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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.

Deep tissue pain can be related to reduced muscle blood flow, which comprises the metabolic demand under muscle work. The tissues and receptors involved in nociception after ischaemic muscle contractions are not known. The concentration of adenosine is increased after ischaemic contractions and might act as an algesic substance. In 15 subjects, adenosine, hypertonic saline (algesic), and isotonic mannitol (placebo) were infused into the tibialis anterior muscle and compared with the pain caused by ischaemic contractions. The muscle pain intensity (visual analogue scale; VAS), distribution, and quality were assessed. Pressure pain thresholds were recorded to assess the deep tissue sensitivity. Adenosine did not induce more pain than the placebo. The maximal VAS score after hypertonic saline and ischaemic contractions was higher compared with adenosine/placebo infusions. The duration and area of pain were significantly increased after hypertonic saline infusions compared with ischaemic contractions. Higher scores on the McGill pain questionnaire were given to the “stabbing”, “burning”, “heavy”, and “exhausting” word categories after ischaemic contractions, and “cramping” was rated higher during hypertonic saline-induced muscle pain compared with ischaemic contractions. During hypertonic saline infusions, the pressure pain threshold was decreased compared with before and immediately after the pain had vanished. The present study shows that pharmacological levels of adenosine in skeletal muscle did not induce pain. Excitation of muscle nociceptors by hypertonic saline evoked hyperalgesia, larger areas of pain, and a different quality of pain compared with ischaemic contractions, suggesting that the pain after ischaemic contractions is mediated by other populations of nociceptors in muscle and/or other tissues than excited by hypertonic saline.

The present study assessed the efficacy and potency of intrathecal (i.t.) administration of the opiate morphine, the gamma-aminobutyric acid-B (GABA(B)) receptor agonist baclofen, the alpha2-adrenoceptor agonist clonidine and the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) on the acute allodynia-like behaviour after photochemically induced spinal cord injury (SCI) in rats. Rats displaying allodynia-like behaviours to brushing, von Frey hairs and cold stimulation 1-2 days after photochemically induced SCI were studied. In a cumulative dose regime, morphine (0.1-10 micrcog), baclofen (0.1-1 microg), clonidine (0.1-10 microg) and R-PIA (0.01-10 nmol) were administered i.t. through an implanted catheter at the lumbar spinal cord. All tested drugs dose-dependently reduced the brushing, von Frey hairs and cold stimulation-induced allodynia-like behaviour. No increase in adverse effects such as motor deficits was found for morphine, clonidine and R-PIA. There was a slight increase in motor impairments at the highest dose of baclofen. For the mechanical allodynia, morphine appeared to be most effective, whereas baclofen, clonidine and R-PIA only provided a partial alleviation. For the cold allodynia, morphine and baclofen were more effective than clonidine and R-PIA. In relieving acute mechanical and cold allodynia-like behaviours in rats 1-2 days after SCI, i.t. morphine and baclofen were superior to clonidine and R-PIA.

THE intrathecal (i.t.) administration of the adenosine A 1 -receptor agonist R-phenylisopropyl-adenosine (R-PIA) reduced pain-related behaviors after peripheral nerve or spinal cord injury in rats. The endogenous ligand adenosine is clinically available and has been tested i.t. as an analgesic. Thus, we set out to investigate whether i.t. adenosine could reduce allodynia in a model of central pain in spinally injured rats. I.t. adenosine did not reduce mechanical and cold allodynia-like behaviors at doses of 10, 100 and 187 nmol, whereas i.t. R-PIA at 10 nmol markedly alleviated allodynia in the same animals. The lack of effect by exogenous adenosine may be due to pharmacokinetic or pharmacodynamic reasons. Alternatively, adenosine may have reduced affinity and selectivity towards the A 1 -receptors which may be important for the antiallodynic effect.

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.

