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

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.

Reperfusion therapy for acute myocardial infarction (AMI) reduces mortality but is also associated with reperfusion injury. The present study tested the hypothesis that adjuvant therapy with a low anti-inflammatory dose of adenosine might prevent reperfusion injury and preserve left ventricular function.Six hundred and eight patients with ST-elevation AMI were randomised to receive infusions of adenosine (10 microg x kg(-1) x min(-1)) or placebo (saline) to be started with thrombolysis and maintained for 6 h. The primary endpoint was global and regional left ventricular systolic and diastolic function, as assessed by two-dimensional and Doppler echocardiography before hospital discharge. The secondary end-point was all cause and cardiovascular mortality, and non-fatal myocardial infarction during 12 months of follow-up.No beneficial effect of adenosine was found regarding echocardiographic indices of left ventricular systolic or diastolic function. Recruitment was stopped due to this apparent lack of effect after an interim analysis. However, after 12 months of follow-up, cardiovascular mortality was 8.9% with adenosine and 12.1% with placebo treatment [odds ratio (OR) 0.71, 95% confidence interval (C.I.) 0.4-1.2, P=0.2] among all patients and 8.4% vs 14.6% (OR 0.53, 95% C.I. 0.23-1.24, P=0.09) among patients with anterior AMI. All cause mortality differed similarly. Non-fatal AMI was not reduced similarly by adenosine treatment. Survival curves indicate that possible survival benefits are maintained after the first year of follow-up.Adenosine, given as adjunctive treatment with thrombolysis, did not provide detectable improvement of echocardiographic indices of left ventricular function when assessed before hospital discharge. Cardiovascular and all cause mortality appear to have been reduced by low-dose adenosine treatment, and the size of the effect appears to be clinically relevant (absolute risk reductions of approximately 4%). The power of the study regarding morbidity and mortality was, however, limited. The results are compatible with a beneficial anti-inflammatory effect of adenosine treatment on reperfusion injury after thrombolysis, which may be mediated by inhibition of leukocytes in peripheral blood. A larger trial is warranted to possibly establish beneficial effects of low-dose adenosine on survival after thrombolysis.

Background: Adenosine (Ado) is known, from studies in both animals and humans, to produce antinociception when administered systemically or intrathecally (IT). The current aim was to evaluate, in a placebo-controlled, randomised, double-blind study, whether IT adenosine given before surgery could reduce anaesthetic requirement and the need of opioids during 48 h after visceral surgery. Method: Forty women (37–66 years, ASA I and II) scheduled for elective hysterectomy were included. Before inducing the standardised O2/N2O/isoflurane/fentanyl anaesthesia, the patients received an IT injection of either adenosine (500 μg in 1 ml volume) or placebo 1 ml (saline). Intraoperative anaesthetic drug doses and haemodynamics were recorded. Postoperative pain was assessed by visual analogue scale. For postoperative analgesia, cetobemidone was provided via intravenous patient-controlled analgesia (PCA). Results: During surgery, there were no differences between groups in anaesthetic requirement or haemodynamic parameters. Postoperative cetobemidone requirements were similar in both groups (median 48 mg for adenosine/50 mg for saline) during the first 48 postoperative hours. Conclusion: IT adenosine did not influence the requirement of anaesthetic drug or postoperative analgesics after hysterectomy.

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.

Background: A low dose of systemic adenosine infusion has been shown to induce antinociception in clinical experimental studies as well as in patients. There is no clinical information about the effect of adenosine on the motility of the gastrointestinal tract. The aim of this study was therefore to evaluate the effect of exogenous adenosine administration on gastric emptying in man. Method: Ten healthy male volunteers (22–45 yrs) were included in a placebo-controlled, double-blind, randomised, cross-over study, where the experiments were separated by at least one week. During one session the volunteers received a continuous intravenous infusion of adenosine (50 μg · kg−1 · min−1) initiated 15 min prior to the test of gastric emptying (a standard test meal, followed by oral acetaminophen, 2 g) and lasting throughout the experiment (2 h). During the other experimental session an infusion of saline was given. Acetaminophen absorption test was used as an indirect measure of the rate of gastric emptying. Venous acetaminophen concentration curves were produced and the maximum acetaminophen concentration (Cmax), the time to reach the maximum concentration (Tmax), and the area under the serum acetaminophen concentration time curve from 0 to 60 min (AUC60) were calculated. Results: There was no difference between placebo and adenosine in Cmax (197 vs. 199 μmol · L−1, P=0.80), Tmax (23 vs. 45 min, P=0.14), AUC60 (9633 vs. 9111 min · μmol · L−1, P=0.28). Conclusion: The results demonstrate that adenosine in a clinically antinociceptive dose of 50 μg · kg−1 · min−1 does not affect the rate of gastric emptying in healthy volunteers.

