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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.

UNLABELLED In this study, we evaluated whether combined treatment with ketamine (KET), an N-methyl-D-aspartate receptor antagonist, and morphine (MO) results in positive analgesic effects. Eleven volunteers were exposed to a skin burn injury on the leg. The effects of IV KET (9 microg. kg(-1). min(-1); 45 min) and MO (10 microg. kg(-1). min(-1); 10 min) alone and in combination, as well as placebo (saline; 10 min), were studied in a randomized, crossover, double-blinded design. The area of secondary hyperalgesia (SH) for mechanical stimulation was diminished by KET as compared with placebo. Mechanical pain thresholds were increased severalfold with KET and with KET plus MO, both in the primary hyperalgesic (PH; burn injury) and SH area. MO infusion showed no effect on the SH area or pain threshold. Windup-like pain was evaluated by continuous assessment on a visual analog scale during 30 s of repetitive stimulation (40-g load at 3 Hz) and analyzed as a sum of pain scores. The combined treatment (KET plus MO) almost abolished windup-like pain both in the PH and the SH areas, an effect that was not present with monotherapy with KET or MO. This study provides experimental support for a positive analgesic interaction between an N-methyl-D-aspartate receptor antagonist and an opioid on central summation of pain. IMPLICATIONS This is the first experimental study in humans to find synergistic analgesic effects with coadministration of the N-methyl-D-aspartate receptor antagonist ketamine and morphine on pain involving central sensitization phenomena.

This study in 20 volunteers examines whether changes in cutaneous blood flow distribution (laser Doppler flow scanning, LDS) and visible flare correlate in time and in distribution with the development of secondary hyperalgesia (SH, punctate stimulation of a 45-g von Frey filament) induced by a superficial skin burn injury. Areas of LDS and flare were at their largest at 5 minutes after the burn injury (58 ± 30 and 20 ± 11 cm 2 , respectively), whereas the largest area of SH was seen after 60 minutes (50 ± 45 cm 2 ). Although the maximum areas of LDS and SH were of the same magnitude, the blood flow response was essentially abolished when the maximal SH area was noticed at 60 minutes. Furthermore, on an individual basis, there was no correlation between the size of maximal LDS area (at 5 minutes) and maximal SH area (at 60 minutes) ( r = 0.27; P = .26). Therefore, peripheral mechanisms associated with the neurogenic inflammation reaction surrounding a skin burn injury are not directly associated with the induction of SH. Perspective Tissue trauma and inflammation-induced sensory abnormalities are important because they are involved in acute nociceptive pain, as well as in chronic pain conditions. This study notes the significance of central sensitization for the development of secondary hyperalgesia, an important phenomenon underlying many clinical pain conditions.

SUMMARY This study examined the hypothesis that nicotinamide could attenuate endotoxin-induced inflammatory responses in humans as indicated by levels of cytokines and nitric oxide. Ten healthy male volunteers participated in a randomised, double-blind, cross-over design with regard to the effects of nicotinamide. The volunteers received orally 4 g nicotinamide or placebo at 14 h and at 2 h preceding the experiment (total dose of 8 g). Endotoxin (E. coli, 2 ng/kg), was administered intravenously. Blood samples and haemodynamic data were collected prior to and up to 6 h after the endotoxin infusion. Orally exhaled NO was measured hourly. Following endotoxin, body temperature increased from baseline 36·3 ± 0·09°C to a maximum of 38·0 ± 0·1°C for all (mean ± SEM, P In conclusion, there was no effect on the inflammatory parameters by oral nicotinamide at a dose of 8 g, limiting the potential use of this agent for anti-inflammatory purpose in man.

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.

1. The non-selective endothelin (ET) receptor antagonist bosentan has been shown to restore systemic and gut oxygen delivery and reverse intestinal mucosal acidosis in porcine endotoxin shock. 2. To further elucidate the specific role of the ETA as opposed to the ETB receptor and their effects in the splanchnic region a non-selective (ET(MIX)ra) A-182086 and selective ETA (ET(A)ra) PD155080 and ETB (ET(B)ra) A-192621 receptor antagonists were administered, separately or simultaneously (ET(A+B)ra) 2 h after onset of endotoxin shock. These four groups were compared to a control group receiving only endotoxin and vehicle. 3. Thirty-nine pigs were anaesthetized and catheterized for measurement of central and regional haemodynamics. A tonometer in the distal ileum was used for measurement of mucosal PCO2. Blood gases and plasma ET-1-LI levels as well as histological samples from the gut were assessed. Intervention was started 2 h after onset of endotoxemia and the experiments were terminated after 5 h. 4. Endotoxin-induced changes in systemic, gut oxygen delivery and portal hepatic vascular resistance and systemic acidosis were effectively counteracted by both ET(A+B)ra an ET(MIX)ra. ET(A)ra administration was not effective while ET(B)ra proved to be fatal as all animals in this group died prior to full time of the experiment. While both ET(A+B)ra and ET(MIX)ra improved gut oxygen delivery only the latter attenuated the profound endotoxin-induced ileal mucosal acidosis. 5. The lethal effect seen from selective ETB receptor antagonism in the current study may be due to increased ETA receptor activity as plasma levels of ET-1 is increased several fold by blocking the ETB receptor and thereby the plasma-ET-1-clearing function. Furthermore, a loss of endothelial ETB receptor vasodilating properties may also have contributed to the lethal course in the ET(B)ra group. 6. The findings in this study suggest that ET is involved in the profound endotoxin-induced disturbances in splanchnic homeostasis in porcine endotoxaemia. Furthermore, antagonism of both ETA and ETB receptors is necessary to effectively counteract these changes.