Pneumoperitoneum (PP) for laparoscopic surgery induces prompt changes in circulatory parameters. The rapid onset of these changes suggests a reflex origin, and the present study was undertaken to evaluate whether release of vasopressor substances could be responsible for these alterations. The influence of two different anesthesia techniques was also evaluated.American Society of Anesthesiologists (ASA) class I patients, scheduled for laparoscopic cholecystectomy, were investigated. The first group (n = 10) was anesthetized intravenously. The second group (n = 6) had inhalation anesthesia. Plasma vasopressin, catecholamines, and plasma renin activity were investigated as neurohumoral vasopressor markers of circulatory stress. The general stress response to surgery was assessed by analysis of plasma cortisol.Induction of pneumoperitoneum caused no apparent activation of vasopressor substances, although several hemodynamic parameters responded promptly.The hemodynamic alterations, seen at the establishment of PP during stable anesthesia, cannot be explained by elevation of vasopressor substances in circulating blood.

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.

Background: Laparoscopic surgery involves the use of intra-ab-dominal carbon dioxide insufflation (pneumoperitoneum). The increased intra-abdominal pressure causes marked haemodyn-amic changes, which may influence electrocardiographic monitoring. The aim of the present study was to elucidate the influence of pneumoperitoneum on vectorcardiographic recordings. Methods: Vectorcardiographic changes (QRS vector difference= QRSVD, QRS loop area, QRS magnitude, ST vector magnitude, spatial ST vector change) were recorded continuously applying computerized vectorcardiography in 12 anaesthetised cardio-vascularly healthy patients, scheduled for laparoscopic cholecystectomy. Measurements were made before and during pneumoperitoneum in three different body positions (supine, Trendelenburg and reversed Trendelenburg), also employing transesophageal echo-cardiography and invasive blood pressure monitoring. Results: Pneumoperitoneum significantly increased QRSVD, in parallel with an enlargement in loop area and magnitude. The magnitude was significantly increased in the transversal and frontal planes and there was a tendency to increase the magnitude in the sagittal plane. The increase in QRS-VD reached levels previously associated with the development of myocardial ischaemia in patients with coronary artery disease. The ST-variables were not changed by the pneumoperitoneum. The positional changes also influenced QRSVD significantly. Conclusions: When computerized vectorcardiography is used for ischaemia monitoring during pneumoperitoneum, the ST-variables seem reliable. However, vectorcardiographic QRS changes should be interpreted with caution, as the QRS alterations found during pneumoperitoneum mimic the changes seen during myocardial ischaemia.

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.

We studied the effects of propofol on the cerebral circulation and flow/pressure autoregulation in eight anesthetized pigs. Regional cerebral blood flow (rCBF) was measured with a cerebral venous outflow technique. Autoregulation was tested with angiotensin infusions and gradual blocks of the caval vein for hyper- and hypotensive challenges, respectively. Propofol was given in a bolus of 2.5 mg.kg-1 followed by an infusion starting at 12 mg.kg-1.h-1 and gradually reduced to 8 mg.kg-1.h-1. As expected, propofol caused a substantial reduction in cerebral metabolic rate of oxygen, which was accompanied by an increase in cerebrovascular resistance and a decrease in CBF. In the control situation, i.e., during background anesthesia (low-dose isoflurane+nitrous oxide) only, the autoregulation was well preserved, and its lower limit was found at a mean arterial blood pressure (MABP) of 48 mm Hg. Propofol did not affect autoregulation in the group as a whole: the slope of the regression line of regional cerebrovascular resistance (rCVR) versus MABP during blood pressure reduction (caval test) was not significantly changed during propofol when compared to the control, neither was the lower limit of autoregulation (MABP, 54 mm Hg). All pigs but one followed this response pattern. The nonautoregulating pig had a completely pressure-dependent rCBF during propofol anesthesia, despite a perfectly intact auto-regulation in the control situation. It is concluded that propofol in clinical dosage does not affect autoregulation in this pig model, although individual animals may display a different response pattern.