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 rats with abnormally low withdrawal thresholds ('allodynia') in one hindpaw induced by a photochemical sciatic lesion, an intrathecal catheter was inserted to the lumber enlargement and an epidural electrode was implanted at T11. I.t. administration of GABA(B) or adenosine A1 receptor agonists (baclofen, R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA)) suppressed allodynia in a dose-dependent fashion. When the two agonists were given together, each in an ineffective dose, there was a normalization of the thresholds. Rats, in which spinal cord stimulation (SCS) could not suppress the allodynia (non-responders), were transformed into SCS-responders by injection of baclofen and R-PIA in low, ineffective doses, combined with SCS. In SCS responding rats, combination of a selective GABA(B) and an adenosine A1 receptor antagonist (CGP 55845, CPT) in low, ineffective doses abolished the SCS-induced threshold normalization. These results indicate that GABAergic and adenosine-dependent mechanisms are involved in the SCS effect and further suggest a strategy for enhancing the therapeutic efficacy of SCS.

Effects of intrathecally (i.t.) administered R-phenylisopropyl adenosine (R-PIA), an adenosine A1 receptor agonist, on presumed pain behaviour were assessed in a rat model of chronic central pain. Spinal cord injury was induced photochemically via laser irradiation of the spinal cord after intravenous injection of erythrosin B in rats. The chronic allodynia-like behaviour that developed in some animals was studied. R-PIA (3 and 10 nmol), injected i.t. reduced the mechanical and cold allodynia-like symptoms as tested with von Frey filaments and ethyl-chloride spray, respectively. No side effects were observed. The effect of R-PIA was significant for up to 5 h and was reversed by theophylline, an adenosine receptor antagonist.

The aim of the present study was to investigate the intrathecal (i.t.) action of a selective A1-adenosine receptor agonist, R-phenylisopropyl adenosine (R-PIA), on tactile withdrawal thresholds in a rat model of mononeuropathy produced by sciatic chronic constriction injury (CCI). An additional aim was to examine whether adenosine receptor activation is involved in the effects of spinal cord stimulation (SCS), which activates low-threshold fibers and suppresses touch-evoked pain both in patients and in experimental animals with neuropathy. Animals presenting hindlimb withdrawal to von Frey filaments with a bending force of7.5 g on the lesioned side (compared toor = 35 g in the normal limb), were considered as having tactile hypersensitivity ("allodynia'). R-PIA (1-10 nmol i.t.) induced a dose-dependent suppression of the tactile allodynia without producing impairment of motor function. The effect of R-PIA (3 nmol i.t.), a clearly submaximal dose, was abolished by concomitant treatment with the selective A1-adenosine receptor antagonist cyclopentylxanthine (10 nmol i.t.). In animals where SCS failed to influence tactile allodynia, concomitant i.t. administration of R-PIA (3 nmol) and SCS induced a clear-cut and long-lasting suppression of the hypersensitivity to tactile stimulation. In conclusion, adenosine receptor stimulation antagonizes tactile hypersensitivity in a CCI model of mononeuropathy and potentiates the action of spinal cord stimulation.

