Regional O2 consumption and coronary flow during beta adrenoceptor stimulation in reperfused canine myocardium

This study was performed to assess the ability of a reperfused region to increase its flow and O2 consumption upon inotropic stimulation. Isoproterenol (5 micrograms/kg/min) was infused i.v. during the reperfusion phase (4 hr) after 2 hr of the left anterior descending coronary artery occlusion in anesthetized open chest dogs (n = 7). The response was compared to a similar untreated reperfused group (n = 8). Coronary blood flow was obtained with labeled microspheres. Arterial and venous O2 saturations were determined microspectrophotometrically. During reperfusion and isoproterenol infusion, significantly higher heart rate (226 +/- 48 beats/min), maximum positive derivative of left ventricular pressure (3132 +/- 838 mm Hg/sec) and systolic aortic blood pressure (162 +/- 16 mm Hg) were recorded compared to reperfusion in the control group (133 +/- 22, 1615 +/- 184 and 124 +/- 30, respectively). In the control group, coronary blood flow to the reperfused areas decreased from preocclusion values of 85 +/- 22 and 95 +/- 43 to 63 +/- 45 and 47 +/- 31 ml/min/100 g for the subepicardium and subendocardium, respectively. O2 extraction was increased significantly in the reperfused region and O2 consumption was similar to that in the nonoccluded area. The corresponding flow values in the treated group at the end of the reperfusion period were 272 +/- 142 and 183 +/- 150 ml/min/100 g, respectively. With isoproterenol, the O2 extraction was not greater than in the nonoccluded area and the O2 consumption increased about 3-fold in comparison to the control group, although the increase in the reperfused subendocardium was less.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of propranolol on regional O2 supply and O2 consumption in reperfused dog myocardium

This study was designed to assess whether propranolol would improve the relationship between O2 supply and O2 consumption in the reperfused ischemic dog myocardium. In 14 dogs, the left anterior descending coronary artery was occluded for 2 hr, followed by a 4-hr period of reperfusion. In 7 of the 14 dogs, 1 mg/kg of propranolol was administered 10 min before and again 2 hr after reperfusion. Small artery and vein O2 saturations obtained microspectrophotometrically were combined with regional blood flow measurements using radioactive microspheres to determine regional myocardial O2 consumption. In both groups, 2 hr of occlusion lowered the regional flow to a similar level. In the control group, 4 hr of reperfusion returned the blood flow toward normal levels, from 17 +/- 20 ml/min/100 g (mean +/- S.D.) at the end of occlusion to 60 +/- 42 ml/min/100 g in the affected area compared with 84 +/- 28 ml/min/100 g in the nonischemic area. In the propranolol-treated animals, the flow increase with reperfusion was not significant (25 +/- 30 ml/min/100 g to 45 +/- 26 ml/min/100 g). O2 extraction was greater in the ischemic than in the unaffected area in both groups. However, ischemic region O2 extraction was lower in the propranolol-treated group than in the control group. There were a greater number of arteries and veins with reduced O2 saturations in the control group reperfused area compared with the nonischemic area. Propranolol decreased the number of low O2 saturation vessels in the ischemic area.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of thromboxane receptor blockade on oxygen supply/consumption variables during reperfusion in the anesthetized dog