Background: Adenosine (ADO), and stable analogs thereof, have been shown to exert antinociceptive action in cutaneous and deep somatic pain under experimental and clinical conditions in animals and in humans. The aims of this randomized double-blind placebo-controlled study were to evaluate if a low dose of intravenous (i.v.) ADO could reduce the requirements of volatile anesthetic and postoperative opioid in connection to hysterectomy, where visceral nociception significantly contributes to pain. Methods: Forty-three women, age 32–65 years, ASA I and 11, scheduled for abdominal hysterectomy, were assigned to receive an i.v. infusion of either adenosine, 80 μg. kg-1 min-1, or placebo during surgery. Anesthesia was maintained with isoflurane (ISO)/N2O/ O2 inhalation. Postoperatively, a reduced dose of 40 μg. kg-1. min-1 was continued for 3 h. Results: The end-tidal (ET-) IS0 was equal between groups before surgery. During surgery, the IS0 requirement was increased, compared to the preoperative level, in the placebo group, while the requirement declined in the ADO group. The overall IS0 requirement in the ADO group was reduced by 36% (P

The antinociceptive actions of adenosine and adenosine analogs in animal models has been known for more than 10 years. The recent development with regard to the pain modulatory effects of adenosine, primarily in clinical studies, has generated a renewed interest in this principle for pain control. This review summarizes the current knowledge in adenosine mediated pain modulation in acute and chronic conditions, with focus on studies in man. The endogenous compound adenosine has various modulatory effects in the peripheral and central nervous system, mediated through specific cell-surface associated receptors. The current view is that adenosine receptors of the A1-subtype are associated with a modulatory effect on pain transmission at spinal cord level. Animal studies have repeatedly demonstrated adenosine- and adenosine analog mediated inhibitory influences on presumed nociceptive reflex responses (1,2). These examinations in rodents have tested acute pain models involving tactile, pressure and heat stimulations. More recently, animal lesion models presumably reflecting chronic pain, has shown that adenosine analogs can suppress nociceptive behaviour both by systemic and intrathecal (i.t.) administration (3,4). Consequently, there is substantial evidence that adenosine can modulate nociceptive input. Further, it has been proposed that endogenous adenosine formation is involved in physiological pain control at the spinal cord level and that its release is involved in the action of opioid antinociception (1). Clinical studies have revealed that adenosine administration by bolus injection or by infusion at doses above 70 micrograms x kg-1 x min-1 is associated with pain symptoms from different parts of the body. This algogenic effect of higher doses of adenosine is probably related to sensitization/activation of peripheral nociceptive afferents (5).

Adenosine has been suggested to have a role in regulation of the tone of the cardiac resistance vessels. To elucidate the coronary vasoregulatory role of endogenous adenosine in man, we studied the effects of adenosine receptor antagonism by theophylline on coronary blood flow at rest and during light exercise. However, theophylline may also exert pharmacological effects not related to adenosine antagonism. To clarify the contribution of endogenous adenosine in coronary hyperaemia, the effect of theophylline was compared to that of enprofylline, a xanthine which exerts similar pharmacological effects as theophylline while lacking antagonistic action at adenosine receptors. Twenty healthy subjects (10 males) aged 22-39 years were examined. Coronary sinus (CS) blood flow and blood oxygen content were determined at rest and during supine bicycle exercise, at a load of 50 watts, for 10 min. Thereafter, stepwise infusion of adenosine (30 to 60 micrograms/kg/min into the subclavian vein) was performed. Theophylline or enprofylline treatment was instituted randomly and double-blind (10 in each group), and the procedures (i.e. determinations at rest, during exercise and during infusion of adenosine) were repeated. In all 20 subjects, basal CS flow was 70 +/- 6 ml/min and the cardiac oxygen extraction ((A-CS)O2D) was 123 +/- 3 ml/l. During exercise, CS flow and (A-CS)O2D increased to 135 +/- 17 ml/min and 132 +/- 3 ml/l, respectively. Adenosine increased CS flow dose dependently to 161 +/- 27 ml/min, while (A-CS)O2D decreased to 66 +/- 7 ml/l. The vasodilatory effect of adenosine was readily counteracted by theophylline, the increase in CS flow being 33% vs. 133% in the control situation. Enprofylline, on the other hand, enhanced the response to exogenous adenosine. Theophylline, at a dose lacking effect on heart rate and blood pressure, decreased CS flow at rest by 14% (P < 0.05) and during exercise by 18% (P < 0.05). ((A-CS)O2D increased by 14% at rest and during exercise (P < 0.001). Enprofylline, on the other hand, was without effect. The differences in responses between theophylline and enprofylline with respect to coronary flow and oxygen extraction were significant both at rest and during exercise. It is concluded that theophylline increases coronary vascular resistance, while enprofylline, lacking adenosine antagonistic properties, was without such effect. This indicates a physiological role of adenosine in regulation of coronary flow.

