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The potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of the microcirculatory dysfunction seen in sepsis. The mixed endothelin receptor antagonist tezosentan and the selective endothelin A-receptor antagonist TBC3711 were used to investigate the importance of the different endothelin receptors in modulating splanchnic regional blood flow and microvascular blood flow in endotoxaemia.Eighteen anaesthetized pigs were i.v. infused with endotoxin (Escherichia coli lipopolysaccharide, serotype 0111:b4) for 300 min. After 120 min, six animals received tezosentan and six animals received TBC3711. Six animals served as endotoxin-treated controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and ileum. Superior mesenteric artery flow (SMA(FI)) and portal vein flow (PV(FI)) were measured with ultrasonic flow probes, and air tonometry was used to measure Pco₂ in the ileal mucosa.TBC3711 did not improve splanchnic regional blood flow or splanchnic microvascular blood flow compared with endotoxin-treated controls. Tezosentan increased PV(FI) (P0.05), but SMA(FI) was not improved compared with the other groups. In the tezosentan group, microvascular blood flow in the ileal mucosa (MCQ(muc)) improved and mucosal-arterial Pco₂ gap decreased (P0.05 for both) compared with endotoxin-treated controls and the TBC3711 group.Tezosentan improved MCQ(muc) without any concomitant increase in SMA(FI), implying a direct positive effect on the microcirculation. TBC3711 was not effective in improving regional splanchnic blood flow or splanchnic microvascular blood flow. Dual endothelin receptor antagonism was necessary to improve MCQ(muc), indicating a role for the endothelin B-receptor in mediating the microcirculatory failure in the ileal mucosa.

Aim: To evaluate possible anti-inflammatory effects of pre-treatment with adenosine in a human experimental inflammatory model. Methods: The study design was double-blind, crossover, placebo-controlled and randomized. In the Intensive Care Unit of a university hospital, 16 healthy male volunteers were treated for 5.5 h with infusions of adenosine 40 μg kg−1 min−1 or placebo. Thirty minutes after the start of adenosine or placebo, 2 ng kg−1E-Coli endotoxin was administered. Heart rate, body temperature, blood pressure, plasma cytokines (TNF-α, IL-6 and IL-10), soluble RAGE and resistin, exhaled nitric oxide and nitrite/nitrate in urine were determined. Results: Endotoxin elicited the expected clinical signs of an inflammatory reaction (tachycardia, fever) and led to prominent release of the cytokines studied (P

Background Microcirculatory dysfunction is a common feature of sepsis. The potent vasoconstrictor endothelin (ET) is released in sepsis and endotoxemia, potentially contributing to sepsis-induced microcirculatory failure. In this study we tested the hypothesis that mixed ET receptor antagonism with tezosentan would improve splanchnic microcirculatory blood flow in acute porcine endotoxemia. Materials and methods Sixteen anesthetized and mechanically ventilated pigs received an infusion of endotoxin for 300 min. After 120 min eight pigs received a bolus dose of tezosentan 1 mg/kg followed by an infusion of tezosentan of 1 mg/kg/h throughout the experiment. Eight pigs served as endotoxin controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and in the ileal and colon mucosa. PCO2 in the ileal mucosa was measured by air tonometry and portal vein flow by an ultrasonic flow probe. Results Endotoxin administration induced a state of shock with impaired splanchnic microcirculatory blood flow. Microcirculation in the mucosa of the colon and ileum and mucosal-arterial PCO2 gap were improved by tezosentan. Portal vein flow was increased, but hepatic microcirculatory blood flow was not significantly improved. Tezosentan preserved cardiac index and decreased pulmonary capillary wedge pressure compared to controls, without causing any differences in the heart rate or mean arterial blood pressure response. Tezosentan also distinctly improved pH and arterial lactate values. Conclusions The findings of this study indicate that ET is involved in the microcirculatory dysfunction seen in the ileal and colon mucosa in early endotoxemia. Moreover, this detrimental effect was counteracted by i.v. administration of the mixed ET receptor antagonist tezosentan.

