Role of endogenous endothelin on coronary reflow after cardioplegic arrest.

OBJECTIVE: Endothelin plays a role in the regulation of basal coronary tone. We hypothesized that low coronary reflow and reduced cardiac function after prolonged ischemia may be due to increased release of endogenous endothelin. METHODS: Using an isolated perfused rat heart, we examined the effect of the addition of various endothelin antagonists during reperfusion after 4 hours of cardioplegic arrest at 4 degrees C. Hearts were freeze-clamped at the end of reperfusion for analysis of high-energy phosphate levels. Results are expressed as the percentages of preischemic values. RESULTS: The addition of bosentan or Ro61-0612 (nonselective endothelin antagonists) resulted in a significant increase in the recovery of coronary flow after 30 minutes of reperfusion (100.9% vs 85.3% [P =.03] and 122.4% vs 83.7% [P <.001], respectively, versus controls). The addition of PD155080 (endothelin A antagonist) had a similar effect (129.5% vs 91.4%, P =.008). BQ788 (endothelin B antagonist) and phosphoramidon (endothelin-converting enzyme inhibitor) had no effect. Myocardial adenosine triphosphate levels were significantly (12.1%) higher after reperfusion with Ro61-0612 (18.1 +/- 0.4 micromol/g vs 16.2 +/- 0.5 micromol/g, P =.01). There was no difference in the recovery of cardiac mechanical function with any of the antagonists studied. CONCLUSION: These results suggest that endogenous endothelin plays a role in low coronary reflow after prolonged cardioplegic arrest but does not impair recovery of myocardial function.

Role of endogenous endothelin on coronary flow in health and disease.

The role of the endothelium in the control of coronary flow has been demonstrated. Results of recent studies, both on animals and on humans, suggest that endogenous endothelin also plays an important role in basal coronary tone. Disease processes such as ischaemia-reperfusion injury, congestive heart failure, hypertension and atherosclerosis may be contributed to by an imbalance in, or excess of, release of endothelin. With the discovery of newer endothelin antagonists and endothelin converting enzyme inhibitors, especially with fewer hepatic side effects, there is the potential for much future research into novel therapeutic management of these common cardiovascular disorders.

Pyruvate/dichloroacetate supply during reperfusion accelerates recovery of cardiac energetics and improves mechanical function following cardioplegic arrest.

OBJECTIVES: Cardioplegic arrest during cardiac surgery induces severe abnormalities of the pyruvate metabolism, which may affect functional recovery of the heart. We aimed to evaluate the effect of pyruvate and dichloroacetate administration during reperfusion on recovery of mechanical function and energy metabolism in the heart subjected to prolonged cardioplegic arrest. METHODS: Four groups of rat hearts perfused in working mode were subjected to cardioplegic arrest (St. Thomas' No. 1), 4 h of ischaemia at 8 degrees C and reperfusion with either Krebs buffer alone (C) or with 2.8 mM pyruvate (P), with 1 mM dichloroacetate (D), or with a combination of both (PD). Mechanical function was recorded before cardioplegic arrest and at the end of experiments. In groups C and PD, additional experiments were performed using (31)P nuclear magnetic resonance spectroscopy in non-working Langendorff mode to evaluate cardiac high-energy phosphate concentration changes throughout the experiment. RESULTS: Improved recovery of cardiac output (% of the preischaemic value+/-SEM, n=9-12) was observed in all three treated groups (65.7+/-4.3, 59.5+/-5.2 and 59.5+/-5.3% in PD, P and D, respectively) as compared with C (42.2+/-4.6%; P<0.05). Recovery of coronary flow was improved from 66.4+/-3.8 in C to 94.9+/-8.6% in PD (P<0.05). The phosphocreatine recovery rate in the first minutes of reperfusion was increased from 9.9+/-1.5 in C to 31.5+/-4.3 micromol/min per g dry wt in PD (P<0.001). No differences were observed in ATP or phosphocreatine concentrations at the end of experiment. CONCLUSIONS: The administration of pyruvate and dichloroacetate improves the recovery of mechanical function following hypothermic ischaemia. Accelerated restoration of the energy equilibrium in the initial phase of reperfusion may underlie the metabolic mechanism of this effect.