The thromboxane A2/PGH2 receptor antagonist SQ 30,741 has been previously shown to reduce infarct size and to improve subendocardial reflow. The purpose of this study was to determine the effect of SQ 30,741 on reperfusion O2 supply/consumption variables. Anesthetized open-chest dogs treated with vehicle or 1 mg/kg + 1 mg/kg/hr SQ 30,741, i.v. (starting 10 min after the onset of ischemia) were subjected to 90 min left circumflex coronary occlusion and 3 hr reperfusion. Regional myocardial blood flow (radioactive microspheres) and arterial and venous O2 saturations (microspectrophotometry) were determined. Animals treated with SQ 30,741 had significantly higher subendocardial reflow at 3 hr (48 +/- 6 ml/min/100 g) compared with vehicle (27 +/- 10 ml/min/100 g). At 3 hr postreperfusion, O2 extraction was significantly higher in the reperfused region compared with the nonischemic region, although extraction was not at maximal values. O2 extraction was similar in vehicle- and SQ 30,741-treated animals despite the near doubling of reflow into the subendocardial region with SQ 30,741. O2 consumption was significantly reduced in the reperfused subendocardial region (1.65 +/- 0.9 ml O2/min/100 g) in vehicle controls compared with the nonischemic subendocardial region (10.2 +/- 2.6 ml O2/min/100 g). SQ 30,741 significantly improved subendocardial reperfused regional O2 consumption (4.03 +/- 0.41 ml O2/min/100 g) compared with vehicle and this increase was proportional to the flow increment (no change in the O2 supply/consumption ratio). SQ 30,741 is thus increasing subendocardial reflow secondary to an increase in O2 consumption and the increased O2 consumption may be due to preservation of myocardial tissue.     

Effect of reperfusion on O2 supply/consumption balance in ischemic canine left ventricle

This study was designed to assess the effects of reperfusion on regional O2 supply and O2 consumption of ischemic areas of the myocardium in 15 anesthetized open-chested dogs. The left anterior descending coronary artery (LAD) was occluded for 6 h (n = 8), 2 h (n = 5), 2-h occlusion followed by 4-h period of reperfusion (n = 7), and 10-min occlusion followed by 90-min period of reperfusion (n = 3). Small artery and vein O2 saturations obtained microspectrophotometrically were combined with regional flow measurements using radioactive microspheres to determine regional myocardial O2 consumption. Coronary occlusion for 2 or 6 h significantly reduced mean flow to 15 +/- 8 and 13 +/- 14 ml/min/100 g (mean +/- SD), respectively, in the affected LAD areas as compared to 128 +/- 26 and 113 +/- 46 ml/min/100 g in the non-ischemic areas. In the 4-h reperfusion group, reperfusion increased the average flow (60 +/- 42 ml/min/100 g). O2 extraction was greater in the ischemic area than in the unaffected area after both occlusion and 4-h reperfusion. In the affected area, O2 consumption was reduced by 84% after 6-h occlusion. Reperfusion for 4 h increased O2 consumption toward normal values. Coronary artery occlusion produced an increase in the number of arteries and veins with reduced O2 saturations and this was not affected by reperfusion. Short-term occlusion had no significant O2 supply effects after 90 min of reperfusion. It can be concluded that even though there was an increased O2 consumption as a consequence of reperfusion, O2 consumption still appeared to be flow-limited as indicated by the microregions of low O2 supply and/or high O2 extraction.     

Effect of diltiazem on infarct size, reperfusion flow and flow reserve: the effect of timing of treatment

This study was performed to determine if improved subendocardial reflow seen with diltiazem pretreatment after left circumflex coronary (LCX) occlusion is due to a direct vasodilatory effect of diltiazem on the reperfused bed or due to an increased flow maximum or reserve. In the first part of this study anesthetized dogs were subjected to saline or diltiazem (infused starting before, 10 min after LCX occlusion or 2 min before reperfusion; 0.18 mg/kg + 0.45 mg/kg/hr i.v. for all groups) treatment with a 90-min LCX occlusion and 5-hr reperfusion and myocardial blood flow and infarct size were determined at the end of the experiment. In the second part, maximal flow using intracoronary adenosine was determined at 1 and 3 hr postreperfusion in the ischemic bed when pretreated with saline or diltiazem. Myocardial infarct size was reduced significantly only in animals pretreated with diltiazem compared to saline-treated animals. At 1-hr postreperfusion, subendocardial flow (microspheres) was significantly higher only with diltiazem pretreatment compared to the saline group (100 +/- 17 vs. 54 +/- 8 ml/min/100 g, respectively) and subendocardial reperfusion flows were negatively correlated to infarct size (r = 0.97, P less than .05). Thus, diltiazem only improves reflow and infarct size when infused before occlusion and this improved reflow does not occur via a direct vasodilator action of diltiazem. When maximal vasodilating doses of adenosine were given, flow in the ischemic region was nearly identical for saline and diltiazem pretreated groups despite higher preadenosine flows in the diltiazem group (higher resting flow occurred at the expense of the existing flow reserve).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of diltiazem on glycolysis and oxidative metabolism in the ischemic and ischemic/reperfused heart.