Aim: To evaluate the haemodynamic effects of the dual endothelin receptor antagonist tezosentan, both alone and combined with hypertonic saline/dextran (HSD), on porcine endotoxin shock, with focus on cardiopulmonary circulation. The effects on gas exchange and short-term survival were also studied. Methods: A prospective, randomized experimental study was carried out. Thirty-two anaesthetized pigs underwent pulmonary and carotid artery catheterization. Following haemodynamic stabilization and baseline measurements, endotoxaemia was induced by an Escherichia coli-endotoxin infusion over 180 min and the animals observed another 120 min. After 60 min of endotoxaemia, directly before intervention, animals were randomized into four groups: a tezosentan group, an HSD group, a combined tezosentan/HSD group and a control group. The consequent haemodynamic effects and blood gas results were recorded. Results: The endotoxin infusion reduced mean arterial blood pressure from 111 ± 14 (mean ± standard deviation) to 77 ± 27 mmHg and cardiac index from 126.9 ± 27.2 to 109.3 ± 22.6 mL min−1 kg−1 within 90 min in the control group. In addition, endotoxin simultaneously increased mean pulmonary artery pressure from 24 ± 17 to 38 ± 19 mmHg and reduced arterial oxygenation from 18.9 ± 2.0 to 12.2 ± 5.3 kPa. Tezosentan, alone and combined with HSD, reversed the pulmonary hypertension and prevented the reduction in cardiac index and arterial oxygenation, resulting in reduced metabolic acidosis. Additionally, in the tezosentan group, the mean arterial blood pressure was reduced to the same level as in controls, an effect not prevented by the addition of HSD. It was found that all three interventions improved survival rates. Conclusion: Tezosentan, alone and in combination with HSD, improved cardiac index and arterial oxygenation. The addition of HSD to tezosentan treatment did not improve the endotoxin-induced hypotension, but beneficial effects on microcirculation and systemic oxygenation were seen despite low perfusion pressure, as indicated by increased SvO2 and reduced metabolic acidosis.

Background: Ethyl pyruvate has been shown to possess anti-inflammatory and free radical scavenging properties. However, the haemodynamic effects of ethyl pyruvate have not been studied in detail. We investigated the systemic, regional and microcirculatory haemodynamic and metabolic effects of resuscitation with Ringer’s ethyl pyruvate solution (REPS) vs. Ringer’s acetate (RA) in an acute model of porcine endotoxaemic shock. Methods: Fourteen anaesthetized pigs received an infusion of endotoxin that was increased stepwise over 30 min to a rate of 2.5 μg/kg/h. After 60 min of endotoxaemia, the animals were resuscitated with either ethyl pyruvate 40 mg/kg, given as REPS, or the equivalent volume of RA, administered over 10 min. Thereafter, an infusion of either ethyl pyruvate 40 mg/kg/h, given as REPS, or the equivalent volume of RA, was started, and the maintenance fluid was reduced so that the total amount of fluid given was kept constant. The experiment was terminated after 300 min of endotoxaemia. Results: Endotoxin infusion led to a hypodynamic state that was reversed by fluid resuscitation after 60 min. Progressive deterioration ensued and, after 300 min, all animals were again hypodynamic. No differences in response to treatment were found between the groups with regard to systemic haemodynamics, renal artery or portal vein flow or microcirculatory flow in the liver, kidney, ileal serosa or mucosa. Metabolic acidosis and increased arterial blood lactate developed in both groups, but, in the REPS group, the base excess was significantly lower from 150 min and the anion gap was significantly higher at 150 and 210 min. Conclusion: We could not demonstrate any difference between REPS and RA for resuscitation in this model of acute porcine endotoxaemic shock.