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.

This study primarily examined the effect of three endtidal isoflurane concentrations (0.2, 1.0 and 1.4%) on the isocapnic hypoxic ventilatory response (HVR), as well as the hypercapnic ventilatory response (HCVR), in 18 women (ASA I) who were all in the follicular phase of their menstrual cycle. Capnography was used, together with pulseoximetry to indicate desired levels of hypoxia (SpO2 75-80%). This hypoxic challenge resulted, after 3-4 min, in a stable ventilation, and ventilation measurements were then taken during a 90 s period. The HCVR provocation (inhalation of 4.5% CO2 in air) and measurements were conducted using a similar time frame as for HVR. Isoflurane 0.2% did not affect any ventilatory parameter. Isoflurane 1.0 and 1.4% dose-dependently increased endtidal CO2 and respiratory rate, while tidal volumes decreased. Minute ventilation was not reduced. HVR, as well as HCVR, were both uninfluenced by isoflurane 0.2%. HVR was reduced by 60-70% at isoflurane 1.4% (P < 0.01), and was parallelled by a similar depression of HCVR (P < 0.01). The HVR during anaesthesia was accomplished by a respiratory rate response, while the increase in tidal volume, seen in the awake state, was abolished. The HCVR during anaesthesia was, on the other hand, the result of a dose-dependently depressed tidal volume response, without any increase in respiratory rate. In conclusion, isoflurane 0.2% did not affect the ventilatory response to mild isocapnic hypoxia, nor to mild hypercapnic challenge. During anaesthesia with isoflurane (1.0 and 1.4%), there was a parallel reduction of HVR and HCVR.

Adenosine, an endogenous antinociceptive compound acting in the central nervous system, was infused intravenously (50-70 micrograms/kg/min) to 2 patients with peripheral neuropathic pain. In 1 subject, spontaneous pain was alleviated, and tactile allodynia was essentially relieved during 40 min of infusion. Allodynia to warmth and touch were abolished in the other subject. In addition, hyperalgesia to pinprick was markedly attenuated as was pressure-induced allodynia. The reported effects lasted for hours after termination of the infusion. Our preliminary encouraging data call for further controlled studies of the potentially relieving effect of adenosine in painful neuropathic conditions.

The effect of adenosine on tactile allodynia (secondary hyperalgesia) was studied in 6 healthy volunteers, using a double-blind, placebo controlled, cross-over design. Tactile allodynia was induced by topical application of mustard oil on the skin of the volar aspect of the forearm. Adenosine (50 micrograms kg-1 min-1) or saline was given intravenously for 20 min before the mustard oil application and continued for another 50 min. The tactile allodynic areas for brush and von Frey filament stimulation were both significantly reduced by approximately 50% during adenosine infusion, compared with placebo. The threshold for eliciting allodynia with von Frey filaments was not influenced by adenosine. The study shows that adenosine can reduce the area of mustard oil induced tactile allodynia.