We investigated the isocapnic hypoxic (i.e., pulse oximetry monitored arterial saturations 70%‐75%) ventilatory response (HVR) for 20 min in the awake state and during sevoflurane anesthesia at an end-tidal concentration of 1.6% in eight healthy (ASA physical status I) women. Our aims were to determine if a prolonged isocapnic hypoxic period during sevoflurane anesthesia showed a biphasic response pattern (i.e., an initial acute HVR followed by a decline to a lowered sustained HVR) and, if so, to quantify to what extent the acute and sustained HVRs were depressed by anesthesia. The study was conducted before laparoscopic gynecological surgery. Pneumotachography and in-line infrared capnography were used. The pattern of awake biphasic HVR was maintained during anesthesia but was depressed during both the acute and the sustained phases by 60% and 70%, respectively. Further, HVR during anesthesia was accomplished by an increase in respiratory rate, in contrast to an increase in tidal volume in the awake state. In conclusion, sevoflurane anesthesia at 1.6% depresses HVR in women, but the biphasic response is maintained. Implications: Acute and sustained hypoxic ventilatory responses were investigated in eight women before and during sevoflurane anesthesia. A biphasic ventilatory response was persistent but blunted during anesthesia. (Anesth Analg 1999;89:209 ‐14)

UNLABELLED Secondary hyperalgesia is characterized by increased sensitivity to noxious mechanical stimuli in the area surrounding injured skin. The pathophysiological mechanisms involve increased excitability of second-order neurons located in the spinal cord, i.e., central sensitization. The mechanisms behind this phenomenon may be of importance in clinical pain, including neuropathic pain. To study the effects of systemic infusion of the endogenous compound adenosine (ADO) on sensory function, a superficial cutaneous burn injury was induced by the 4-min topical application of mustard oil or by heat (47 degrees C for 7 min) during i.v. ADO infusion (60 microg x kg(-1) x min(-1)). Healthy human subjects (n = 10 for each model) were tested, using a blinded, placebo-controlled procedure. The area of secondary hyperalgesia, as well as tactile and thermal sensory function, was tested using psychophysical methods during and after treatments. ADO significantly reduced the area of secondary hyperalgesia in both models. The maximal reduction compared with placebo was 58% +/- 20% (heat burn) and 39% +/- 13% (mustard oil burn). No other differences in sensory function were observed. The results are interpreted as an ADO-induced modulatory effect on the mechanisms of central sensitization. IMPLICATIONS We tested the effects of adenosine on the development of increased sensitivity in the skin surrounding a superficial skin injury in humans. A superficial skin bum was induced with a chemical irritant or heat. The results show that adenosine reduces the skin area with increased sensitivity surrounding the injury.

Porcine endotoxin shock is characterized by pulmonary hypertension, decreased mean arterial pressure and deteriorated cardiac performance. These pathophysiological findings are accompanied by increased plasma endothelin-1 levels. Previous studies have shown that both the pulmonary and systemic circulation are improved by combined endothelinA- and endothelinB-receptor antagonism. This study was designed to evaluate further the specific involvement of the endothelinA-receptor in cardiopulmonary pathophysiology during endotoxin shock. In a porcine endotoxin shock model, the endothelinA-receptor antagonist PD 155080 was administered after the onset of endotoxaemia. Cardiopulmonary vascular changes, dynamic lung compliance, oxygen-related variables and plasma levels of endothelin-1-like immunoreactivity were compared with a control group receiving only endotoxin. PD 155080 counteracted the increase in pulmonary artery pressure seen in control animals. In contrast, cardiac performance was not improved. Dynamic lung compliance was not affected by PD 155080. Plasma levels of endothelin-1-like immunoreactivity increased to a similar degree in both groups. These findings indicate that the endothelin system is involved in the pathophysiology of endotoxin shock. Furthermore, the change in pulmonary circulation seen in the present shock model is to a large extent mediated by the endothelinA-receptor mechanism. In view of previous findings, the deterioration of cardiac performance may involve the endothelinB-receptor, either alone or in combination with the endothelinA-receptor.