Background: Adenosine (ADO), and stable analogs thereof, have been shown to exert antinociceptive action under experimental conditions in animals and in humans. The aim of this randomized double-blind placebo-controlled study was to evaluate if a low dose of intravenous (i.v.) ADO could reduce isoflurane requirements during joint-associated surgery, as an indication of antinociception in deep somatic pain. Methods: Thirty-two patients, age 19–62 years, ASA I and II, scheduled for shoulder joint surgery, were assigned to receive an i.v. infusion of either adenosine, 80 μg kg-1 min-1, or placebo, during the surgical procedure. Anesthesia was maintained with isoflurane/N2O/O2 inhalation. Results: The peroperative isoflurane concentration was significantly reduced at 50 minutes of surgery in the group receiving adenosine infusion. Also, the systolic blood pressure level was peroperatively more stable during adenosine infusion than during placebo. Other clinical parameters, such as pain, postoperative analgesic requirements and nausea, were not different between groups. Conclusion: A peroperative infusion of a low dose of adenosine during shoulder joint surgery may reduce the peroperative isoflurane requirement.

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

Adenosine is an endogenously produced substance which in animal experiments exerts anti-nociceptive effects. In humans, algcsic effects have been presented following exogenous adenosine administration. A recent study on anaesthetized patients, however, suggested an anti-nociceptive effect during i.v. adenosine. We have studied the pain-reducing effect in healthy volunteers using adenosine 50–80 μg · kg-1 · min-1 (n = 10), morphine 0.1 mg · kg-1 (n = 5), adenosine 50 μg · kg -1 · min-1 + morphine 0.1 mg · kg-1 (n=6), and ketamine 0.1 mg · kg-1 (n=5); all drugs given i.v., single-blind. Quantitative sensory tests (QST) revealed a significantly increased cutaneous heat pain threshold following adenosine. No effect was seen following ketamine or morphine. Suprathreshold heat pain perception was unchanged in all subjects. Furthermore, warm and cold perception thresholds were not influenced significantly by any drug. Adenosine, morphine and kctamine produced well-known side-effects but of a mild intensity not necessitating any treatment. The present results show that i.v. adenosine can provide a modest but selective increase of cutaneous heat pain thresholds, suggesting a pain-reducing capacity of adenosine in humans.

BACKGROUND Intrathecal injection of sufentanil offers labour pain relief of short duration. This double-blind randomised study evaluates if the combination of adenosine to sufentanil could give relevant prolongation (40%) of the duration of sufentanil spinal analgesia. METHODS Twenty-five healthy parturients requesting labour analgesia were included. Patients received 10 micro g of sufentanil + 500 micro g of adenosine or 10 micro g of sufentanil intrathecally. Pain intensity and duration of pain relief were assessed. RESULTS Pain relief was equal between groups. Duration of analgesia was not increased by adenosine + sufentanil, 99 +/- 54 min, vs. sufentanil, 89 +/- 56 min. CONCLUSION Adding 500 micro g of adenosine to 10 micro g of sufentanil could not provide any prolongation of labour pain relief.

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

1. The anti-aggregatory effect of adenosine (0.3–10 μmol/l), alone or in combination with the adenosine-uptake inhibitor dipyridamole (2 μmol/l), was studied in vitro in whole blood from 11 healthy subjects by filtragometry. 2. ADP (0.05–0.1 μmol/l) was used to reduce the filter occlusion time (tA, a measure of platelet aggregate formation in blood) from approximately 600 s to 71–101 s in the absence of other agents. 3. Adenosine was infused into the tubing system of the filtragometer, yielding a contact time of >25 s with the blood before the filter. Adenosine did not influence the aggregatory response to ADP significantly at 0.3 μmol/l in plasma, whereas tA was prolonged by 19 ± 6% (P 4. When the rapid elimination of adenosine from plasma was prevented by 2 μmol/l dipyridamole, adenosine caused marked prolongation of ADP-induced tA, with significant effects at 0.3 μmol/l (± 143 ± 72%, P 5. The present results suggest that adenosine has a transient anti-aggregatory effect in whole blood at about 0.3 μmol/l, as this is the highest possible calculated concentration of adenosine at the filter of the apparatus when 1 μmol/l adenosine is infused in the absence of dipyridamole or when 0.3 μmol/l adenosine is infused in its presence. 6. It is concluded that adenosine has anti-aggregatory effects at submicromolar (physiological) concentrations in human whole blood. The effect of adenosine seems to be transient, indicating a role for adenosine as a localized platelet-stabilizing factor in the vicinity of, for example, the endothelium.