Anti-inflammatory effects of adenosine were evaluated in two randomized, double-blind, placebo-controlled studies. In one study healthy male volunteers received no endotoxin (adenosine study, n = 10), in the other intravenous endotoxin (4 ng/kg, endotoxin study n = 11) was given. All subjects were treated with adenosine infusion (40 microg/kg/min) and placebo (saline) infusion in a crossover design. Heart rate, body temperature, blood pressure and plasma cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6, IL-10, and soluble TNF receptors I and II), nitric oxide oxidation products, nitrite and nitrate, as well as superoxide anions were determined. There were no significant changes of any measured parameter after adenosine treatment alone. Endotoxin elicited clinical signs of an inflammatory reaction, prominent release of all cytokines and O2- synthesis by neutrophils (N-formyl-methionin-leucyl-phenylalanin-stimulated cells measured by cytochrome C reduction). The plasma IL-6 response to endotoxin was attenuated by adenosine, as IL-6 increased from 0.9 (0.8-1.6) to 1345 (743-1906) pg/mL (median; 25-75th percentiles) with adenosine infusion, and from 0.8 (0.5-1) to 1,959 (1,344-2,505) pg/mL with placebo (P = 0.0065). There was no significant influence of adenosine infusion on the other variables examined. In conclusion, systemic adenosine infusion counteracts the release of IL-6 in healthy volunteers, indicating an anti-inflammatory effect of adenosine which should be further explored.

Background: Previous studies have shown that pneumoperitoneum transiently reduces venous admixture as assessed by a calculation based on the shunt formula, and increases arterial oxygen tension (PaO2) in patients without heart or lung disease. The aim of the present study was to further explore the relationship between ventilation-perfusion (V˙A/Q˙) before and during pneumoperitoneum by using the multiple inert gas technique. Methods: Nine patients without heart or lung disease (ASA I), with a mean age of 42 years, scheduled for laparoscopic cholecystectomy were included. After premedication and induction of anaesthesia, radial artery and pulmonary artery catheters were introduced percutaneously. The V˙A/Q˙ relationships were evaluated by the multiple inert gas elimination technique before and during pneumoperitoneum to obtain a direct measure of the pulmonary shunt. Results: Induction of pneumoperitoneum decreased the pulmonary shunt from 5.8 (4.5) to 4.1 (3.2)% (P

The splanchnic region is particularly susceptible to shock. The purpose of this study was to evaluate microdialysis of the liver and small intestine as a monitor of splanchnic metabolic deterioration (elevation of lactate and hypoxanthine) in porcine endotoxic shock. Tonometry of the small intestine was used as a reference. Microdialysis probes (liver, ileum, and artery), tonometer, and pulmonary artery catheter were inserted. Eight animals were given Escherichia coli lipopolysaccharide endotoxin (20 micrograms kg-1 h-1 for 2 h). Five animals served as controls. Measurements were made every half-hour. Three hours after onset of endotoxin challenge, there were significant differences between endotoxin and control groups in intestinal lactate and hypoxanthine, as well as liver lactate, in addition to mucosal pH obtained by tonometry. Lactate elevation in blood was first seen at 4 h, while there was no significant hypoxanthine elevation in arterial blood over 5 h. Hence, data obtained from the splanchnic region became significantly different early, when compared with data obtained from arterial blood. Microdialysis of liver and small intestine as well as intestinal tonometry are sensitive tools for detection of splanchnic metabolic deterioration during endotoxin shock.

The aim of the present study was to investigate the effect of intravenous or intrathecal (i.t.) administration of R-phenylisopropyladenosine (R-PIA), a selective A1 adenosine receptor agonist, on spontaneous scratching behaviour, a phenomenon presumably related to pain in a mononeuropathy model (sciatic nerve ligation) in rats. The acute effect of daily i.t. R-PIA injections was studied up to 21 days following nerve ligation. The results demonstrate that both i.v. (30 nmol) and i.t. (3 nmol) R-PIA, in doses not producing any motor impairment, significantly reduces scratching behaviour in this animal model. The mechanism of action for this presumed antinociceptive effect is suggested to occur at the spinal cord level.