Effect of surgical training on outcome and hospital costs in coronary surgery.

BACKGROUND: There is a perceived conflict between the need for service provision and surgical training within the National Health Service (NHS). Trainee surgeons tend to be slower (thereby reducing theatre throughput), and may have more complications (increasing hospital stay and costs). OBJECTIVE: To quantify the effect of training on outcome and costs. DESIGN: Data on 2740 consecutive isolated coronary artery bypass (CABG) operations were analysed retrospectively. Redo and emergency procedures were excluded. The seniority of the operating surgeon was related to operating times, risk stratified outcome, and overall hospital costs. SETTING: Regional cardiothoracic surgery unit. MAIN OUTCOME MEASURES: Postoperative mortality; hospital costs. RESULTS: Consultants, senior trainees, intermediate trainees, and junior trainees performed 1524, 759, 434, and 23 procedures, respectively. Trainees at the three different levels were directly supervised by a consultant in 55%, 95%, and 100% of cases. The unadjusted mortalities were 3.2%, 2.0%, 2.3%, and 4.3%, respectively (NS). There were no significant differences between the groups with respect to time in the intensive care unit and length of hospital stay. The mean cost per patient was pound6619, pound6572, pound6494, and pound6404 (NS). CONCLUSIONS: Trainees performed 44.4% of all CABG operations. There was no detrimental effect on patient outcome, length of hospital stay, or overall hospital costs. There need be little conflict between service and training needs, even in hospitals with extensive training programmes.

Clinical versus actual outcome in cardiac surgery: a post-mortem study.

BACKGROUND: Clinical attribution of the cause of death can be misleading, with the only true outcome measure being post-mortem analysis. Despite this there is very little published data on post-mortems following cardiac surgery. METHODS: Prospective consecutive post-mortem data were collected on 167 patients (84.4% of all in-hospital cardiac surgical deaths) in a single institution. Clinical diagnoses were compared with post-mortem findings. RESULTS: The mean age at death was 69.8 with 67.6% male. The proportion undergoing coronary artery bypass graft (CABG) alone was 52.1%, valve surgery 18.6%, valve+CABG 19.2% and other procedures 10.1%. The mean time to death was 7.9 days (range 0-87). The causes of death were cardiac 67.7%, gastrointestinal 9.6%, respiratory 8.4%, haemorrhage/technical failure 4.8%, stroke (cerebrovascular accident) 3.6%, multiorgan failure 3.0%, sepsis 1.8%, malignancy 0. 6% and trauma 0.6%. Post-mortem revealed an unsuspected cause of death in 19 (11.4%). These were gastrointestinal (infarction nine, perforation two), cardiac three, adult respiratory distress syndrome two, technical two and pulmonary embolus one. In addition, an unsuspected lung cancer was found in 1 patient who died of cardiac causes. When cardiac deaths were compared with non-cardiac causes the Parsonnet score was higher 20.0 (+/-1.4) vs. 15.3 (+/-1.6), P=0. 07; and a greater proportion tended to have poor ejection fractions (34 vs. 15%), P=0.12. There was no significant difference between the groups in terms of age, sex, operation, hypertension, diabetes, creatinine and body mass. CONCLUSIONS: Post-mortem can determine unsuspected diagnoses in a significant proportion of cases. Pre-operative risk factors do not correlate with eventual cause of death. Post-mortem still has an important role to play in cardiac surgery.

Endothelins and the lung.