We have recently demonstrated that calcium channel blockers can protect the ischemic myocardium at concentrations which do not decrease myocardial workload or metabolic demand before ischemia. In this study, we extended these observations by determining what effect the calcium channel blocker, diltiazem, has on overall myocardial energy substrate metabolism in aerobic, ischemic and reperfused ischemic hearts. Isolated working rat hearts were perfused at a 11.5-mm Hg preload, 80-mm Hg afterload, with Krebs-Henseleit buffer containing 11 mM glucose, 1.2 mM palmitate and 500 microU/ml insulin. Glycolysis and glucose oxidation rates were determined in aerobic and reperfused ischemic hearts perfused with [3H]/[14C]glucose, whereas fatty acid oxidation rates were determined under similar conditions in hearts perfused with [14C]palmitate. Addition of diltiazem (0.8 microM) before subjecting hearts to a 30-min period of global no-flow ischemia resulted in a significant improvement in recovery of mechanical function (heart rate x developed pressure during reperfusion recovered to 28 and 53% of preischemic levels, in control and diltiazem-treated hearts, respectively). If diltiazem was added at reperfusion, no improvement of functional recovery was seen. Addition of diltiazem before or after ischemia had no effect on palmitate or glucose oxidation during reperfusion, but did significantly decrease rates of glycolysis during reperfusion. In hearts subjected to low-flow ischemia (coronary flow = 0.5 ml/min), diltiazem significantly decreased glycolytic rates during ischemia (glycolytic rates were 2.09 +/- 0.25 and 1.58 +/- 0.28 mumol/min.g dry wt. in control and diltiazem-treated hearts, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of Propranolol in Improvement of the Relationship between O2 Supply and Consumption in an Ischemic Region of the Dog Heart

Several aspects of the myocardial O₂ supply/consumption relationship were determined after coronary artery occlusion and subsequent β-adrenergic blockade in 16 anesthetized open-chest dogs. Small artery and vein O₂ saturations, and hence extraction, were obtained microspectrophotometrically and combined with radioactive microsphere blood flow determinations to calculate regional myocardial O₂ consumption. Eight dogs remained untreated after coronary artery ligation while another group was given 2 mg/kg propranolol, 10 min after occlusion. Untreated occlusion resulted in decreased arterial and especially venous O₂ saturations, indicating an increased O₂ extraction. Ischemic O₂ consumption was reduced and the subendocardial/subepicardial consumption ratio was reversed (1.26 vs. 0.37) due to the pattern of occluded area flow. Calculated O₂ supply/consumption also decreased. Propranolol produced no significant changes in volume or distribution of flow within the ischemic region while reducing flow, extraction, and consumption in the unoccluded region. The heterogeneity of arterial and particularly venous O₂ saturations within the ischemic region decreased dramatically. Venous O₂ saturations were elevated relative to the control group resulting in a reduced O₂ extraction. The decrease in heterogeneity of arterial and venous O₂ saturations suggest that propranolol eliminates microregions of relatively high O₂ extraction, consumption, and/or a majority of vessels with extremely low flow. This leads to a significant improvement in the O₂ supply/consumption ratio in the ischemic myocardium of the dog. This may be due to a reduction in the heterogeneity and level of β₁-adrenergic receptor activity within the heart.     