Ventilatory responses to hypoxia (HVR) were investigated using poikilocapnic conditions (i.e. end-tidal CO2's allowed to seek it's own level) in 15 cardio-pulmonary healthy patients who were first studied awake and then at 0.85 MAC isoflurane. The influence of hypercapnia (HyperCapnic Ventilatory Response, HCVR) was also elucidated. Pneumotachography, capnography and airway occlusion pressures at 0.1 s (P degree 0.1) were used before and during both mild hypoxia (end-tidal O2 tension 8.7 kPa) and hypercapnia achieved by an inspired CO2 concentration of 5%. HCVR was attenuated by 60% during anesthesia (P < 0.01). In the awake state, five of the 15 patients decreased HVR during hypoxia as compared with during normoxia. This resulted in a VE that on average increased by 0.6 l.min-1 (P < 0.05) whereas P degree 0.1 was unchanged. In the anesthetized state, no case of decreased HVR was seen and hypoxia induced a mean VE increase (+/- s.d.) by 1.0 +/- 0.2 l.min-1 (P < 0.001) and a P degree 0.1 that on average was improved by 0.63 +/- 0.27 cm H2O (P < 0.01). It is suggested that when the aim is to evaluate the influence of volatile anesthetic agents on HVR and to quantitate its clinical relevance during and immediately after anesthesia, a poikilocapnic technique should be used. It is concluded that the poikilocapnic HVR to PEO2's of 8.7 kPa was maintained during 0.85 MAC isoflurane.

The effect of a non-hypotensive dose of adenosine infusion on myocardial performance after coronary artery bypass surgery was examined. Upon arrival at the intensive care unit, 16 patients (14 males, 2 females; mean age 64.5, range 46–71) were randomized to a blinded infusion of either low-dose adenosine (n = 8) or placebo (n = 8). The infusion continued at a rate corresponding to 30 μg. kg-1. min-1 of adenosine into the right ventricle over 4 h. Data were collected from the arterial line, thermodilution pulmonary artery catheter, transoesophageal echocardiogram (TEE), and 12-lead ECG on six occasions: before infusion, hourly during the infusion, and 1 h after terminating the infusion. Mean arterial blood pressure did not differ between the adenosine and placebo groups at any measurement point. Heart rate increased by approximately 15% during the first hour of adenosine infusion. Cardiac index increased by approximately 50% during infusion of adenosine and cardiac index remained higher while systemic vascular resistance remained lower in the adenosine-treated group during infusion. The E/A ratio (ratio between peak left ventricular inflow blood velocities during early filling and atrial contraction) was significantly higher in the adenosine-treated group after treatment for 1 h while the area injection fraction did not differ between groups at any time. The number of patients with ischaemic events as judged from ECG and from left ventricular regional wall motion abnormalities (RWMA) as visualized by TEE did not differ between groups (ECG: one patient in the adenosine group and one patient in the placebo group - RWMA: four patients in the adenosine group versus three in the placebo group). According to enzyme determinations, three patients (two in the adenosine group and one in the placebo group) developed a perioperative myocardial infarction. In conclusion, adenosine could be infused at a rate that induced peripheral vasodilation and improved cardiac output, without affecting arterial blood pressure. The echo Doppler indices area ejection fraction and E/A ratio revealed no signs of impaired ventricular function during the infusion of adenosine.

Background In addition to clinical risk markers, indices of left ventricular (LV) systolic function are valuable prognostic markers after acute myocardial infarction (MI). Previous studies have also suggested that LV diastolic function may contribute with prognostic information. The present study assessed whether this assumption applies to a large population of patients with acute MI who underwent thrombolytic therapy. Methods and results 520 out of 608 patients participating in the ATT enuation by A denosine of C ardiac C omplications (ATTACC) study, with an ST-elevation acute MI underwent two-dimensional and Doppler echocardiographic examination at 4 (range 2–10) days after admission. During the follow-up period of 31 (S.D.±11) months, cardiovascular death occurred in 57 (11%) patients, nonfatal acute MI occurred in 77 (15%), and 124 (24%) patients suffered a combined cardiovascular end-point (either nonfatal acute MI or cardiovascular death). Univariate regression analysis showed that all indices of LV systolic function predicted cardiovascular death and combined cardiovascular end-points. Regarding LV diastolic function only a restrictive filling pattern predicted cardiovascular death. In a multistep multivariate regression analysis in which the variables were introduced in a hierarchic order age, history of systemic hypertension, wall motion score index (WMSi), and history of previous MI and diabetes mellitus were independent predictors of cardiovascular death. A history of systemic hypertension or congestive heart failure were independent predictors of nonfatal acute MI, while a history of systemic hypertension, wall motion score index and diabetes mellitus independently predicted combined cardiovascular end-points. Conclusions The results of this study confirmed that clinical risk indicators and LV systolic function were the most important independent predictors of cardiovascular death and combined cardiovascular end-points. LV diastolic function assessed by Doppler-echocardiography did not provide additional prognostic information.