Since endothelins were discovered by Yanasigawa in 1988 it has been recognised that they may have an important role in lung pathophysiology. Despite their biological importance as vasoconstrictors the physiological role of endothelin has not yet been defined within the lungs. This review explores their role in acute and chronic disease. During acute inflammation and ischaemia-reperfusion injury cytokines may induce release of endothelin. This is important in the realm of acute lung injury and during surgical procedures such as cardiopulmonary operations including lung resections and transplantation. Complications of surgery including primary organ failure resulting in poor gas exchange as well as increased pulmonary vascular resistance have been linked to the presence of excessive endothelin. Endothelin may have an important role in transplantation biology. The complex process leading to successful lung transplantation includes optimising the donor with brain death, harvesting the lungs, managing acute and chronic rejection, and protecting the vital organs from toxic effects of immunosuppressants. During chronic disease processes, the mitotic action of endothelin may be important in vascular and airway remodelling by means of smooth muscle cell proliferation. We also explore recent advances in drug development, animal models and future directions for research.

Effects of heat stress on metabolism of high-energy phosphates. Comparison of normothermic and hypothermic ischemia.

BACKGROUND: Alterations in metabolic pathways may contribute to the cardioprotective effects of heat stress (HS). We investigated the effects of HS on ATP and phosphocreatine (PCr) levels in the ischemic rat myocardium, after both normothermic and hypothermic ischemia. METHODS: Two protocols were used: (1) normothermic ischemia (20 min at 37 degrees C) with no myocardial protection (n=6 HS; n=6 control); (2) hypothermic ischemia (4 hrs at 4 degrees C) after cardioplegic arrest (n=6 HS; n=6 control). ATP and PCr levels in the heart were measured using 31P nuclear magnetic resonance spectroscopy. RESULTS: At the end of normothermic ischemia, ATP levels were better maintained in HS hearts (C vs HS: 4.51+/-0.66 vs 7.81+/-1.06 micromol/g dry wt+/-SEM, p=0.04). A trend for higher ATP content in HS hearts was observed after 40 min of reperfusion (C vs HS: 11.7+/-1.5 vs 16.9+/-2.0 micromol/g dry wt+/-SEM, p=0.09). PCr content was also higher at the end of 40 minutes of reperfusion in HS hearts (C vs HS: 46.4+/-2.9 vs 56.9+/-3.0 micromol/g dry wt+/-SEM, p=0.03). After prolonged hypothermic ischemia under cardioplegic arrest, heat stress again led to better preservation of ATP levels at the end of ischemia (C vs HS: 5.71+/-0.88 vs 9.23+/-1.38 micromol/g dry wt+/-SEM, p=0.05) and after 40 minutes of reperfusion (C vs HS: 16.8+/-1.4 vs 24.6+/-2.8 micromol/g dry wt+/-SEM, p=0.03). PCr levels were also better maintained at the end of ischemia (C vs HS: 4.87+/-0.77 vs 12.4+/-3.0 micromol/g dry wt+/-SEM, p=0.03) and after 40 minutes of reperfusion in HS hearts (C vs HS: 55.1+/-7.0.vs 79.8+/-7.3 micromol/g dry wt+/-SEM, p=0.03). CONCLUSIONS: Heat stress induces changes in the energy profile of the heart which results in better preservation of ATP and phosphocreatine levels. These changes could be observed after brief normothermic ischemia and also after prolonged hypothermic ischemia under cardioplegic arrest, mimicking conditions of preservation for cardiac transplantation.

Endothelin-1 stimulates proliferation of human coronary smooth muscle cells via the ET(A) receptor and is co-mitogenic with growth factors.

We investigated the effects of endothelin-1 (ET-1) on growth of cultured human coronary artery smooth muscle cells (cSMC). ET-1 alone stimulated DNA synthesis in growth-arrested cSMC as measured by [3H]thymidine incorporation, with a maximum 63 +/- 23% increase above control by 10(-7) M (P < 0.05). ET-1 (10(-7) M) also stimulated increases in cyclin D1 protein levels after 24 h, and in absolute cell number after 4 days. Furthermore, ET-1 stimulated protein synthesis (maximum 73 +/- 32% increase in [3H]leucine incorporation by 10(-7) M (P < 0.05)), as well as triggering intracellular calcium transients in human cSMC, as visualised under fura-2 fluorescence microscopy. The selective ET(A) receptor antagonist BQ123 inhibited the increases in DNA synthesis, cell number, protein synthesis and intracellular calcium concentration in response to ET-1, whereas the ET(B) receptor antagonist BQ788 had no such effects. Furthermore, the ET(B) agonist sarafotoxin 6c had no effect on cSMC DNA synthesis. In addition, co-incubation of ET-1 with threshold concentrations of the growth factors, platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), resulted in pronounced synergistic increases in DNA synthesis over that observed with the factors alone. In conclusion, we have shown that ET-1 stimulates proliferation of human cSMC via the ET(A) receptor and is also a co-mitogen with the growth factors tested. These findings indicate a role for ET-1 in the development of coronary intimal hyperplasia in man.

