion pressure, CPP, increased significantly from 60 to 90 min(-1) with no further significant increase to 120 min(-1) (28 +/- 13, 46 +/- 23 and 49 +/- 19 ml min(-1) 100 g(-1) and 25 +/- 8, 31 +/- 11 and 32 +/- 9 mmHg, respectively). Renal and hepatic blood flow also increased with increasing rate. No significant differences in the expired CO2 levels were observed. In conclusion increasing the compression-decompression frequency from 60 to 90 and 120 min(-1) improved the haemodynamics during ACD-CPR in a pig model with VF.

Importance of endogenous adenosine during ischemia and reperfusion in neonatal porcine hearts.

BACKGROUND: Adenosine has several potentially cardioprotective effects. We hypothesized that the effects of endogenous adenosine vary with degree of ischemia and that elevating endogenous levels is protective. METHODS AND RESULTS: Isolated blood-perfused piglet hearts underwent 120 minutes of low-flow ischemia (10% flow) or 90 minutes of zero-flow ischemia, all with 60 minutes of reperfusion. Hearts were treated with either saline, the adenosine receptor blocker 8-sulfophenyltheophylline (8SPT, 300 micromol x L(-1)), or the nucleoside transport inhibitor draflazine (1 micromol x L(-1)). In separate groups, biopsies were obtained before and at the end of ischemia. Compared with saline, 8SPT did not significantly alter functional recovery in either protocol. Draflazine significantly improved percent recovery of left ventricular systolic pressure both in the low-flow protocol (92+/-3% versus 75+/-2% [saline] and 73+/-3% [8SPT], P<.001 for both) and in the zero-flow protocol (76+/-3% versus 59+/-4% [saline] and 46+/-9% [8SPT], P<.05 for both). In the zero-flow protocol, draflazine also significantly reduced ischemic contracture and release of creatine kinase. Tissue adenosine at the end of ischemia was elevated by draflazine compared with saline-treated hearts: after low-flow ischemia to 0.10+/-0.05 versus 0.00+/-0.00 micromol x g(-1) dry wt (P<.05) and after zero-flow ischemia to 1.73+/-0.82 versus 0.15+/-0.03 micromol x g(-1) dry wt (P<.05). CONCLUSIONS: In neonatal porcine hearts, endogenous adenosine produced during ischemia does not influence ischemic injury or functional recovery. Elevating endogenous adenosine by draflazine elicits cardioprotection in both low-flow and zero-flow conditions.

Importance of nitric oxide in hepatic arterial blood flow and total hepatic blood volume regulation in pigs.

The importance of nitric oxide in regulating basal arterial blood flow has been examined in several different vascular beds by intra-arterial infusion of inhibitors of nitric oxide synthesis, but not in the arterial vascular bed of the liver. In the present study, N(G)-nitro-L-arginine (L-NNA), in a dose of 0.5 and 1.0 mumol mL-1 of hepatic arterial blood flow, was infused for 5 min into the hepatic artery in seven pigs anaesthetized with pentobarbital sodium. The haemodynamic effects observed by the first infusion were not further enhanced by the second infusion. Hepatic arterial resistance increased by 143 +/- 38% and hepatic arterial blood flow declined by 38 +/- 10%. A systemic effect due to 'spillover' was observed, as evidenced by an increase in mean aortic blood pressure of 24 +/- 4 mmHg. However, no significant increase in arterial mesenteric resistance was observed and total liver blood flow remained unchanged. Hepatic arterial vasodilation in response to occlusion of the portal vein, the arterial buffer response, remained intact after inhibition of nitric oxide synthesis. Liver lobe thickness, measured by an ultrasonic technique, was not found to change with inhibition of arterial nitric oxide synthesis, excluding a significant direct effect of arterial nitric oxide on liver capacitance. In conclusion, nitric oxide is an important regulator of hepatic arterial resistance, but does not mediate the hepatic arterial buffer response and was not found to play any significant role in total hepatic capacitance regulation.

Preconditioning with ischaemia reduces both myocardial oxygen consumption and infarct size in a graded pattern.

We tested the hypothesis that ischaemic preconditioning reduces pre-ischaemic energy demand and thereby reduces the energy supply-demand mismatch imposed by coronary artery occlusion. Experiments were performed in 52 open chest pigs anaesthetised with sodium pentobarbital. One or two cycles, each of 10 min LAD occlusion followed by 30 min reperfusion, served as the preconditioning stimuli. The degree of protection was evaluated by measuring infarct size (tetrazolium stain) as percentage of area at risk (fluorescent particles) after 45 min LAD occlusion followed by 2 h reperfusion. One preconditioning cycle reduced regional myocardial oxygen consumption (MVO2) by 15+/-3% (P<0.05), whereas two cycles of preconditioning reduced MVO2 by 25+/-3% (P<0.05 v one cycle). This reduction was probably due to reduced energy demand, as both coronary blood flow and arteriovenous oxygen differences decreased, without lactate release or reduction in peak hyperaemic flow response. Energy requirements were most likely also reduced during ischaemia since repayment of flow debt after the second ischaemic period was 33+/-7% less than after the first ischaemic period (P<0.001). One preconditioning cycle reduced infarct size from 58+/-3% of area at risk to 40+/-5% (P<0.05), whereas two cycles of preconditioning reduced infarct size to 15+/-4% of area at risk (P<0.05 v one cycle). We conclude that preconditioning with ischaemia reduces energy consumption in a graded pattern. This effect may contribute to the graded protective effect of ischaemic preconditioning.

Proarrhythmic effects of ischemic preconditioning in anesthetized pigs.

Conflicting data exist on how ischemic preconditioning affects the incidence of arrhythmias during ischemia. The present study was, therefore, performed to clarify if ischemic preconditioning alters the incidence of arrhythmias during the early phase of ischemia in pigs. Twenty-four pigs (23-36.5 kg) in pentobarbital anesthesia were preconditioned by a 10 min LAD-occlusion and 30 min reperfusion prior to a second 10 min occlusion. The first occlusion served as the preconditioning ischemic period, and the second occlusion as the test ischemic period. To verify that the preconditioning protocol induced protection, infarct size was assessed in an additional nine pigs. The arrhythmic index (arrhythmic beats/min) increased from 12+/-3 during the first occlusion to 38+/-8 during the second occlusion (P < 0.05). Four pigs (17%) fibrillated during the first ischemic period, while 10 pigs (42%) fibrillated during the second ischemic period (P < 0.05). All pigs that fibrillated during the first occlusion also fibrillated during the second occlusion. Mean heart rate was 108+/-4 beats/min before the first occlusion and increased to 113+/-4 beats/min before the second occlusion (P < 0.001). There was a positive correlation between heart rate before the second occlusion and occurrence of fibrillation during this occlusion (rs = 0.42; P < 0.05). The preconditioning protocol reduced infarct size, after a subsequent 45 min ischemic period followed by two hours of reperfusion, from 58+/-3% of area at risk to 40+/-5% (P < 0.05). In conclusion, our data show that ischemic preconditioning increases both the arrhythmic index and the incidence of ventricular fibrillation during the early phase of a subsequent ischemic period.