UNLABELLED We examined the development of tolerance to the antiallodynic effect of chronic intrathecal (IT) administration of the adenosine analog R-phenylisopropyladenosine (R-PIA) in a rat model of central pain after ischemic spinal cord injury. After 10 days of IT R-PIA treatment, the effect of IT morphine was also assessed to examine whether cross-tolerance between R-PIA and morphine was present. IT R-PIA completely alleviated allodynia-like behaviors to mechanical and cold stimuli in spinally injured rats. The anti-allodynic effect of R-PIA was maintained for 6-7 days with twice-daily administration and was reduced thereafter, particularly with respect to cold allodynia. IT morphine alleviated mechanical and cold allodynia in rats rendered tolerant to R-PIA to a degree comparable to that in R-PIA-naive (control) rats, which indicates that the anti-allodynic property of R-PIA is independent of the mechanisms by which morphine acts. The possibility of using agonists of adenosine receptors in treating refractory pain in patients with spinal cord injury is discussed. IMPLICATIONS There is often no satisfactory treatment for chronic pain after spinal cord injury. Our study suggests such pain can be treated with a spinal injection of R-phenylisopropyladenosine in rats. Reduced effect to R-phenylisopropyladenosine was noted with repeated administrations. However, there was no cross-tolerance to morphine.

Background Several animal studies show antinociceptive effects of intrathecally administered adenosine and its analogs. However, there is no clinical experience regarding the effects of intrathecal adenosine in humans. Methods The side effects and analgesic effects of intrathecal adenosine (500-2,000 microg) on experimental pain were studied in 12 healthy volunteers. Before and after adenosine was given, the authors evaluated the cold pain rating of the foot (submersion in ice water for 1 min), the forearm ischemic pain rating during a 30-min tourniquet test, and the thermal and tactile pain thresholds on healthy and inflamed skin after application of mustard oil (4 min) to the calf. The areas of secondary allodynia surrounding the inflammation were also determined. The cerebrospinal fluid level of adenosine was determined before and after injection. Results Intrathecal adenosine caused a 1,000- to 2,000-fold elevation of the cerebrospinal fluid concentration. One volunteer experienced transient (30 min) lumbar pain after injection at a dose of 2,000 microg. There were no other complications in any other volunteers. Adenosine reduced, in a non-dose-dependent manner, the areas of secondary allodynia after skin inflammation (brush, P < 0.06; and von Frey hair, P < 0.03) and reduced the forearm tourniquet ischemic pain rating (P = 0.01). Tactile pain thresholds were significantly reduced by mustard oil inflammation during control, whereas adenosine treatment prevented this reduction. The ice water-induced cold pain rating was not influenced by adenosine. Conclusions An intrathecal adenosine injection of 1,000 microg lacked side effects in healthy volunteers. The compound attenuated different types of experimental pain.

In the awake state, isocapnic hypoxic ventilatory responses (HVRs) are biphasic, with an acute response within 5 min of hypoxic stimulation followed by a less pronounced sustained response.In this study, we investigated the influence of isoflurane anesthesia (endtidal concentration 1.1 kPa) on acute and sustained isocapnic HVRs in eight healthy women at pulse oximetry arterial saturations of 75%-80%. The aims were to determine whether HVR (20 min of hypoxia) during anesthesia was biphasic and to quantify ventilatory responses. Pneumotachography and in-line infrared capnometry were used. A biphasic HVR was found both in awake and anesthetized patients. Of the subjects, six had decreased and two had increased acute and sustained isocapnic HVRs in the anesthetized, compared with the awake state, which resulted in an approximately 50% reduction in both acute and sustained HVRs. In addition, the ventilatory response pattern was altered by anesthesia. Awake HVR was accomplished by increased tidal volumes while respiratory rates were unchanged. The opposite occurred during anesthesia. The underlying mechanisms for this biological action of inhaled anesthetics remains to be elucidated. In conclusion, this study clearly demonstrates the persistence of hypoxic ventilatory sensitivity during clinical anesthesia. Implications: We studied the ventilatory effects of 20 min of breathing air with low oxygen content (hypoxic) in eight women, before and during anesthesia with inhaled isoflurane. We demonstrated a persistent but blunted hypoxic ventilatory response during clinical anesthesia. (Anesth Analg 1998;86:403-9)

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.