In order to evaluate the difference between poikilo-capnic (no CO2 added to inspired gas) and iso-capnic (CO2 added to keep end-tidal CO2 constant) hypoxic ventilatory responses (HVR) awake and during 0.6 MAC isoflurane anaesthesia, seven cardio-pulmonary healthy patients were investigated. Pneumotachography and capnography were used before and during hypoxia (end-tidal O2 tension approx. 7 kPa). In the awake stale, poikilo-capnic hypoxic challenges resulted in an increased HVR as indicated by a VE that on average increased by 1.4 ± 1.0 (mean ± s.d.) 1 · min−1, whereas the iso-capnic hypoxic challenges resulted in a VE increase that was 4.7 ± 2.3 1 · min−1 on average. In the anaesthetized state, the corresponding value during poikilocapnia was 1.3 ± 0.8 1 · min−1 (88% of the awake responses, n.s.) and during iso-capnia 2.3 ± 1.4 1 · min−1 (49% of the awake, P < 0.02). Awake HVR was achieved by greater tidal volumes during poikilocapnia as well as during isocapnic challenges, while respiratory rates were unchanged. In the anaesthetized state, during poikilocapnia, however, HVR was mediated by an increased respiratory rate, (from 17.5 ± 1.7 breath · min−1 to 20.2 ± 2.2) and during isocapnia by a combination of increased rate (from 17.1 ± 1.9 breath · min−1 to 19.1 ± 1.8) and tidal volume (from 496 ± 80 to 560 ± 83 ml). It is concluded that poikilocapnic HVR is maintained at 0.6 MAC isoflurane whereas iso-capnic HVR is depressed by 50%. In addition, both poikilo- and iso-capnic HVR were accomplished by greater tidal volumes at unchanged respiratory rates in the awake state while the opposite occurred during isoflurane anaesthesia. The more dominating chronotropic HVR during hypoxic challenge under anaesthesia will have to be further clarified in experimental studies.

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.

1. The effects of local intra-arterial infusion of adenosine on renal blood flow, glomerular filtration and renin release in eight healthy awake subjects have been examined. 2. Renal blood flow and glomerular filtration rate were measured as the clearances of p-aminohippurate and inulin, respectively. After basal samplings, adenosine was infused intra-arterially at successive rates of 2 and 10 μg min−1 kg−1 for 40 min at each rate. 3. Apart from a small increase in heart rate (65 ± 4 to 71 ± 4 beats/min), there were no signs of sympathetic activation (unchanged blood pressure and catecholamine levels) during the infusion. Clearance of p-aminohippurate tended to increase, but not significantly, during adenosine infusion (518 ± 48 ml/min basal, 563 ± 52 ml/min during the highest dose of adenosine). The arterial plasma concentration of p-aminohippurate decreased by 9 ± 3% (P < 0.05), consistent with a small increase in renal blood flow in the infused kidney. Inulin clearance was reduced from 115 ± 3 to 97 ± 2 ml/min (P 4. The total excretion of Na+ was unchanged, but there was a minor decrease in K+ clearance. Thus, the K+/Na+ excretion ratio decreased from a basal value of 13 ± 2 to 10 ± 2 (P 5. During continued intra-arterial adenosine infusion, nitroprusside was infused (0.3-2.5 μg min−1 kg−1) for 15 min to decrease blood pressure and stimulate renin production. Mean blood pressure decreased from 90 ± 2 to 63 ± 2 mmHg, whereas heart rate remained unaffected. There were increases in the arterial concentrations of adrenaline (0.3 ± 0.1 to 1.3 ± 0.3 nmol/l; P 6. In conclusion, the direct renal effects of adenosine in healthy awake subjects include a local dilatation of postglomerular vessels, thereby decreasing glomerular filtration, and a reduction in renal oxygen consumption. Furthermore, adenosine prevents an increase in renin release during nitroprusside-induced hypotension.

The effect of the calcium blocker nimodipine on the cerebral blood flow (CBF) and cerebral autoregulatory responses was examined in seven fentanyl/N2O/anesthetized pigs. CBF was measured continuously from the sagittal sinus by a venous outlet flow technique. Cerebral autoregulation tests were performed before, after 30 min of nimodipine infusion (0.5 microgram.kg-1.min-1), and at 30 min after the infusion. The autoregulatory response to a gradual blood pressure increase was tested by infusion of angiotensin, and to a gradual blood pressure decrease was tested by caval block. The slope of the relationship between the regional cerebral vascular resistance (rCVR) and mean arterial blood pressure (MABP) was used as a measure of the autoregulatory capacity. The lower limit of autoregulation was determined as the MABP at which rCVR did not further decrease. An i.v. bolus dose (10 micrograms.kg-1) of nimodipine resulted in a transient increase in rCBF during 3 min, together with an MABP reduction. After 1 h of nimodipine infusion, MABP was reduced (19%), while rCBF, rCVR, and cerebral metabolism were unaffected. In the control condition, a preserved cerebral autoregulatory response to the increase of MABP (+30 mm Hg) was indicated by an unaffected rCBF and determined by the slope of the rCVR/MABP regression line (0.053), not different from the slope during blood pressure decrease (0.063). The cerebral autoregulatory responses to increase or decrease in MABP were not attenuated by nimodipine infusion. The lower limit of autoregulation (48 +/- 6 mm Hg) was not altered by nimodipine.