Contrasting effects of verapamil and nifedipine on pH of ischemic myocardium in the dog

It remains unknown whether the actions of verapamil to depress and nifedipine to enhance contractile function of ischemic myocardium influence the degree of myocardial ischemic injury. Thus, we measured intramyocardial pH using fiberoptic pH probes in 43 anesthetized open-chest dogs pretreated for 30 min with verapamil, or nifedipine in doses that decreased aortic pressure 10 to 15 mm Hg before ligation of the left anterior descending coronary artery for 15 min. Drugs were continued during the 15-min ischemic period until the animals were euthanized without reperfusion: verapamil, 10-20 micrograms/kg/min and nifedipine, 2 to 4 micrograms/kg/min i.v. Verapamil-treated dogs showed higher pH of ischemic subendocardium after 15 min ischemia (6.75 +/- 0.07) than did the nifedipine (6.48 +/- 0.04) or placebo (6.43 +/- 0.05) groups, even if the animals were paced (6.71 +/- 0.11) to prevent the negative chronotropic effect of verapamil (P less than 0.01). Neither verapamil nor nifedipine changed collateral myocardial blood flow from 0.10 +/- 0.02 in the subendocardium and 0.17 +/- 0.03 ml/min/g in the subepicardium. Left ventricular function estimated by left ventricular dp/dt was depressed 15% by verapamil and enhanced 26% by nifedipine. Thus, verapamil, but not nifedipine, relieves acidosis of ischemic myocardium after acute coronary occlusion in doses that sustain a 10 to 15 mm Hg decrease in aortic pressure. Nifedipine, in doses that produced the same 10 to 15 mm Hg decrease in mean aortic pressure, did not increase intramyocardial pH, as it enhanced contractile function, estimated by left ventricular dp/dt.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thromboxane A2 antagonist and diltiazem-induced enhancement of contractile function: the effect of timing of treatment

We determined the ability of the thromboxane A2 antagonist SQ 29,548 or diltiazem to enhance postischemic myocardial function and if the effects of these compounds were occurring during occlusion or reperfusion periods. Anesthetized open-chest dogs were pretreated with i.v. saline, SQ 29,548 (0.20 mg/kg + 0.20 mg/kg/hr) or diltiazem (0.18 mg/kg) 15 min before the left anterior descending coronary artery was occluded. In another group, animals were given saline, SQ 29,548 or diltiazem 1 min before reperfusion. The occlusion was maintained for 15 min and reperfusion instituted for 5 hr. Subendocardial segmental shortening was monitored throughout the experiment using sonomicrometry. Left anterior descending coronary artery occlusion resulted in marked systolic bulging to similar levels in all groups. Upon reperfusion, function returned immediately but, after several min, hypokinesia existed in saline-treated animals. At 5-hr postreperfusion, percentage of shortening returned to only 20% of base-line values in saline-treated animals. Both diltiazem and SQ 29,548 pretreatment resulted in significant (P less than .05) improvements in function such that at 5-hr postreperfusion, shortening returned to 60% of base-line values. When given immediately before reperfusion, SQ 29,548 still resulted in significant protection of function, although this occurred much later compared to pretreated animals. Diltiazem did not improve function when given immediately before reperfusion. SQ 29,548 improves reperfusion function and, thus by inference, thromboxane A2 may play a role in postischemic hypokinesia and some of its protective effects may occur during reperfusion. Diltiazem seems to protect reperfusion function only when present during ischemia per se.     

Myocardial reperfusion: leukocyte accumulation in the ischemic and remote non-ischemic regions

Neutrophil accumulation in the first hour of myocardial reperfusion was assessed in dog hearts submitted to ischemia with and without necrosis. In anesthetized dogs, the left anterior descending coronary artery was occluded for 20 min (group IS-20 n = 7) and for 90 min (group IS-90 n = 6). Immediately after reperfusion, 99m Tc-Ceretec (Exametazime-Amersham) labeled neutrophils were injected into a central vein and 60 min later the dogs were killed. The left ventricle was isolated, weighed, and sliced. Six sections, 3 from normal and 3 from reperfused regions, were divided into endocardial and epicardial layers. Myocardial and blood radiometry were used to evaluate the neutrophil accumulation during reperfusion. The differences between leukocyte accumulation in both groups were assessed comparing the ischemic/normal relations in the endocardial and epicardial layers. A second comparison considered myocardium/blood relations to allow the evaluation of differences between remote normal myocardial areas of the two experimental groups. In dogs submitted to 20 min of ischemia, leukocytes accumulated significantly more (P < 0.01) in the reperfused myocardium as compared with the non-ischemic region. The increase occurred both in the endocardial (1.49+/-0.20) and epicardial (1.48+/-0.29) regions. After 90 min ischemia, leukocyte accumulation was more intense and predominant in endocardium where there was a 4-fold (3.97+/-1.28) increase over the non-ischemic region, while in the epicardium this relation was only 2.5-fold (2.56+/-0.98). In the remote non-ischemic myocardium, leukocyte accumulation was greater in dogs submitted to 90 min of ischemia compared to the 20 min group (P < 0.01), without distinction between endocardial and epicardial layers. This accumulation in territories of non-culprit coronary arteries may be related to the blood flow abnormalities and matrix structure changes that occur in these regions during the development of an acute myocardial infarction and its natural repair.     