Nitric oxide (NO) is believed to be involved in the pathophysiology of sepsis. This study evaluated the activity of the NO pathway in a human endotoxin model. At baseline and after endotoxin, on-line measurements of exhaled NO (eNO) were made using a chemiluminescence technique with a single-breath method. NO-free air was inhaled prior to exhalation against a resistance. NO in orally and nasally exhaled air and in rectal gas was investigated. Plasma nitrite, nitrate, and guanosine 3′, 5′-monophosphate (cGMP) and the events after diclophenac administration were also studied. Endotoxin infusion resulted in tachycardia and fever. An early increase in oral eNO concentration was observed and oral eNO decreased after diclophenac administration. NO exhaled nasally, NO in rectum gas and nitrite/nitrate levels remained unchanged over the study period. cGMP increased after 4 h. These findings suggest an early increase in nitric oxide production from the lungs, probably due to increased activity of the constitutive nitric oxide synthase upon endotoxin stimulation. In contrast, nitric oxide production in the upper airways, measured as nasally exhaled nitric oxide and nitric oxide in rectal gas, remained unchanged. Further studies will elucidate if exhaled nitric oxide is a valuable marker of sepsis-induced lung injury and if monitoring of treatment is possible.

Adenosine and adenosine analogs decrease pain-like behavior in animal models of both acute nociceptive and neuropathic pain via adenosine receptor activation at spinal and/or supraspinal levels. This open study is the first in a series of intrathecal (IT) adenosine administration studied for the evaluation of efficacy and side effects in 14 patients. All had chronic neuropathic pain with tactile hyperalgesia and/or allodynia primarily of traumatic origin. The effects of IT adenosine (500 microg [n = 9] or 1000 microg [n = 5]) were evaluated. Approximate areas of tactile pain were mapped. Spontaneous and evoked pain (visual analog scale score 0-100) and tactile pain thresholds were assessed before and 60 min after injection. The injection caused transient pain (60 min) in the lumbar region in five patients. There were no other side effects. Spontaneous and evoked pain was reduced (median score from 65 to 24 [P0.01] and from 71 to 12 [P0.01], respectively) in parallel with increased tactile pain thresholds in allodynic areas. Areas of tactile hyperalgesia/allodynia were reduced (median reduction 90%; P0.001). Twelve patients experienced pain relief (median 24 h). We conclude that IT adenosine transiently causes lumbar pain in a subgroup of patients and may reduce various aspects of chronic neuropathic pain.This is the first series of patients with chronic neuropathic pain in which tolerability to spinal adenosine administration has been evaluated. A subset of patients reported transient low back pain as the only side effect. Spontaneous and evoked pain intensity decreased in most patients, an effect lasting for a median of 24 h.

Background—Endothelin-1, the most potent vasoconstrictor known, is produced in septic states and may be involved in the pathophysiology of the deteriorated splanchnic circulation seen in septic shock.Aims—To elucidate the capability of bosentan, a non-peptide mixed endothelin receptor antagonist, to attenuate splanchnic blood flow disturbances and counteract intestinal mucosal acidosis in endotoxic shock.Methods—In 16 anaesthetised pigs, central and regional haemodynamics were monitored by thermodilution and ultrasonic flow probes, respectively. A tonometer in the ileum was used for measurement of mucosal pH. Onset of endotoxin challenge was followed by bosentan administration (to eight pigs) two hours later.Results—Endotoxin infusion reduced cardiac index and systemic oxygen delivery; bosentan restored these parameters. The reduced mean arterial blood pressure and renal blood flow remained unaffected by bosentan. The profound reduction in gut oxygen delivery in response to endotoxin was completely abolished by bosentan. Bosentan significantly improved the notably deteriorated intestinal mucosal pH and mucosal-arterial Pco2 gap. The mucosal-portal vein Pco2 gap, used to monitor the mucosa in relation to the gut as a whole (including the spleen and pancreas), was also greatly increased by endotoxaemia and significantly reversed by bosentan.Conclusion—Bosentan completely restored the profound endotoxin induced reductions in systemic and gut oxygen delivery with a concomitant reversal of intestinal mucosal acidosis. Results suggest that endothelin is involved in the pronounced perfusion disturbances seen in the gut in endotoxic shock. Bosentan may prove useful in reducing gut ischaemia in septic shock.

UNLABELLED: Adenosine and adenosine analogs induce analgesia in humans and presumed antinociception in animal models when administered both systemically and intrathecally. In the present investigation in rats, we studied the effects of intrathecally administered adenosine analogs, with or without systemic coadministration of an adenosine antagonist (theophylline), on substance P (SP) and calcitonin gene-related peptide (CGRP) concentrations in cerebrospinal fluid (CSF). In parallel, nociceptive reflex testing (tail immersion latency) and motor function were evaluated. The potent unselective adenosine receptor agonist N-ethylcarboxamide-adenosine (NECA) and the relatively adenosine A1 receptor selective agonist R-phenyl-isopropyl-adenosine (R-PIA) both reduced SP-like immunoreactivity (-LI) by 50%, whereas CGRP-LI remained unchanged. There was a dose-dependent increase in tail immersion latency. This effect was present without motor impairment when R-PIA was administered in doses up to 5 nmol. R-PIA (10-100 nmol), as well as 1-100 nmol of the unselective agonist NECA, produced dose-dependent motor impairment. The reduction of SP-LI as well as the behavioral effects were reversed by theophylline. We conclude that SP reduction in CSF, which possibly reflects reduced SP turnover after adenosine receptor stimulation, provides an additional possible mechanism of action for the analgesic effects of adenosine. IMPLICATIONS: We studied the interactions between the known pain mediator substance P and substances with effects similar to the endogenous pain modulator adenosine in rats. The results suggest that the pain-reducing effect of adenosine is, at least partly, due to a reduction of substance P in cerebrospinal fluid.