Introduction : In the intensive care, many patients are at risk of developing procoagulant changes leading to severe coagulopathy and disseminated intravascular coagulation (DIC). Close monitoring of the coagulation is therefore crucial. In this study, we assess a novel bedside instrument based on free oscillating rheometry, measuring the degree of coagulation activity as clotting onset time, COT. COT measurements are conducted in whole blood, and thus reflect the overall hemostasis. Materials and methods : Nine healthy volunteers were subjected to intravenous injection of 2 ng/kg endotoxin. To quantify the activation of the coagulation system, COT was assessed along with prothrombin fragment 1+2 (F1+2) and activated partial thromboplastin time (aPTT). Results : Baseline COT was 10.6±3.6 min. Three hours after endotoxin injection, maximal body temperature and heart rate were registered. At this time, an activation of the coagulation was observed as a significant decrease in COT to 8.0±1.0 min, a decrease in aPTT and increased levels of F1+2. COT levels, body temperature and heart rate subsequently normalized towards initial levels. F1+2 however continued to increase throughout the study. Conclusions : COT is a rapid test, performed in less than 15 min. COT was superior to F1+2 in monitoring the endotoxin-induced activation of the coagulation, since COT covariated with clinical symptoms, whereas F1+2 did not. This is, to our knowledge, the first time an overall coagulation monitoring method has been assessed bedside to detect endotoxin-induced activation of the coagulation. The COT test shows promising results, but further studies are needed to reveal its potential in the intensive care monitoring arsenal.

Study objective – The aim was to study the influence of complete myocardial ischaemia during aortic occlusion on release of neuropeptide Y and noradrenaline from the human myocardium. Design – Coronary sinus neuropeptide Y and noradrenaline were measured after 46(SEM 7) min of aortic occlusion with cold cardioplegia in patients undergoing coronary artery surgery. Patients – Seven patients (six male), aged 64(SEM 3) years, were studied. All were undergoing coronary artery bypass grafting. Measurements and main results – Reperfusion was associated with an increase in coronary sinus blood flow as determined by thermodilution. Simultaneously there was cardiac release of both neuropeptide Y and noradrenaline during the first two sampling periods: 3(0.6) and 7(0.6) min after the start of reperfusion. The outflow of neuropeptide Y and noradrenaline returned to preischaemic values by 14(1) min after reperfusion. Coronary sinus blood lactate and pyruvate concentrations were also increased at the start of reperfusion, while the lactate/ pyruvate ratio remained unchanged. Myocardial oxygen uptake was not influenced by cardiac ischaemia. Conclusions – Ischaemia of the human heart in vivo is associated with an enhanced outflow of neuropeptide Y and noradrenaline from the heart. Since arterial blood concentrations of these substances were also increased on reperfusion, their release is probably due to increased sympathetic nerve activity, though other mechanisms such as temperature change and local metabolite formation could also participate. Local release of neuropeptide Y during cardiac ischaemia may be involved in the regulation of coronary vascular tone as well as in the release of noradrenaline and acetylcholine.