The aim of this in vitro study was to evaluate the effect of a clinical concentration (2 microM) of dipyridamole alone or in combination with adenosine, 5'-N-ethyl-carboxamido-adenosine (NECA), or prostaglandin E2 on ADP-induced whole blood aggregability. Cyclic AMP accumulation in platelet-rich plasma was also evaluated. For comparison, R-E 244 (a dipyridamole analogue with low phosphodiesterase inhibition) was examined. In whole blood, dipyridamole (2 microM), but not R-E 244 (2 microM), had a small inhibitory effect (16% +/- 5%, p less than 0.01) on aggregation. Adenosine (1 or 5 microM) had an inhibitory effect that was enhanced by the combination with dipyridamole or R-E 244. Adenosine + dipyridamole produced an inhibition almost equal to that of adenosine + R-E 244. Dipyridamole and R-E 244 had no influence on the antiaggregatory effect of NECA and prostaglandin E2. In platelet-rich plasma, dipyridamole and R-E 244 did not enhance cyclic AMP, nor did they reinforce the cyclic AMP production during treatment with adenosine, NECA, and prostaglandin E2. Our results suggest that inhibition of the uptake of adenosine into red blood cells may play a more important role than the inhibition of phosphodiesterase as the pharmacological mechanism for the antiaggregatory effect of dipyridamole in clinical treatment.

The effects of adenosine and prostacyclin (PGI2) infusions on hypoxia-induced pulmonary hypertension in the pulmonary and systemic circulatory systems of nine pigs were compared. The animals received the drugs in random order, and they were allowed to recover between each experimental sequence. Hypoxia was induced by reducing FiO2 to 0.12-0.13 so as to result in an arterial PO2 of approximately 6 kPa. Dose rates of adenosine or PGI2 during hypoxia were individualized in order to achieve a maximal reduction of 15% in the mean arterial blood pressure. Adenosine and PGI2 produced a fall in pulmonary vascular resistance of 36 +/- 4% (s.e.mean P less than 0.01) and 37 +/- 6% (P less than 0.01), respectively. The mean pulmonary artery pressure was reduced by 19 +/- 3% (P less than 0.01) during adenosine infusion and by 36 +/- 4% (P less than 0.01) during PGI2 infusion. The systemic haemodynamic responses to the two drugs were similar but adenosine produced a 7 +/- 2% (P less than 0.01) increase in cardiac output. Arterial PO2 during hypoxia and vasodilator treatment did not differ from the hypoxic situation without drug infusion. It is concluded that adenosine and PGI2 counteract hypoxia-induced increases in pulmonary vascular resistance similarly, but the reduction in pulmonary artery pressure was greater with PGI2 at infusion rates, causing minor systemic haemodynamic changes.

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.

STUDY OBJECTIVE - The aim of the study was to measure plasma neuropeptide Y, which is related to sympathetic nerve stimulation, in patients admitted to a coronary care unit and to relate the findings to clinical information. DESIGN - Plasma neuropeptide Y was measured on admission and the results were related to the cause of admission and to clinical information collected prospectively and retrospectively. SUBJECTS - Plasma subjects were obtained from 377 consecutive daytime admissions to the coronary care unit at Sodersjukhuset. Results of only the first sample in each patient are included in this study, so 45 cases observed more than once (readmitted patients) were omitted. Six samples were abandoned because of technical failures. The study therefore comprises 326 patients. Clinical diagnoses were defined as acute myocardial infarction, arrhythmia, angina pectoris, and miscellaneous (all other diagnoses). Heart failure was defined according to a modified Killip scheme. MEASUREMENTS and RESULTS - Neuropeptide Y like immunoreactivity was measured by radio-immunoassay. Plasma concentrations above normal (greater than 30 pmol.litre-1) were found in association with: increased age, female sex, diuretic treatment, tachycardia, arterial hypotension, increased respiratory rate, and mortality in the unit. There was a strong relationship between high neuropeptide Y concentrations and: moderate left heart failure (63%), pulmonary oedema (90%), and cardiogenic shock (100%). Of patients without heart failure only 25% had raised neuropeptide Y. In multivariate analysis, the severity of heart failure (Killip class), heart rate and respiratory rate were the only variables that were significantly and independently related to plasma neuropeptide Y. CONCLUSIONS - The presence and degree of circulatory disturbance, in particular tachycardia and left heart failure, were strongly related to increased plasma concentrations of neuropeptide Y in coronary care patients.