Coronary vascular injury due to ischemia-reperfusion is reduced by pentoxifylline.

Myocardial ischemia and reperfusion cause coronary vascular injury involving both the large epicardial arteries and the microcirculation. Although the mechanisms are unclear, leukocytes appear to play an important role. Since the methylxanthine derivative pentoxifylline (PTX) decreases neutrophil activity in vitro, we hypothesized that it might diminish coronary vascular injury due to ischemia and reperfusion. We investigated the effects of PTX on coronary microvascular and epicardial artery injury in open chest, anesthetized dogs undergoing moderate (60 min) or more prolonged (90 min) ischemia due to left anterior descending coronary artery occlusion followed by 60 min of reperfusion. As an index of microvascular injury, we assessed regional permeability with a dual radioisotope protein leak index (PLI) method. Both ischemic periods with reperfusion increased the PLI of severely ischemic (flow less than or equal to 20/ml/min/100 g) myocardium by 2.5- and 3-fold, respectively, compared to nonischemic (flow greater than or equal to 100 ml/min/100 g) myocardium. Treated dogs received PTX (20 mg/kg bolus plus 0.1 mg/kg/min infusion) before ischemia. PTX reduced the increase in the PLI by 40% after 60 min of ischemia (PLI = 5.87 +/- 0.48 vs. 4.10 +/- 0.52 untreated vs. PTX-treated; P less than .05), and by 25% after 90 min of ischemia (6.84 +/- 0.49 vs. 4.84 +/- 0.42; P less than .05). The amount of protein leak was inversely related to ischemic blood flow, and the magnitude of this relationship was significantly reduced in PTX-treated animals. In arterial rings from untreated dogs exposed to 90 min of ischemia followed by reperfusion, there was impaired relaxation to ADP and acetylcholine, but not to sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)     

Failure of interventions to maintain mitochondrial function in ischemic myocardium

The purpose of this study was to investigate whether pyruvate (2.5 mmol/kg), the combination of glucose (3.9 mmol/kg) and insulin (0.13 unit/kg) with potassium (9.27 meq/kg), or sodium dichloroacetate (120 mg/kg) infused for 15 minutes before and 20 minutes after ligation of the left anterior descending coronary arterv in anesthetized dogs restricted the depression in mitochondrial respiratory function induced by ischemia. Myocardial blood flow after ligation in the three groups was o.2 ml/min per gram or less in ischemic subendocardium and was similar to that in saline-infused controls that had also undergone coronary artery ligation. The depressions induced in mitochondrial respiratory control index and state 3 respiration by ischemia in the subendocardium and subepicardium of the three treatment groups, when compared with corresponding nonischemic tissue, were not significantly improved from the control values. It was concluded that these three interventions fail to preserve mitochondrial respiration in ischemic myocardium.     