The tissue content of adenine nucleotides and their metabolites, inosine monophosphate, adenosine, hypoxanthine, and uric acid, were determined in biopsy specimens from the left ventricle of six patients during cardioplegia for open heart surgery. Biopsy specimens were collected immediately after the induction and at the end of cardioplegia (51-82 min) and were analysed by high performance liquid chromatography. After the induction of cardioplegia (cold potassium enriched solution) the left coronary artery was continuously perfused with cold (10°C), potassium enriched, diluted blood. The adenosine triphosphate concentration decreased from 13 to 8 mmol·kg−1 dry muscle (p

After 1 hour of arterial or venous occlusion, the circulatory and metabolic events in island skin flaps of the pig were studied. Both occlusion types showed significant but transient increases in glucose uptake and a parallel release of lactate, hypoxanthine, and potassium. Oxygen uptake and noradrenaline release were not significantly affected. No significant difference between the arterial and venous occlusions was seen in the metabolic parameters. The flap blood flow, measured by total venous outflow and laser Doppler flowmetry, was significantly lower after venous than after arterial occlusion. This long-lasting difference in flow response may help to explain the observation that venous occlusion is more deleterious to skin flaps than arterial occlusion. A mechanism underlying these results may be more pronounced microthrombotization and/or edema formation after venous occlusion than after arterial occlusion.

The influence of systemic adenosine infusion (30-50 micrograms/kg/min) on peroperative coronary graft flow was investigated in 16 patients undergoing bypass surgery. The central hemodynamic and graft flow (electromagnetic flow determination) responses were studied after 5-min, and in nine patients also after 30-min infusion. The low-dose adenosine infusion had little effect on the central hemodynamic parameters, while the graft flow increased in all patients (mean 84 +/- 12%, total 22 grafts). The adenosine-induced increase in graft flow was maintained when the infusion was prolonged. It is concluded that adenosine can produce marked coronary vasodilation in man at infusion rates that exert only minor systemic hemodynamic effects.

The results, briefly summarized above, indicate that adenosine could be a physiologically important modulator of several aspects of cardiovascular regulation. Most cells are equipped with adenosine receptors. These receptors are of at least two subtypes which can be defined by the relative agonist potency. At these adenosine receptors, methylxanthines, including caffeine and theophylline, act as competitive antagonists. The role of adenosine antagonism, as a mechanism behind the cardiovascular effects of these xanthines, was recently reviewed (Fredholm, 1984). The concentrations of adenosine are low during resting conditions, but may be raised substantially by, for example, hypoxia, ischaemia and increased mechanical or biochemical work. The adenosine levels can also be raised by drugs, including uptake inhibitors such as dipyridamole. Already the concentrations of adenosine that occur during basal conditions are sufficient to produce significant effects, for example, on blood-flow. When the concentrations are raised the importance of endogenous adenosine becomes even greater. Adenosine may not only be of physiological significance but may also be pharmacologically important. First, there are several drugs that may act by affecting the levels of adenosine or by influencing its receptors. Second, the possibility exists that adenosine itself could be used clinically. For example, adenosine may be an attractive alternative to sodium nitroprusside or nitroglycerin when controlled hypotension is to be achieved. Adenosine may also be used to preserve blood platelets during extracorporal circulation or to produce selective regional vasodilatation. Both the physiological and pharmacological aspects are subject to intense study in several laboratories.