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)

The effects of physiological adenosine concentrations on platelet aggregation in vitro were studied. Furthermore, we evaluated the effect of elevated adenosine levels in vivo, produced by the administration of dipyridamole, on platelet aggregation in whole blood. Platelet aggregation in plasma was significantly inhibited in vitro by adenosine at all concentrations tested in the physiological range (0.1-1.0 microM, 14-63% inhibition). Dipyridamole by itself had no effect at a therapeutic plasma concentration in vitro. Ten patients with ischaemic cerebrovascular disease were given 100 mg dipyridamole orally, and the level of adenosine increased from 0.22 to 0.29 microM (p less than 0.05). This was accompanied by a decrease in ADP-induced platelet aggregation in whole blood (17 to 15 ohms, p less than 0.05). When dipyridamole was infused in 11 healthy subjects, the adenosine level was not significantly elevated but the platelet aggregation was inhibited (from 13 to 11 ohms, p less than 0.05). It is concluded that adenosine may be of importance in the physiological regulation of platelet aggregation. Furthermore, dipyridamole treatment is associated with an anti-aggregatory effect that is probably mediated by its effect on endogenous adenosine levels.

Adenosine appears to regulate resting blood flow in canine subcutaneous adipose tissue. Sympathetic nerve stimulation has been shown to enhance the adenosine production in this tissue. This study therefore tested the possibility that adenosine may influence the vascular responses to sympathetic nerve stimulation. Intraarterial infusion of adenosine (5-20 microM in arterial blood) increased the resting vascular conductance (from 0.048 +/- 0.007 to 0.095 +/- 0.013 ml . min-1 . 100 g-1. mmHg-1) and the percental reduction in vascular conductance due to sympathetic nerve stimulation (4 HZ) by 34 per cent (p less than 0.05) and to i.a. noradrenaline by 27 per cent (p less than 0.05). The vasodilator response due to nerve stimulation after alpha-blockade was reduced by adenosine. Dipyridamole (0.5-1.5 microM) + EHNA (3-10 microM), which increases plasma adenosine levels, had similar effects to adenosine, while theophylline (30-80 microM) decreased the vasoconstrictor response. The vasoconstrictor escape was enhanced by EHNA alone and in combination with dipyridamole, but was reduced by theophylline. On the other hand, the poststimulatory hyperemia was unaffected by adenosine, dipyridamole and EHNA, and theophylline. The results show that adenosine does not reduce the magnitude of the initial vasoconstrictor response in proportion to the increase in resting blood flow. The autoregulatory escape in adipose tissue during nerve stimulation appears to be mediated both by adenosine and by noradrenaline acting on beta-adrenoceptors. Poststimulatory hyperemia does not seem to be greatly influenced by exogenous or endogenous adenosine.