Effect of intraaortic balloon counterpulsation (IABP) on myocardial infarct size and collateral flow in an experimental dog model

To determine the influence of IABP on infarct size and collateral blood flow in each of 12 openchest anaesthetised mongrel dogs two small branches of the left coronary artery were occluded consecutively. The perfusion areas of both branches were comparable in size. IABP was started immediately before ligation of the first branch for a 90-min period followed by a reperfusion period of 90 min. Subsequently the second vessel was also occluded for 90 min as a control without IABP while myocardial oxygen consumption remained constant and was then reperfused. Infarct size was expressed as a percentage of the perfusion area. A difference in infarct size with and without IABP (18±17, 18±10% respectively) could not be observed. However a significant increase of collateral blood flow due to IABP in the subendocardial layer from 8.9±4.8 to 14.9±4.6 ml/100 g/min (p<0.05) was prevalent. In the subepicardial layer the augmentation from 23.7±19.9 to 26.9±15.2 was not significant. Thus, in spite of a small increase of collateral blood flow in the subendocardial layer of the ischemic myocardium the infarct size was not reduced by IABP in our dog model.     

Nicotinic acid, free fatty acids and myocardial function during coronary occlusion and reperfusion in the dog

The effect of nicotinic acid on regional myocardial blood flow, percentage of segment shortening and myocardial uptake of free-fatty acids during a 15-min occlusion of the left anterior descending coronary artery and 3-hr reperfusion period was compared to a saline-treated control group. Nicotinic acid (2.4 mumol/kg/min i.v.) was infused 30 min before and throughout the occlusion period. Heart rate, arterial blood pressure and left ventricular systolic and end diastolic pressures were not different during occlusion and reperfusion in the nicotinic acid or saline-treated groups. However, left ventricular dP/dt, an index of global myocardial function and percentage of segment shortening in the ischemic region were greater during occlusion and reperfusion after nicotinic acid. Even though myocardial blood flow was unaltered in the normal or ischemic region during nicotinic acid infusion, subendocardial blood flow during reperfusion was enhanced significantly when compared to the control group. Nicotinic acid also decreased free-fatty acid uptake by the heart during occlusion which returned gradually to the pretreatment control during 3 hr of reperfusion. Thus, the improvement in percentage of segment shortening, dP/dt and subendocardial blood flow during reperfusion may be related to the ability of nicotinic acid to reduce free-fatty acid uptake by the heart during coronary occlusion.     

Alterations in regional blood flow during positive end-expiratory pressure ventilation

PEEP improves the gas-exchange abnormalities that accompany adult respiratory distress syndrome (ARDS). However, since PEEP decreases cardiac output, it may also alter regional blood flow and therefore, substrate delivery to specific organs. To test this hypothesis, radiolabeled 15-mu microspheres were used to directly quantify the effects of mechanical ventilation with PEEP on regional blood flow to individual organs in animals. Mechanical ventilation alone produced a -21.2 +/- 3.6% and a -28.1 +/- 5.2% decrease in cardiac output at 30 and 60 min, respectively. The addition of 14 cm H2O PEEP resulted in little further reduction in cardiac output at 30 and 60 min (-28 +/- 2.3% and -36.4 +/- 4.9%, respectively). However, 25 cm H2O PEEP reduced markedly (p less than .01) cardiac output (-59.2 +/- 6.1% at 30 min and -55.1 +/- 4.0% at 60 min). Although blood flows to the kidney and brain were maintained, decreases in cardiac output were invariably accompanied by proportional decreases in blood flow to the heart. Intravascular volume expansion with saline (20 ml/kg) during 14 cm H2O PEEP significantly improved cardiac output (3.23 +/- 0.34 to 4.22 +/- 0.13 L/min; p less than .01) and proportionately increased blood flow to several regional vascular beds, including the heart. These data suggest that PEEP decreases cardiac output to produce reversible alterations in blood flow to a number of regional vascular beds. These PEEP-induced alterations in regional blood flow may have important implications for the development of multiple-organ failure in ARDS patients.     