The effect of adenosine-induced controlled hypotension (CH) on myocardial performance, blood flow, and metabolism was studied in nine pentobarbital-anaesthetized, open-chest dogs. Adenosine was continuously infused i.v. (0.69 +/- 0.06 and 1.36 +/- 0.11 mg/kg/min) at two stepwise increased rates (12-14 min-periods) in order to induce approximately 20 and 40% reduction of the mean arterial pressure (MAP 62 +/- 4 and 43 +/- 1 mmHg, respectively). The reduction of MAP was associated with decreases in heart rate (6 +/- 2%, P less than 0.05 and 21 +/- 4%, P less than 0.01), left intraventricular systolic pressure (14 +/- 3%, P less than 0.01 and 32 +/- 3%, P less than 0.01), left ventricular end-diastolic pressure (23 +/- 9%, P less than 0.05 and 42 +/- 9%, P less than 0.01) and ventricular intramyocardial systolic pressure (15 +/- 6% n.s. and 27 +/- 6%, P less than 0.01). The rate pressure product was markedly reduced by 49 +/- 3% (P less than 0.01) at the highest infusion rate. The mean coronary vein pressure (20.3 +/- 2.8 mmHg) was unaffected by the adenosine infusion. The systolic pressure time index (SPTI) was decreased by 33 +/- 3% (P less than 0.01) during the highest infusion rate of adenosine, while the diastolic perfusion time index (DPTI) was 15.4 +/- 2.2 mmHg X s and remained unchanged. The DPTI:SPTI ratio increased by 40 +/- 13% (P less than 0.05), suggesting a sufficient endocardial oxygen supply.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial energy metabolism during deep general hypothermia (20 degrees C) and multidose crystalloid cardioplegia, and also during subsequent reperfusion, was studied in eight patients undergoing isolated aortic valve replacement. Six serial transmural biopsy samples from the left ventricular apex were analyzed for high-energy phosphates and their degradation products. Reductions in ATP, total adenine nucleotide content and energy charge were insignificant during cardioplegia, as were changes in adenosine and uric acid concentrations. During reperfusion, however, there was slight but significant reduction in total adenine nucleotide content, despite adequate oxygenation as indicated by reversal of lactate accumulation. These observations suggest that the reperfusion phase is accompanied by metabolic aberrations which are not overcome by good oxygenation in relation to the metabolic rate.

Severe hypertension and cardiac arrhythmias are well known problems during surgical removal of pheochromocytoma. This is due to extremely high circulating catecholamines during tumor manipulation. In this study, peroperative blood pressure control was obtained by the infusion of adenosine, which antagonized cardiovascular effects of catecholamines. During operation of 10 patients, none had systolic blood pressure exceeding 200 mm Hg or any cardiac arrhythmias despite extremely high plasma catecholamine levels. A mean blood pressure of 120–150 mm Hg was maintained in all patients. Peroperative use of adenosine seems to be a most effective compound for hemodynamic control during pheochromocytoma surgery.

The influence of adenosine on blood flow, lipolysis and adrenergic neurotransmission was studied in canine subcutaneous adipose tissue in situ. Tissue concentrations of endogenous adenosine were elevated in 2 ways: (1) by inhibition of adenosine elimination by i. a. infusion of the uptake blocker dipyridamole (0.5–1.5 μM in arterial plasma) + the deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA; 3–5μM) or (2) by prolonged nerve stimulation (4 Hz for 30 min). Furthermore, effects of exogenous adenosine and the adenosine antagonist theophylline were studied. Dipyridamole+EHNA increased resting vascular conductance from 0.055 to 0.096 ml×min−1×100 g−1×mm Hg−1, whereas lipolysis induced by sympathetic nerve stimulation (2,4 and 8 Hz during 2 min) was inhibited (by 91, 71 and 34%, respectively). “Therapeutic” concentrations of theophylline (5–15 μg/ml plasma) completely reversed the effects of dipyridamole + EHNA on blood flow and significantly reversed the antilipolytic effect of these drugs. In untreated adipose tissue theophylline reduced resting vascular conductance by 40% and enhanced the lipolytic response to prolonged nerve stimulation but not that to brief nerve stimulation. Transmitter release, evaluated by the outflow of endogenous noradrenaline and/or by the outflow of radioactivity after 3H-noradrenaline labelling, was linearly related to the stimulation frequency (2,4 and 8 Hz). Dipyridamole + EHNA increased plasma noradrenaline by inhibiting uptake or binding of noradrenaline to blood cells. However, noradrenaline release induced by nerve stimulation was not significantly affected by dipyridamole + EHNA or by theophylline. It is concluded that a rise in endogenous adenosine concentration caused by drugs or by prolonged sympathetic nerve stimulation inhibits the lipolytic response to nerve stimulation without any effect on noradrenaline release. The results also show that theophylline in a therapeutic dose range is capable of enhancing lipolysis only if endogenous adenosine concentrations are raised.