In seven patients with peripheral neuropathic pain, the effect of systemic adenosine infusion on pain symptoms was evaluated in a double-blind, placebo controlled, cross-over study. The study infusions, adenosine (50 micrograms.kg-1.min-1) or placebo, were given intravenously (IV) during 45-60 min at two separate occasions. Before and during infusions, bedside examination of sensibility and quantitative sensory testing (QST), i.e., assessments of perception thresholds for touch, touch-evoked pain, cold, warmth, painful heat, and cold, were performed. In the neuropathic area, sensation magnitude was rated by a visual analog scale (100 mm VAS) using a pin and at perception threshold for touch-evoked pain using von Frey filaments. Adenosine infusion reduced spontaneous pain (P0.05), and caused an increase of the touch-evoked pain threshold from 10.8 +/- 5.3 to 22.2 +/- 6.9 g (P0.05), whereas placebo had no effect. Pain intensity at perception threshold for touch-evoked pain was, however, unaltered. Pinprick-evoked pain in the neuropathic areas was reduced from 53 +/- 11 to 29 +/- 10 mm (P0.05). No other sensory modality was consistently changed during adenosine infusion. In conclusion, the present study demonstrates that adenosine infusion alleviates spontaneous neuropathic pain, tactile allodynia, and pinprick hyperalgesia in patients with peripheral neuropathic disorders, probably by a central mechanism of action.

Adenosine, intrathecally administered, produces antinociception in experimental studies on animals. The effect of intravenous (i.v.) adenosine on experimentally induced pain in humans has not been studied. The present single-blind, randomized, placebo-controlled study was conducted in nine healthy volunteers. The pain-reducing effects of adenosine (70 micrograms.kg-1.min-1 i.v.), morphine (0.1 mg/kg i.v.), ketamine (0.1 mg/kg i.v.), adenosine + morphine, and adenosine + ketamine were compared to each other and to placebo in random order. Ischemic pain was induced by the submaximum effort tourniquet technique. Pain was assessed using the visual analog scale (VAS, 0-100 mm). The sums of pain scores (SPS) were compared and found significantly 30%-40% lower for adenosine as well as for the other compounds and combinations (P < 0.03), compared to placebo. The number of subjects who reached VAS 100 within 30 min was significantly lower (P < 0.03) when receiving adenosine + morphine (0/9) and adenosine + ketamine (2/9) than when receiving placebo (7/9). This may indicate an additive effect on pain reduction when adenosine is given in combination with morphine or ketamine. In conclusion, the results indicate that i.v. adenosine, as well as morphine and ketamine, can reduce experimentally induced ischemic muscle pain in healthy volunteers.

Endothelin (ET), the most potent endogenous vasoconstrictor known, is highly produced in septic states. High plasma levels of ET are associated with morbidity and mortality in septic patients. Being a potent vasoactive peptide produced in sepsis, ET may be involved in the pathophysiology of the markedly deteriorated splanchnic circulation seen in septic shock. In this study, bosentan, a non-peptide mixed ET receptor antagonist was utilised in order to attenuate splanchnic blood flow disturbances and counteract intestinal mucosal acidosis in a porcine model of endotoxin shock.

Endothelin 1, an endothelium derived peptide, is the most potent vasoconstrictor known. In experimental endotoxin models as well as in human septic shock, a three- to fourfold elevation of plasma levels of endothelin-1-like immunoreactivity is seen [1]. In a porcine endotoxin shock model, the mixed non-peptide endothelin receptor antagonist bosentan [2] was administered 2 h after onset of endotoxemia (n = 8). Cardiopulmonary vascular changes, oxygen related variables and plasma levels of endothelin-1-like immunoreactivity were compared to a control group only receiving endotoxin (n = 8). Bosentan abolished the progressive increase in mean pulmonary artery pressure and pulmonary vascular resistance seen in controls. Further, bosentan restored cardiac index to pre-endotoxin level by an increase in stroke volume index, improved systemic oxygen delivery and acid base balance, and since mean arterial blood pressure was unaffected, reduced systemic vascular resistance. Endotoxemia increased plasma levels of endothelin-1-like immunoreactivity (from 14 ± 1 to 37 ± 2 pmol/l) and tumor necrosis factor-alpha, the former being further increased by bosentan (from 37 ± 2 to 180 ± 30 pmol/l). Effects of endotoxin infusion, started at T0 h and bosentan, administered after 2 h of endotoxemia (T2 h), in pigs (n = 8) compared to control pigs (n = 8) not receiving bosentan. Groups are compared at T0 h, T2 h and T5 h. *P < 0.05 and ***P < 0.001 for differences between groups in time-matched between-group contrasts. In conclusion, in porcine endotoxemia, treatment with the endothelin receptor antagonist bosentan, administered during established shock, abolished pulmonary hypertension and restored cardiac index. These findings suggest that bosentan could be an effective treatment to reverse a deteriorated cardiopulmonary state during septic shock. Table