Comparative evaluation of the effects of isradipine and diltiazem on antipyrine and indocyanine green clearances in elderly volunteers

Calcium antagonists have been shown to depress hepatic enzymes and accelerate hepatic blood flow. This study was designed to compare the effects of two calcium antagonists, isradipine and diltiazem, on antipyrine and indocyanine green (ICG) clearances in the elderly. Eighteen elderly subjects (aged 65 to 80 years) received either isradipine (5 mg every 12 hours), diltiazem (90 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the third day after the study treatment, a 0.5 mg/kg dose of ICG was administered. Blood samples were obtained over 20 minutes for HPLC determination of ICG plasma concentrations. Ten minutes later, subjects ingested 1.2 gm antipyrine. Blood samples were obtained over 48 hours for HPLC determination of antipyrine plasma concentrations. Mean +/- SD antipyrine clearance after diltiazem (0.0258 +/- 0.0065 L/hr/kg) was significantly lower than that observed after isradipine (0.0334 +/- 0.0098 L/hr/kg) or placebo (0.0329 +/- 0.0082 L/hr/kg). Antipyrine clearance after isradipine was not significantly different from that after placebo. Mean +/- SD ICG clearances after diltiazem (9.17 +/- 1.35 ml/min/kg) or isradipine (9.57 +/- 1.82 ml/min/kg) were significantly higher than that observed after placebo (8.06 +/- 1.45 ml/min/kg). These findings suggest that diltiazem, but not isradipine, affects hepatic enzyme activity in the elderly. Both agents accelerate ICG clearance, a marker of hepatic blood flow.     

Global and regional cerebral blood flow in neonatal piglets undergoing pulsatile cardiopulmonary bypass with continuous perfusion at 25 degrees C and circulatory arrest at 18 degrees C.

To investigate the influence of hypothermic cardiopulmonary bypass (HCPB) at 25 degrees C and circulatory arrest at 18 degrees C on the global and regional cerebral blood flow (CBF) during pulsatile perfusion, we performed the following studies in a neonatal piglet model. Using a pediatric physiologic pulsatile pump, we subjected six piglets to deep hypothermic circulatory arrest (DHCA) and six other piglets to HCPB. The DHCA group underwent hypothermia for 25 min, DHCA for 60min, cold reperfusion for 10 min, and rewarming for 40 min. The HCPB group underwent 15 min of cooling, followed by 60 min of HCPB, 10min of cold reperfusion, and 30 min of rewarming. The following variables remained constant in both groups: pump flow (150 ml/kg/min), pump rate (150 bpm), and stroke volume (1 ml/kg). During the 60-min aortic crossclamp period, the temperature was kept at 18 degrees C for DHCA and at 25 degrees C for HCPB. The global and regional CBF (ml/100g/min) was assessed with radiolabeled microspheres. The CBF was 48% lower during deep hypothermia at 18degrees C (before DHCA) than during hypothermia at 25 degrees C (55.2 +/- 14.3ml/100g/min vs 106.4 +/- 19.7 ml/100 g/min; p < 0.05). After rewarming, the global CBF was 45% lower in the DHCA group than in the HCPB group 48.3 +/- 18.1 ml/100g/min vs (87 +/- 35.9ml/100g/min; p < 0.05). Fifteen minutes after the termination of CPB, the global CBF was only 25% lower in the DHCA group than in the HCPB group (42.2 +/- 20.7 ml/100 g/min vs 56.4 +/- 25.8ml/100g/min; p = NS). In the right and left hemispheres, cerebellum, basal ganglia, and brain stem, blood flow resembled the global CBF. In conclusion, both HCPB and DHCA significantly decrease the regional and global CBF during CPB. Unlike HCPB, DHCA has a continued negative impact on the CBF after rewarming. However, 15 min after the end of CPB, there are no significant intergroup differences in the CBF.     

Effect of corticosteroid prophylaxis on lipopolysaccharide levels associated with intestinal ischemia in cats