Coronary vasoconstriction to endothelin-1 increases with age before and after ischaemia and reperfusion.

OBJECTIVE: Ageing is known to be associated with changes within the heart. We investigated whether the coronary response to endothelin-1 (ET) and sarafotoxin S6c (S6c) is altered with increasing age, before and after cardioplegic arrest. METHODS: Using an isolated rat heart model, increasing concentrations of ET and S6c were administered to rats of different ages (group I = one month; group II = five months; group III = 21 months). An identical series of experiments was performed following the addition of indomethacin and NG-nitro-L-arginine methyl ester (L-NAME) to the Krebs perfusion fluid. In a third series of experiments, increasing doses of ET-1 were added to hearts following 4 h of cardioplegic arrest at 4 degrees C. RESULTS: Coronary flows are expressed as a percentage of initial coronary flow +/- SEM. There was a greater decrease in coronary flow in the older rats for all doses of ET-1. ET-1 (10(-9) M) reduced coronary flows to 72.8 +/- 3.7, 53.2 +/- 6.7 and 56.5 +/- 10.7% for groups I-III respectively (P = 0.01 I vs. II; P = 0.1 I vs. III). A similar response to ET-1 was seen in hearts perfused with indomethacin and L-NAME when compared to those perfused without (P = NS). Perfusion with ET-1 (10(-9) M) following 4 h of cardioplegic arrest reduced coronary flows to 40.5 +/- 4.9, 26.8 +/- 4.8 and 24.1 +/- 3.9%, respectively (P = 0.08 I vs. II; P = 0.03 I vs. III). Perfusion with S6c (10(-10) M) produced coronary flows of 93.3 +/- 5.5, 77.0 +/- 3.5 and 73.9 +/- 3.9% for groups I-III, respectively (P = 0.03 I vs. II; P = 0.01 I vs. III). Perfusion with S6c (10(-9) M) in the presence of L-NAME and indomethacin reduced coronary flows to 85.7 +/- 3.0, 81.6 +/- 2.2 and 74.6 +/- 3.6% (P = NS I vs. II; P = 0.03 I vs. III). CONCLUSIONS: The coronary vasoconstrictor response to ET-1 and S6c increases with age. The increased vasoconstriction in response to ET-1 is independent of the decrease in NO release seen with ageing.

Role of endogenous endothelin in the regulation of basal coronary tone in the rat.

1. Coronary vascular tone is a vital factor that regulates the delivery of oxygen to cardiac muscle. We tested the hypothesis that basal coronary tone may depend on the release of an endogenous vasoconstrictor peptide, endothelin (ET). 2. Using an isolated, Krebs solution-perfused rat heart we measured the changes in coronary flow following the administration over a 30 min period of the ET antagonists Ro61-0612 (mixed ETA/ETB), PD155080 (ETA) and BQ788 (ETB). 3. In a second series of experiments, hearts were randomly assigned to perfusion with plain Krebs solution, or with Krebs solution to which L-NAME and/or indomethacin had been added. The effect on coronary flow following the addition of Ro61-0612 was then measured. 4. Perfusion with Ro61-0612 (10-4 M) alone increased coronary flow by 57.8 % vs. control (P = 0.00001). PD155080 (10-4 M) increased coronary flow by 28.9 % (P = 0.009), whereas BQ788 had no effect on coronary flow. 5. In the second series of experiments, Ro61-0612 increased coronary flow by 6.6 +/- 0.8 ml min-1 in hearts perfused with plain Krebs solution, by 3.8 +/- 0.8 ml min-1 in hearts to which both L-NAME and indomethacin had been added, by 3.3 +/- 0.7 ml min-1 in hearts to which L-NAME had been added, and by 6. 9 +/- 0.5 ml min-1 in hearts to which indomethacin had been added to the Krebs buffer. 6. In hearts perfused with Krebs solution alone, nitric oxide (NO) release into the coronary sinus increased from 219. 8 to 544.9 pmol min-1 g-1 following the addition of Ro61-0612 (P = 0. 06). There was no detectable release of NO from hearts perfused with L-NAME alone or in combination with indomethacin either before or after the addition of Ro61-0612. 7. We conclude that endogenous ET plays a role in coronary tone mediated via ETA receptors. This vasodilatation is partially due to an increase in endogenous NO release. However, a significant vasodilatation is still seen following the inhibition of NO synthesis. We propose that basal coronary tone depends on a balance between the endogenous release of vasodilators such as NO and vasoconstrictors such as ET.