Neuropeptide Y is co-stored with noradrenaline in peripheral sympathetic nerves, but is not present in the adrenal chromaffin cells in the pig. Plasma levels of neuropeptide Y-like immunoreactivity and catecholamines were studied upon haemorrhagic shock in the anaesthetized pig. The animals were bled in two successive steps (30 and 10 ml kg-1), resulting in a reduction of the mean arterial blood pressure by 44% and 53%, respectively. Plasma levels of noradrenaline increased abruptly after the first bleeding from 1.21 +/- 0.27 to 26.5 +/- 6.3 nmol l-1. Plasma neuropeptide Y showed a progressive increase from 62 +/- 8 pmol l-1 in the basal state to 365 +/- 98 pmol l-1 at 60 min after the first bleeding. After the second bleeding plasma neuropeptide Y and noradrenaline showed a largely parallel increase and finally reached levels of 2524 +/- 580 pmol l-1 and 316 +/- 117 nmol l-1, respectively. A veno-arterial gradient of neuropeptide Y and noradrenaline indicating local release was present over the spleen after both bleeding steps. The overflow of neuropeptide Y was delayed about 15 min compared to noradrenaline after the initial bleeding. Depletion of the neuropeptide Y content after shock in the heart and skeletal muscle supported local release also from these organs. Infusions of neuropeptide Y to obtain similar plasma concentrations as during shock (nM range) caused reduction in blood flow as determined by the radionuclide-labelled microsphere technique in several organs including spleen and skeletal muscle (threshold response at 319 +/- 22 pmol l-1) but not in heart and brain. In conclusion, both neuropeptide Y and noradrenaline were markedly elevated in plasma upon haemorrhagic shock, suggesting release from sympathetic nerve terminals. Neuropeptide Y could therefore have a role as a sympathetic neurotransmitter, and during severe stress, circulating plasma levels are in the range where vasoconstriction is evoked by exogenous NPY.

The overflow of noradrenaline (NA) and dopamine (DA) to plasma in the kidney in response to hypotension induced by sodium nitroprusside were studied in barbiturate-anaesthetized dogs in order to evaluate the possible existence of separately regulated renal noradrenergic and dopaminergic nerve fibres. When mean arterial blood pressure was lowered to 55 +/- 5 mmHg, arterial plasma NA, DA and adrenaline concentrations were increased and renal blood flow decreased. Renal sympathetic nerve activity was assessed by measuring the renal overflow of catecholamines to plasma. To obtain more accurate estimates of the renal contribution to catecholamines in renal venous plasma we corrected for the renal extraction of arterial catecholamines, assessed by the extraction of endogenous adrenaline. The corrected renal NA overflow to plasma increased from 164 +/- 52 to 419 +/- 137 pmol min-1 (P less than 0.05) during sodium nitroprusside induced hypotension. The renal overflow of DA to plasma was, however, not influenced significantly. The DA/NA ratio for renal venous plasma concentration as well as for renal overflow to plasma was decreased (P less than 0.05) by sodium nitroprusside induced renal nerve activation. In contrast, electrical renal nerve stimulation has previously been shown to enhance the overflows of DA and NA in parallel. One possible interpretation of these findings is that sodium nitroprusside selectively activated renal noradrenergic but not the putative dopaminergic nerve fibres while electrical stimulation activated both types of fibres.

The effects of graded elevations of intracranial pressure (ICP) on cardiac metabolism, blood flow and electrophysiology, and plasma catecholamines were studied in eight open-chest pigs. ICP was consecutively elevated from 15 +/- 3 mmHg in the control state to 40 +/- 4, 84 +/- 4 and 152 +/- 11 mmHg. Mean arterial blood pressure and heart rate were significantly increased at the two highest ICP levels. Cardiac oxygen uptake was also increased from 2.9 +/- 0.4 ml X min-1 to a maximum of 7.1 +/- 2.0 ml X min-1, and coronary sinus blood flow increased from 49 +/- 7 to 131 +/- 35 ml X min-1 at the highest ICP level. The transmyocardial blood flow distribution was unchanged, as determined by the microspheres technique. Arterial plasma catecholamine concentrations were significantly elevated at the two highest ICP levels, but noradrenaline overflow from the heart did not increase. The high arterial adrenaline concentrations (51 +/- 25 nmol X 1(-1) at the highest ICP level) may be responsible for the cardiac stimulation seen in these experiments. No signs of ischaemia, as judged by myocardial lactate production or the relative flow distribution to the endocardium were observed. Changes in the T-wave morphology appeared in the subendocardial ECG at all ICP levels, the changes being more prominent with increasing ICP levels. It is concluded that the increase in circulating catecholamine levels, adrenaline in particular, together with an elevation of afterload cause an increase of myocardial work, which may explain the T-wave changes in the ECG which are observed upon rapid elevation of intracranial pressure.