The influence of sodium nitroprusside (SNP) on cerebral blood flow and cerebrovascular autoregulation at doses that produced 36% +/- 3% (slight) and 52% +/- 4% (moderate) reductions of mean arterial blood pressure (MABP) was evaluated in mechanically ventilated fentanyl/N2O-anesthetized pigs. The blood flow of the frontal hemispheres was evaluated by sagittal sinus outflow, which was determined by an electromagnetic method. Integrity of cerebral autoregulation was evaluated by two formal tests: one hypertensive challenge with an angiotensin infusion (n = 12) and one hypotensive challenge with reduced venous return to the heart (blockade of the vena cava, n = 7). The tests were performed before, during, and after hypotension. Cerebral blood flow tended to increase during hypotension, but this change was not significant. Impaired autoregulation was seen in both tests during slight hypotension (MABP = 89 +/- 3 mm Hg) with an SNP infusion of 12 +/- 3 micrograms.kg-1.min-1. Cerebral autoregulation was completely abolished at both tests during moderate hypotension (MABP = 61 +/- 2 mm Hg with an SNP infusion of 38 +/- 7 micrograms.kg-1.min-1). Despite a posthypotensive increase in cerebral blood flow without rebound hypertension, the autoregulatory response to angiotensin-induced hypertension was restored within 15-25 min. The autoregulatory response to a decrease in MABP was impaired for more than an hour after discontinuation of the SNP infusion. No acidosis was observed. The authors conclude that during slight and moderate SNP-induced hypotension, there was a dose-dependent impairment of cerebral autoregulation. Further, the autoregulatory response to the hypotensive challenge after SNP hypotension was markedly delayed, whereas the response to hypertension was rapidly restored.

1. The possible involvement of neuropeptide Y (NPY) in relation to noradrenaline (NA) and adenosine triphosphate (ATP) mechanisms in the sympathetic nervous control of the vascular tone and capsule contraction in the blood perfused pig spleen was investigated in vivo. 2. Local injections or infusions of NA, NPY and alpha-, beta-methylene ATP (mATP) caused vasoconstriction (perfusion pressure increase) and capsule contraction (increased venous blood flow). ATP only evoked vasodilatation. NPY was about 50 fold more potent than NA as a vasoconstrictor, and the NPY response was more long-lasting. Reserpine treatment did not change the effects of NPY. 3. Electrical stimulation of the splenic nerves in control animals caused a frequency-dependent, guanethidine-sensitive output of both NPY-like immunoreactivity (-LI) and NA, suggesting co-release. The output of NPY-LI relative to NA was enhanced at high frequency stimulation. Furthermore, alpha-adrenoceptor blockade by phentolamine enhanced both the output of NPY-LI and NA while inhibition of the neuronal uptake of NA with desipramine reduced the low frequency stimulation-evoked overflow of NPY-LI. Preganglionic denervation did not change the output of NPY-LI or NA. 4. Reserpine treatment reduced both the splenic content of NA and NPY-LI. Preganglionic denervation inhibited the reserpine-induced depletion of the NPY content but not of NA in terminal areas. The stimulation-evoked NPY overflow was markedly enhanced, especially at low-frequency stimulation after reserpine, and the plasma levels of NPY-LI in the venous effluent were then in the nmolar range (i.e. where exogenous NPY induced vasoconstriction). The perfusion-pressure increase upon stimulation in reserpine-treated, preganglionically-denervated animals was highly correlated (r = 0.91) to the NPY overflow. The functional 0.5 Hz responses were reduced after reserpine, while at higher frequencies the functional effects were of similar magnitude to controls but longer-lasting. 5. Tyramine induced a release of NA but not of NPY-LI. Furthermore, the increase in perfusion pressure induced by tyramine was absent after reserpine. 6. After tachyphylaxis to the vasoconstrictor effects of mATP, the nerve stimulation-evoked, functional response as well as the NA and NPY-LI overflow were unchanged. After reserpine treatment, both the perfusion-pressure increase and NPY-LI overflow to nerve stimulation were reduced after mATP tachyphylaxis. 7. In conclusion, release of NPY rather than ATP may explain the long-lasting, non-adrenergic, splenic functional responses in reserpinized animals upon sympathetic stimulation. However, NA is most likely the main splenic transmitter when low-frequency stimulation is used under control conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Umbilical blood was collected immediately at birth (less than 30 s) in full-term infants after vaginal deliveries (n = 33) and elective cesarean sections (n = 11). Blood gases, plasma adenosine, hypoxanthine, and catecholamine concentrations were determined. In vaginally born infants the median arterial adenosine concentration was found to be 0.46 microM (range 0.13-2.06) and the venous 0.48 microM (0.09-1.62). These levels were significantly higher (p less than 0.01) than in infants delivered by elective cesarean section; 0.16 microM (0.04-0.42) in the artery and 0.17 microM (0.02-0.56) in the vein. Vaginally born infants showed about a 4-fold higher level of umbilical arterial catecholamines than infants born by elective cesarean section. There was a strong inverse correlation between arterial hypoxanthine concentration and pH (r = -0.81, p less than 0.01). It is suggested that increased adenosine release at vaginal delivery modulates the stress response elicited by the strong catecholamine surge and may furthermore exert protective effects in perinatal asphyxia.