Influence of heat stress on myocardial metabolism and functional recovery after cardioplegic arrest: a 31P N.M.R study.

OBJECTIVE: Heat stress and induction of heat shock proteins confer protection against myocardial ischemia-reperfusion injury; however the precise mechanisms of this effect remain unknown. We investigated the influence of heat stress on metabolic and functional recovery after cardioplegic arrest, in a protocol mimicking clinical donor heart preservation. METHODS: Langendorff perfused rat hearts in control group (C, n = 6) and heat stressed (24 h prior to experiment) group (HS, n = 6) were subjected to 4 h of ischemia at 4 degrees C following cardioplegic arrest (St. Thomas' No. 1). 31P nuclear magnetic resonance spectroscopy was used to follow changes in ATP, phosphocreatine and inorganic phosphate concentrations during the pre-ischemic, ischemic and reperfusion periods. Myocardial adenine nucleotide levels in hearts at the end of experiments and purine catabolite release in coronary effluent during reperfusion, were evaluated using high performance liquid chromatography. Mechanical function in the pre-ischemic and reperfusion periods was evaluated using an intraventricular balloon. Western immunoblotting was used to quantitate HSP70 expression. RESULTS: Although baseline concentrations of ATP and phosphocreatine were similar in C and HS groups, the rate of high-energy phosphate depletion was attenuated during the early phase of ischemia in HS groups. On reperfusion, recovery of ATP was 10-20% greater in HS versus C groups; phosphocreatine levels also recovered better in the HS group, transiently reaching levels 40% higher in HS versus C groups. The concentrations of adenine nucleotides in hearts were significantly higher in the HS versus C groups. These changes were associated with an attenuation of total purine catabolite release in the coronary effluent in HS versus C groups. A significant improvement in relative recovery of developed pressure was shown in HS versus C groups in the post-ischemic periods. CONCLUSIONS: Heat stress causes beneficial changes in high-energy phosphate metabolism in the rat heart subjected to cardioplegic arrest and ischemia. Improved mechanical recovery in HS versus C groups was associated with a decreased rate of high-energy phosphate depletion and increased recovery of ATP and phosphocreatine levels during reperfusion. Changes in energy metabolism may play a role in the mechanism of cardioprotection by heat stress during prolonged hypothermic cardiac arrest. rights reserved.

Influence of ageing on functional recovery and guanine nucleotide levels of the heart following cold cardioplegic arrest.