Ischemia of the intestines damages the permeability of the intestinal wall, allowing lipopolysaccharide (LPS) (endotoxin) to leak from the gut lumen into the blood circulation, causing shock and death. We measured LPS levels associated with corticosteroid treatment vs. no treatment in cats whose superior mesenteric artery had been occluded for 60 min. In untreated cats, the preocclusion mean plasma LPS concentration remained stable at 0.069 +/- 0.015 ng/ml. Toward the end of the occlusion period, mean plasma LPS rose to 0.239 +/- 0.032 ng/ml (p less than .01). Release of the clamp and reperfusion with oxygenated blood was followed within 20 min by a large rise in plasma LPS concentration to 0.825 +/- 0.11 ng/ml (p less than .01), which had returned to preocclusion levels about 80 min later. Methylprednisolone (30 mg/kg) was infused into a second group of cats 1.5 h before SMA occlusion. In these cats there was a complete inhibition of the LPS rise both during and after occlusion. These data suggest that the reported beneficial effect of corticosteroids in the treatment of septic shock may be mediated, in part, by reducing LPS leakage from the gut.     

慢性缺血性功能异常心肌血管重建术后跨壁收缩的背向散射研究

目的利用超声背向散射（IBS）技术研究慢性缺血性功能异常心肌在血管成功再灌注后跨壁收缩的变化特征。方法分别在血管重建术前、术后3d、术后6～8周，检测58例慢性冠心病伴有左室壁节段性功能障碍患者（共88个异常心肌节段，43个正常心肌节段）相关心肌节段心内膜下层心肌及心外膜下层心肌的IBS周期变化幅度（cycle variation of IBS，CVlB），并在常规超声下测量相应心肌节段的室壁增厚率（WT）。结果正常心肌节段心内膜下心肌CVIB明显高于心外膜下心肌CVIB（P〈0．001）。血管重建术前，慢性缺血性功能异常心肌节段心内膜下和心外膜下心肌的CVIB均减低，以前者为著，二者间无显著性差异（P=0．067）。成功再灌注后，心内膜下心肌CVIB恢复较心外膜下慢，出现“心内膜下顿抑”。术后WT的恢复与心内膜下心肌层CVIB的恢复相平行（r=0．816，P〈0．0001），而与心外膜下心肌CVIB的恢复无明显相关性（r=0．125，P=0．056）。结论CVIB可以无创检测心肌的跨壁收缩性。在慢性缺血心肌的再灌注恢复过程中，心内膜下心肌跨壁收缩性的变化与心脏收缩功能的恢复密切相关。     

Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O]water, and [18F]fluoro-deoxy-glucose and positron emission tomography.

Defects in insulin stimulation of blood flow have been used suggested to contribute to insulin resistance. To directly test whether glucose uptake can be altered by changing blood flow, we infused bradykinin (27 microgram over 100 min), an endothelium-dependent vasodilator, into the femoral artery of 12 normal subjects (age 25+/-1 yr, body mass index 22+/-1 kg/m2) after an overnight fast (n = 5) and during normoglycemic hyperinsulinemic (n = 7) conditions (serum insulin 465+/-11 pmol/liter, 0-100 min). Blood flow was measured simultaneously in both femoral regions using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET), before and during (50 min) the bradykinin infusion. Glucose uptake was measured immediately after the blood flow measurement simultaneously in both femoral regions using [18F]-fluoro-deoxy-glucose ([18F]FDG) and PET. During hyperinsulinemia, muscle blood flow was 58% higher in the bradykinin-infused (38+/-9 ml/kg muscle x min) than in the control leg (24+/-5, P<0.01). Femoral muscle glucose uptake was identical in both legs (60.6+/-9.5 vs. 58.7+/-9.0 micromol/kg x min, bradykinin-infused vs control leg, NS). Glucose extraction by skeletal muscle was 44% higher in the control (2.6+/-0.2 mmol/liter) than the bradykinin-infused leg (1.8+/-0.2 mmol/liter, P<0.01). When bradykinin was infused in the basal state, flow was 98% higher in the bradykinin-infused (58+/-12 ml/kg muscle x min) than the control leg (28+/-6 ml/kg muscle x min, P<0.01) but rates of muscle glucose uptake were identical in both legs (10.1+/-0.9 vs. 10.6+/-0.8 micromol/kg x min). We conclude that bradykinin increases skeletal muscle blood flow but not muscle glucose uptake in vivo. These data provide direct evidence against the hypothesis that blood flow is an independent regulator of insulin-stimulated glucose uptake in humans.