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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.

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

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

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