OBJECTIVE: The effect of age on metabolism and mechanical recovery of the heart after cardioplegic arrest is important, but remains a relatively unexplored subject. In this study, functional recovery and nucleotide levels were compared in the heart at different ages subjected to prolonged hypothermic cardioplegic arrest. METHODS: Three different age groups of rats: 1 (A); 4 (B); and 16 months (C) were perfused in working mode and subjected to cardioplegic arrest (St. Thomas' No. 1) and ischemia for 4 h at 4 degrees C, followed by reperfusion for 35 min. Cardiac function (cardiac output and aortic pressure) was recorded before and after ischemia. Another series of hearts in all three age groups underwent 5 min of normoxic perfusion to obtain pre-ischemic baseline metabolite concentrations. Hearts were freeze-clamped at the end of each experiment and used for determination of nucleotide and creatine metabolites by HPLC. RESULTS: The post-ischemic recovery (% of the pre-ischemic value) of the cardiac power was 48.9 +/- 7.8% for group A, which was significantly higher than the functional recovery of group B (24.1 +/- 3.5%) or C (21.4 +/- 4.7%, P < 0.05, respectively). There was no difference in ATP or the total adenine nucleotide or creatine metabolite concentrations between the three age groups. In contrast, both GTP and the total guanine nucleotide concentration was highest in A (P < 0.05). Total guanylate pool was 1.52 +/- 0.10 1 micromol/g dry wt. in A, as compared to B (1.05 +/- 0.04) or C (1.12 +/- 0.04). NAD was significantly higher in B (4.1 +/- 0.1. P < 0.05), when compared to A (3.6 +/- 0.1) and C (3.8 +/- 0.1). CONCLUSION: Best post-ischemic functional recovery after cardioplegic arrest was observed in the 1-month-old hearts (A) and was associated with highest guanine nucleotide concentration; preservation of guanine nucleotide pool in the youngest hearts may be an important mechanism for improved cardioprotection due to the important role of GTP in signalling pathways.

Relative induction of heat shock protein in coronary endothelial cells and cardiomyocytes: implications for myocardial protection.

OBJECTIVES: Induction of the 70 kd heat shock protein in the heart is known to exert a protective effect against postischemic mechanical and endothelial dysfunction. However, the exact site of induction and the mechanisms involved remain unknown. The aim of this study was to investigate the relative capacity of endothelial and myocardial cells to express the 70 kd heat shock protein in response to heat stress, as well as their significance. METHODS: (1) Postischemic recovery of cardiac mechanical and endothelial function was studied in isolated rat hearts with and without endothelial denudation with saponin. (2) Semiquantitative determination of induction of 70 kd heat shock protein by Western immunoblotting was performed in the whole cardiac homogenate, in isolated cardiac myocytes, and in coronary endothelial cells. (3) Immunocytochemistry was used to visualize the distribution of induction of 70 kd heat shock protein in both cell types. RESULTS: Postischemic recovery (percent preischemic value +/- standard error of the mean) of cardiac output in hearts from heat-stressed animals was significantly improved (66.7 +/- 6.9 vs 44.5 +/- 4.5 in the control group, p < 0.01). In heat-stressed hearts treated with saponin no improvement in the recovery of cardiac output was noted (44.7 +/- 6.9 in heat-stressed hearts vs 38.0 +/- 4.0 in heat-stressed, saponin-treated hearts, p = not significant). Endothelial function (as assessed by the vasodilatory response to the endothelium-dependent vasodilator 5-hydroxytryptamine) improved from 31.0 +/- 5.2 in the control group to 65.8 +/- 7.1 in heat-stressed hearts (p < 0.02 vs control) and dropped to -1.9 +/- 3.8 in heat-stressed hearts treated with saponin. Immunocytochemistry showed that only sections of hearts from heat-treated rats showed a strong specific reaction with heat shock protein antibody. The positive staining was seen in endothelial cells. Induction of 70 kd heat shock protein content in the whole cardiac homogenate from heat-stressed rats as measured by Western immunoblotting was 5.2 +/- 1.9 (vs 0.0 in non-heat-stressed rats, p < 0.0001) and dropped to 0.0 in heat-stressed hearts treated with saponin. The tentative amount of 70 kd heat shock protein was 18.1 +/- 7.8 in isolated endothelial cells from heat-stressed hearts and 2.3 +/- 2.3 in isolated cardiac myocytes (p < 0.01 vs endothelial cells). CONCLUSIONS: Coronary endothelial cells are the main site of induction of 70 kd heat shock protein in the heart and appear to contribute to the protective effects of heat stress on the recovery of mechanical and endothelial function.