An open–chest preparation was carried out in 14 pentobarbitone anaesthetized dogs in order to evaluate the myocardial effects of controlled hypotension induced by adenosine in the presence of a severe coronary stenosis that caused ischaemia of the left anterior ventricular wall. Myocardial performance, blood flow and metabolism were studied before and during a 78 ± 3% reduction of flow in the left anterior descending coronary artery (LAD) and during adenosine–induced hypotension (approximately 40% reduction of the mean arterial pressure) in the presence of the LAD stenosis. The LAD stenosis decreased the myocardial lactate uptake (P

The influence on cerebral blood flow (CBF) and autoregulation of systemic adenosine infusion, at doses that produced a 29 +/- 4% (0.28 +/- 0.06 mg/kg/min) or a 55 +/- 2% (0.49 +/- 0.07 mg/kg/min) reduction of mean arterial blood pressure (MABP), was evaluated in 12 normoventilated fentanyl/N2) anesthetized pigs. CBF was determined as sagittal sinus outflow and recorded continuously by an electromagnetic technique. Autoregulation was evaluated by two formal tests: infusion of angiotensin for elevation of MABP, and reduction of myocardial filling pressure by caval block for graded MABP decrease before, during and after adenosine infusion. CBF as well as cerebral metabolic rate of oxygen were unaffected during both levels of hypotension and were not significantly altered after the hypotension. Signs of impaired autoregulation were found during the angiotensin test as well as during the caval block at light hypotension (92 +/- 3 mmHg, 12.3 +/- 0.4 kPa), while autoregulation was completely abolished at moderate hypotension (59 +/- 2 mmHg, 7.9 +/- 0.3 kPa). After termination of adenosine-induced hypotension, autoregulation was restored in all animals within 60 min. It is concluded that systemically administered adenosine preserves CBF, even at low MABP levels, by a direct cerebral vasodilatory effect. However, the cerebral autoregulatory mechanisms are impaired or abolished in a dose-dependent and reversible manner.

Circulatory and metabolic skin-flap events were studied prior to and up to 6 hours after elevation of buttock island flaps in pigs. During the elevation, significant reductions in superficial skin blood flow, measured by laser Doppler flowmetry (LDF) and dermal flap temperature, were seen. Significant correlations were found between blood flow and temperature. Total flap blood flow, measured as venous outflow, also showed an initial transient decrease, but 2 hours after flap construction, venous outflow had returned to preoperative values. A significant increase in lactate release, together with increased oxygen consumption and glucose uptake, was seen 4 hours after the surgical intervention. Hypoxanthine release, indicating ischemia, was seen only during the first hour after flap elevation. Noradrenaline outflow was noted after 4 and 6 hours, but there was no parallel reduction in flap blood flow. A great deal of the flow reduction in acutely elevated island flaps may thus be due to primary hypothermia rather than to the degenerative release of noradrenaline, which seems to have no early effect on skin flap blood flow. On the other hand, the noradrenaline release may be linked to an increased metabolic activity in the skin flaps.

The cardiovascular effects of adenosine-induced hypotension were studied in 47 patients undergoing intracranial vascular surgery under neurolept anesthesia. Adenosine infusion (214 +/- 18 micrograms X kg-1 X min-1) decreased mean arterial pressure (MAP) by 42 +/- 1% from 80 +/- 1 to 46 +/- 1 mm Hg for an average of 29 +/- 5 min of hypotension. Hypotension was associated with a minor increase in heart rate (13 +/- 2%) and with prolongation of the PR interval (9 +/- 2%). ST-T depression did not occur except in one patient with a previous history of myocardial infarction. The adenosine-induced increase in cardiac index (42 +/- 9%, n = 7) was associated with a 63 +/- 10% decrease in systemic vascular resistance index (n = 7) while the pulmonary capillary wedge pressure remained unchanged. Adenosine metabolism was limited and there was no accumulation of the end metabolite, uric acid. Serum creatinine levels were normal in all patients postoperatively. We conclude that adenosine rapidly induces a stable and easily controlled hypotension in man without tachyphylaxis or rebound hypertension. There were no signs of renal or myocardial dysfunction except for dysrhythmias that occurred in two patients with a history of myocardial infarction.