The effect of intravenous infusion of adenosine on CBF was studied in seven patients with cerebral arteriovenous malformation. The patients were examined with positron emission tomography with controlled ventilation using [15O] water and [11C] fluoromethane as tracers. Total and regional CBF were determined before and during infusion of adenosine at rates producing a reduction of the MABP by ∼10–40%. Six patients were normoventilated, and one was hyperventilated. Mean CBF in areas with normal brain tissue was 54 ml/100 g/min before adenosine infusion under normoventilation. Adenosine infusion increased mean CBF with 23–85%. Mean CVR was decreased with 43–65% and exceeded the percentage reduction of MABP in all normoventilated subjects. In the hyperventilated patient, the reduction of CVR was similar to the reduction of MABP, and CBF was unaffected, except for a 30% increase in the thalamus. It is concluded that intravenous administration of adenosine produces marked cerebral vasodilation in normoventilated subjects and that this response can be counteracted by hyperventilation.

Central and splanchnic hemodynamic effects during controlled hypotension induced by the administration of the endogenous vasodilator adenosine were studied in ten artificially ventilated dogs under neurolept anesthesia. Adenosine was administered as a continuous infusion in the aorta (n = 3), in the inferior vena cava (n = 3), and after pretreatment with dipyridamole (which inhibits the cellular uptake of adenosine) (n = 4) in a dose sufficient to maintain a mean arterial blood pressure (MABP) level of approximately 50 mmHg. Observations were made before and after 20 min of controlled hypotension. Basal arterial plasma levels of adenosine were in the 10(-7) M range (means = 0.4 microM). The hemodynamic response was similar in all three settings. Adenosine caused a profound decrease in systemic vascular resistance (SVR) (52%, P less than 0.01) and preportal vascular resistance (PPR) (64%, P less than 0.01), while hepatic arterial vascular resistance ( HAR ) increased by 49% (P less than 0.05). Cardiac output increased (22%, P less than 0.05) through increase of stroke volume (77%, P less than 0.01), while heart rate decreased (28%, P less than 0.01). Whole-body oxygen uptake decreased (14%, P less than 0.01). Portal venous blood flow increased by 28% (P less than 0.05), whereas hepatic arterial blood flow decreased by 70% (P less than 0.01). In the preportal tissues, oxygen uptake decreased by 21% (P less than 0.01). In contrast, hepatic oxygen consumption increased (53%, P less than 0.05). Adenosine-induced hypotension was not associated with changes in plasma renin activity or the plasma concentration of norepinephrine. It is concluded that adenosine causes a rapidly induced and easily maintained hypotension and may be a potentially useful agent for controlled hypotension in patients.

The cardiovascular effects of adenosine-induced controlled hypotension were studied in 10 patients undergoing cerebral aneurysm surgery. Adenosine and its metabolites were measured in arterial plasma using high-pressure liquid chromatography. Whole body and cerebral arteriovenous oxygen content differences (AVDO2), arterial lactate levels, and arteriojugular lactate differences were determined. In order to reduce the dose requirement of adenosine, the patients were pretreated with the adenosine uptake inhibitor, dipyridamole (0.3-0.4 mg . kg-1). During the infusion of adenosine (0.14 +/- 0.04 mg . kg-1 . min-1) the mean arterial blood pressure decreased by 43%, from 82 to 46 mmHg, during a mean hypotensive period of 32 min, without signs of tachyphylaxis. The arterial adenosine level increased from 0.15 +/- 0.02 to 2.45 +/- 0.65 microM (P less than 0.01). Hypotension was caused by a profound decrease in peripheral vascular resistance (61 +/- 3%, P less than 0.01), which was accompanied by an increase in cardiac output (44 +/- 9%, P less than 0.01). Heart rate increased moderately by 16 +/- 5% (P less than 0.01). Pulmonary vascular resistance and central venous pressures were unaffected. Arterial lactate and PaO2 were unchanged, while whole body oxygen consumption was decreased by 13 +/- 4% (P less than 0.05). The AVDO2 across the brain was decreased by 37 +/- 5% (P less than 0.05) without signs of lactate formation. The authors conclude that adenosine rapidly induces a stable and easily controlled hypotension in humans by dilation of arterial resistance vasculature.