The effect of L-arginine on myocardial recovery after cardioplegic arrest and ischemia under moderate and deep hypothermia.

BACKGROUND: Depletion of L-arginine (L-arg), the substrate for nitric oxide (NO) synthesis, could be one of the mechanisms responsible for the reduced production of NO and decreased coronary flow (CF) during reperfusion. This, in turn, may adversely affect mechanical function. We aimed to study the benefits of exogenous administration of L-arg under conditions that mimick preservation of the heart for transplantation and routine cardiac surgery. METHODS AND RESULTS: Isolated working rat hearts perfused with oxygenated Krebs-Henseleit buffer were subjected to one of the two experimental protocols: (1) cardioplegic arrest with St Thomas' No 1 cardioplegic solution and 240 minutes of deep hypothermic (4 degrees C) ischemia, and (2) cardioplegic arrest with St Thomas' No 1 cardioplegic solution and 60 minutes of moderate hypothermic (20 degrees C) ischemia. In each protocol, hearts were divided into four groups (1 to 4 for protocol A and A through D for protocol B; n=6 in each group). In groups 1 and A (controls), hearts were arrested with the St Thomas' No 1 and were reperfused with standard Krebs-Henseleit buffer. In groups 2 and B, L-arg was added to cardioplegic fluid; in groups 3 and C, L-arg was added to reperfusate; and in groups 4 and D, L-arg was added to both cardioplegic fluid and reperfusate. Cardiac output, dP/dt, CF, and NO concentrations in the coronary effluent were evaluated in all groups before and after ischemia. After 4 degrees C ischemia (protocol A), the postischemic recovery of dP/dt for the control hearts in group 1 was 51.0+/-3.4%, which increased significantly to 73.3+/-2.7% and 70.1+/-4.4% in groups 3 and 4, respectively. In group 2, recovery of dP/dt was similar to the control group's and was 56.5+/-4.5%. Increased postischemic cardiac output and CF and increased production of NO correlated with improved functional recovery. After 20 degrees C ischemia (protocol B), the postischemic recovery of dP/dt was 47.2+/-3.5% in control group A and significantly increased to 79.2+/-2.6% in group B, to 82.0+/-3.5 in group C, and to 83.9+/-3.3 in group D. Increased postischemic CF and increased production of NO were closely related to improvement in mechanical function. CONCLUSIONS: Exogenous L-arg considerably improves the postischemic recovery of cardiac mechanical function and CF after cardioplegic arrest and ischemia by stimulation of NO production when given in the reperfusate after both 4 degrees C and 20 degrees C ischemia. However, L-arg as an additive to cardioplegia was only beneficial after 20 degrees C, and not after 4 degrees C ischemia.

Inhibition of endogenous endothelin during cardioplegia improves low coronary reflow following prolonged hypothermic arrest.

OBJECTIVE: Endothelin-1 (ET) is a potent endogenous vasoconstrictor which has been shown to be increased following ischaemia and cardiopulmonary bypass. We tested the hypothesis that inhibition of ET synthesis during cardioplegic arrest using phosphoramidon (an ET converting enzyme inhibitor) or blockade of ET receptors using bosentan (a mixed ET(A)/ET(B) antagonist), might improve the postischaemic recovery of coronary flow. METHODS: Using an isolated Langendorff perfused rat heart model we compared the addition of phosphoramidon or bosentan to St Thomas' Hospital No. cardioplegia vs. control (plain cardioplegia). We measured recovery of coronary flow following 4 h of cardioplegic arrest at 4 degrees C. In a second series of experiments using an isolated working rat heart model we measured the recovery of cardiac function following 4 h of cardioplegic arrest at 4 degrees C. Results are expressed as percentages of preischaemic values (+/- S.E.M). RESULTS: In the first series of experiments, addition of phosphoramidon to cardioplegia improved the postischaemic recovery of coronary flow after 30 min of reperfusion: control 81.3% (+/- 3.5); phosphoramidon 10(-6) M 86.2% (+/- 3.1); phosphoramidon 10(-5) M 95.0% (+/- 3.0) P = 0.03 vs. control. Likewise, addition of bosentan 10(-5) M improved coronary flow following 20 min of reperfusion: control 96.7% (+/- 4.0), and bosentan 109.6% (+/- 4.7) P = 0.04. The addition of phosphoramidon or bosentan had no effect on the postischaemic recovery of mechanical function following 30 min of reperfusion. CONCLUSION: Both inhibition of ET synthesis and ET receptor blockade during prolonged hypothermic arrest improves postischaemic coronary flow, but appears to have no effect on the recovery of cardiac mechanical function.