1. Haemodynamic and metabolic effects of intravenous infusion of adenosine, an endogenous vasodilator, were studied in healthy humans. 2. Catheters were inserted into pulmonary and brachial arteries and into the hepatic and subclavian veins. Cardiac output was determined according to the Fick principle, and splanchnic blood flow was measured by using extraction of Indocyanine Green. Skin blood flow was estimated by a laser Doppler technique, calf blood flow by venous occlusion plethysmography and skeletal muscle and adipose tissue blood flow by a local isotope clearance technique. 3. Adenosine (infused in steps from 40 to 80 μg min−-1 kg−-1 into a central vein) elicited a gradual reduction in the peripheral vascular resistance to less than 50% of the basal level. There was a slight increase in the systemic blood pressure, but the pulmonary arterial and the ventricular filling pressures were unchanged. Cardiac output was doubled, accomplished by a combination of a positive chronotropic effect and an increase in stroke volume, which may be secondary to diminished peripheral resistance. 4. Skin blood flow increased by 100% at 50 μg of adenosine min−-1 kg−-1, whereas splanchnic blood flow rose significantly at 60 μg of adenosine min−-1 kg−-1. Blood flow in the calf, gastrocnemius muscle and adipose tissue did not change significantly. 5. Arterial concentrations of noradrenaline and adrenaline increased by 62 and 43%, respectively, during infusion of adenosine. Arterial levels of glycerol were depressed by more than 50%, but those of glucose and pyruvate were unchanged. 6. In conclusion, exogenous adenosine caused a marked systemic vasodilatation, with different responsiveness in the investigated vascular beds. The vasodilatation occurred in the presence of an increase in generalized sympathetic activity. Adipose tissue blood flow was unaltered despite a considerable reduction in fat mobilization.

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

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.

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.

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.

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.

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 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.

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.

The hemodynamic effects of ATP and adenosine (i.v. infusions) were studied in dogs in parallel with quantitative determination of purines in plasma by HPLC. In two experiments, infusion were performed during treatment with dipyridamole, an uptake inhibitor of adenosine. A 50-60% reduction of mean arterial blood pressure (MABP) was induced by both ATP and adenosine at infusion rates ranging between 17-290 mumoles/min. Cardiac output was unaffected by the purine infusions, indicating that the reduction of MABP was caused by a reduction of the systemic vascular resistance. Elevated ATP and adenosine concentrations were seen in venous plasma (pulmonary artery) during infusion, while only approximately 10% recovered ATP had been degraded to adenosine. On the other hand, in arterial plasma, virtually all nucleotides had been eliminated whereas the adenosine concentrations in plasma ranged between 5 and 20 microM. The magnitude of the vasodilatation was strictly related to the arterial plasma adenosine level irrespective of whether ATP or adenosine was infused. Thus, adenosine probably mediates the vasodilatory effect of ATP.

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

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

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

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

Adenosine has been found to contract human bronchial smooth muscle in vitro and to induce bronchoconstriction in asthmatic patients when administered by inhalation. The aim of the present study was to investigate if elevation of circulating levels of adenosine influence bronchial tone or bronchial reactivity. Seven patients with bronchial asthma in whom bronchial hyperreactivity had been confirmed in a pretrial bronchial histamine challenge (PC20 FEV1 0.064 to 2.45 mg/ml) received intravenous infusions of adenosine in increasing doses (10, 30 and 50 micrograms/kg/min, 6 min on each dose step) or placebo (saline solution) on two different days in a randomized, single-blind manner. Heart rate, blood pressure and lung function (lung volumes, flow-volume loops and airway conductance) were measured on each dose step. Infusion rate was held constant (at 50 micrograms/kg/min) throughout the trial and a bronchial methacholine challenge was performed during the infusion of adenosine or placebo. Infusions of adenosine and placebo did not influence heart rate, blood pressure or bronchial tone on either day and bronchial reactivity was similar on both days. We conclude that bronchial tone and bronchial reactivity in asthmatic patients are not increased by intravenously administered adenosine at a dose level which, in other studies, has been shown to induce regional effects in the systemic arterial circulation.

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

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