The effects of adenosine on central and myocardial hemodynamics and metabolism were evaluated during fentanyl anesthesia (100 micrograms.kg-1) in six patients with peripheral vascular disease. Adenosine was intravenously infused, at a rate of 90 +/- 20 (SEM) micrograms.kg-1.min-1, to reduce mean arterial blood pressure by approximately 20% (23 +/- 2% SEM, from 82 +/- 3 to 63 +/- 3 SEM mmHg) during a 20-min period. Systemic and pulmonary vascular resistance indices decreased by 36 +/- 3 and 32 +/- 6% (SEM), and cardiac index increased by 18 +/- 5%. Heart rate, ventricular filling pressures, and whole body oxygen consumption were not affected by adenosine. Despite the reduced mean arterial blood pressure, coronary sinus flow increased by 128 +/- 26% (SEM) in parallel with a 96 +/- 11% (SEM) increase in coronary sinus oxygen content. Left and right ventricular stroke work indices, as well as myocardial oxygen consumption, were maintained. ECG (12-lead) demonstrated signs of ischemia in one subject, while myocardial lactate uptake was unchanged in all subjects. In conclusion, adenosine-induced hypotension in patients with peripheral vascular disease increased cardiac index without affecting myocardial work, whole body, and myocardial oxygen consumptions. The marked increase in coronary sinus blood flow, indicating coronary vasodilation, was not related to increased myocardial work. Further information regarding myocardial effect of adenosine in patients with ischemic heart disease is warranted.

Myocardial ischemia is associated with adenine nucleotide degradation and accumulation of nucleosides and bases. Data regarding adenine nucleotide degradation in ischemic human myocardium is limited. The adenine nucleotides, IMP, adenosine, inosine, hypoxanthine and uric acid were determined by high pressure liquid chromatography, in biopsies (1.5-4 mg) from human left ventricular myocardium during cardioplegia (at 10-15°C) in six patients (aged 35-64 year) subjected to aortic valve replacement surgery. The study was performed after informed consent and approval from the Ethics Commite. The first biopsy was collected after induction of cardioplegia and the second 45-60 min later. The myocardium was perfused with diluted cold blood 25-30 ml/min (with 20 mM potassium). The ATP concentration was 12.64±1.96 mmoles/kg dry muscle (d.m.) after induction and decreased by 37±5% (p

Adenosine is released from the mammalian heart during ischemia. Yet, it has proven difficult to demonstrate adenosine release following coronary sinus (cs) catheterization in pacinginduced angina. In this study, dipyridamole (Dip, an inhibitor of adenosine uptake) was used to facilitate detection of adenosine release during myocardial ischemia. Methods: Seven patients with ischemic heart disease (IHD) and five healthy volunteers were studied by arterial (a) and cs catheterization, after informed consent and approval from the Ethics Commite. Atrial pacing to angina or heart rate (HR) 150 (in volunteers) were performed before and during continuous dipyridamole infusion (5 μg/kg/min). Cs blood flow (CSBF, thermodilution technique), a-cs differences for adenosine and hypoxanthine (by high pressure liquid chromatography), lactate and O2 were measured before, during and after pacing. Results: Pacing increased CSBF (53% in IHD and 60% in volunteers) and O2 uptake. IHD released lactate and hypoxanthine but not adenosine. Dipyridamole (1-1.5 μM in plasma) did not affect HR, BP or O2 uptake but increased resting CSBF (18%) in all subjects. During pacing, CSBF was enhanced in volunteers but not in IHD, in comparison to control pace. The a-cs difference for adenosine (-0.17±0.06 μM, p

The effect of adenosine on central hemodynamics and cerebral blood flow were studied in 30 patients during anesthesia. The studies were approved by the local Ethics committe and performed after informed consent. Hemodynamics were recorded by a Swan-Ganz catheter and an intraarterial cannula. Cardiac output was determined by the thermodilution technique and cerebral blood flow was quantified by positron-emission-tomography. Adenosine concentrations in plasma was determined by high pressure liquid chromatography. Adenosine infusion (0.05-0.3 mg/kg/min) induced a stable hypotension (mean arterial blood pressure, MABP 40-50 mmHg), corresponding to 40-50% reduction of MABP, at an arterial adenosine concentration in the μmolar range (10-20 fold elevation of basals levals). Dipyridamole pretreatment (0,3-0,4 mg/kg,n=11) decreased the dose requirement for adenosine by 50% (p