Routine use of ultrasound 24 hours before laparoscopic cholecystectomy can predict the need for intraoperative cholangiogram: results of a 12-month prospective audit.

Intraoperative cholangiograms and exploration of the common bile duct (CBD) during laparoscopic cholecystectomy are technically more demanding than during open cholecystectomy. This has led to many surgeons using a selective policy for cholangiography. In this study we prospectively assessed whether biliary ultrasound (CBD diameter > or = 6 mm) or one or more abnormal liver function tests (LFTs) performed in the 24 hours preoperatively could predict the need for cholangiography. Forty-five patients were studied (14 male, 31 female), mean age 47.8 years. All patients with one or both tests abnormal preoperatively (19 patients) underwent intraoperative cholangiograms. Seven CBD stones were identified (16%). There was no evidence of CBD stones in patients not undergoing cholangiography at a median follow-up of 18 months. In patients with stones, three underwent open CBD exploration, and four underwent endoscopic retrograde choledochopancreatography (ERCP) and sphincterotomy in the early postoperative period without complications. CBD diameter > or = 6 mm is a useful predictor of CBD stones. These may be treated successfully by postoperative ERCP.

Can serum interleukin-6 levels predict the outcome of patients with right iliac fossa pain?

In patients with right iliac fossa (RIF) pain it can be difficult to distinguish between appendicitis and nonspecific abdominal pain (NSAP). In this study we sought to determine whether serum interleukin-6 (IL-6) levels, an early marker of acute inflammation, taken at the time of admission could predict the outcome of patients admitted with RIF pain. Data were collected in a prospective manner on 53 consecutive patients (23 male, 30 female), mean age 22.1 years (range 10-79 years). Nineteen (36%) patients underwent surgery, of whom 16 had appendicitis (histologically proven). The mean (SEM) IL-6 levels (pg/ml) in patients undergoing operation vs those receiving non-operative management were 270.8 (106.3) vs 265.0 (80.4) (P = NS). The mean white blood cell (WBC) counts (x10(9)/l) in these patients were 14.28 (0.81) vs 9.66 (0.67), respectively (P = 0.0002). When patients with a confirmed diagnosis of appendicitis were compared with patients with a diagnosis of NSAP, the IL-6 levels were 149.4 (69.1) vs 363.6 (113.2), respectively (P = NS). In the same groups of patients, the WBC counts were 14.21 (0.81) vs 9.51 (0.68) (P = 0.004). We conclude that IL-6 levels taken at the time of admission are not useful in predicting the outcome of RIF pain.

Ageing is associated with reduced basal and stimulated release of nitric oxide by the coronary endothelium.

The ageing process is known to be associated with biochemical and functional changes in the heart. In an attempt to determine whether the ability of the coronary endothelium to secrete nitric oxide (NO) both at rest and in response to pharmacological stimulation is age dependent, we studied four groups of rats of different ages (1, 5, 15 and 26 months, respectively). Basal release of NO by endothelium as assessed by response of coronary flow to L-monomethylarginine, an inhibitor of NO synthase, was higher in the younger age groups. Similarly, the response of coronary flow to 5-hydroxytryptamine, a selective probe of endothelial capacity to secrete NO, was diminished in the older animals. This was confirmed by direct measurement of NO by chemiluminescence in the coronary effluent. In contrast, the response to glyceryl trinitrate appeared to be unaltered by age. It is concluded that in rats, basal and stimulated release of nitric oxide by the coronary endothelium deteriorates with age.