Atsuo Fukunaga

Hypotensive Effects of Adenosine and Adenosine Triphosphate Compared with Sodium Nitroprusside

Hypotensive effects of the intravenous injection of adenine compounds [adenosine triphosphate (ATP), adenosine] were compared with those of sodium nitroprusside (SNP) in rabbits during light, stable halothane anesthesia. ATP and adenosine were almost equipotent in their effects on blood pressure and heart rate. The hypotensive potencies of ATP and adenosine were approximately 1/6 (bolus injection) and 1/40 (continuous infusion) that of SNP, but the adenine compounds had a more rapid onset of action and shorter recovery times than SNP. With bolus injection, SNP invariably caused a baroreceptor-mediated reflex increase in heart rate. In contrast, ATP and adenosine caused a dose-related decrease in heart rate and hypotension. With continuous infusion, ATP and adenosine produced immediate onset of hypotension without tachycardia. Blood pressure remained rematkably stable throughout the infusion; neither tachyphylaxis nor rebound hypertension were observed. Thus, the adenine compounds offer possible advantages over SNP as they are physiologic agents with little or no acute toxicity and may be devoid of tachycardia, tachyphylaxis, and rebound hypertension.

Characterization of the analgesic actions of adenosine: comparison of adenosine and remifentanil infusions in patients undergoing major surgical procedures

&NA; Perioperative pain is still a major problem, and new pharmacological means should be explored to mitigate such pain. Adenosine is an ubiquitous endogenous substance; when exogenously administered, it provides a number of salutary effects including neuromodulation, antinociception, and cytoprotective actions. The aim of this study was to characterize the perioperative antinociceptive–analgesic effects of intraoperative adenosine infusion and determine the duration of actions in the postoperative period, and compare them to those of remifentanil in patients undergoing major surgical procedures in a double‐blind study. Sixty‐two patients were randomly assigned to one of the two treatments. After standard induction of anesthesia, the lungs were mechanically ventilated. Anesthesia was maintained with a constant alveolar concentration of inhaled anesthetics (3% desflurane and 65% nitrous oxide in oxygen). A variable‐rate of intravenous infusion of adenosine (50–500 &mgr;g kg−1 min−1) or remifentanil (0.05–0.5 &mgr;g kg−1 min−1) was initiated 5 min before the skin incision and was titrated to maintain systolic blood pressure and heart rate within 20% of baseline values during surgery. Postoperative evaluations included the level of sedation, degree of pain severity, opioid analgesic (fentanyl, morphine) consumption, and cardiorespiratory variables for 48 h. Intraoperative inhibition of the cardiovascular responses to surgical stimulation could be equally achieved by adenosine or remifentanil, and both could maintain excellent hemodynamic stability. Postoperatively, however, there were striking differences: (1) initial pain score was reduced by 60% (P<0.001) in the adenosine group compared to the remifentanil group and it remained lower throughout the 48 h recovery period; (2) postoperative morphine requirements during the first 0.25, 2 and 48 h were consistently lower in the adenosine group as compared to the remifentanil group (78, 71 and 42%, P<0.001, respectively); (3) adenosine patients remained significantly less sedated at all evaluations; (4) the end‐tidal and arterial carbon dioxide values in the remifentanil group were significantly higher when patients were admitted to the postanesthesia care unit. No adverse effect of adenosine was observed at any time. Intraoperative adenosine infusion provided a salutary recovery from anesthesia associated with a pronounced and sustained postoperative pain relief. Compared to remifentanil, adenosine significantly reduced the opioid requirements and minimized the side effects including protracted sedation, cardiorespiratory instability, nausea, and vomiting in the postoperative recovery period.

Clinical application of adenosine and ATP for pain control

This review summarizes clinical application of adenosine and adenosine 5′-triphosphate (ATP) in pain conditions. Investigations have been performed in patients with acute perioperative pain or chronic neuropathic pain treated with intravenous adenosine or ATP, or intrathecal adenosine. Characteristic central adenosine A1 receptor-mediated pain-relieving effects have been observed after intravenous adenosine infusion in human inflammation/sensitization pain models and in patients with chronic neuropathic pain. Adenosine compounds, in low doses, can reduce allodynia/hyperalgesia more consistently than spontaneous pain, suggesting that these compounds affect neuronal pathophysiological mechanisms involved in central sensitization. Such pain-relieving effects, which are mostly mediated via central adenosine A1 receptor activation, have a slow onset and long duration of action, lasting usually for hours or days and occasionally for months. With acute perioperative pain, treatment with a low-dose infusion of adenosine compounds and the A1 receptor-mediated central antisensitization mechanisms may play only a minor part in the total perioperative pain experience. By administering sufficient doses of adenosine compounds during surgery, however, significant and long-lasting perioperative pain relief can be achieved via central A1 receptor-mediated antinociceptive/analgesic actions as well as via peripheral A2a or A3 receptor-mediated antiinflammatory actions. Thus, adenosine compounds have significant potential for alleviating various types of pain.

Detection of acute tolerance to the analgesic and nonanalgesic effects of remifentanil infusion in a rabbit model.

Although acute tolerance to analgesia develops rapidly with remifentanil, it is unknown whether acute tolerance also develops to its nonanalgesic effects. We investigated the analgesic and cardiorespiratory effects of remifentanil during a continuous infusion in a rabbit model. Ten tracheotomized New Zealand White rabbits with arterial and venous accesses were placed on a sling that allowed for reasonably free movement. In spontaneously breathing conscious animals, remifentanil was infused IV at a constant-rate of 0.3 &mgr;g · kg−1 · min−1 for 360 min. Sedative/analgesic and cardiorespiratory variables were assessed repeatedly during remifentanil infusion, including the number of animals behaviorally unresponsive to clamping the forepaw (nonresponders) and subcutaneous electrical stimulation thresholds required to elicit head lift (HLT: pain detection/arousal threshold) and escape movement responses (EMT: pain tolerance threshold). Within 60–120 min of starting the infusion, the number of nonresponders, HLT, EMT, and Paco2 increased significantly, whereas blood pressure, heart rate, and respiratory rate decreased. Thereafter, all variables returned towards preinfusion levels despite continuing infusion. These results indicate that during a remifentanil infusion acute tolerance develops for both its analgesic and cardiorespiratory effects.

Myocardial Hemodynamics during Induced Hypotension: A Comparison between Sodium Nitroprusside and Adenosine Triphosphate

Adenosine triphosphate (ATP) has been reported to be a hypotensive agent similar in effect to sodium nitroprusside (SNP). The purpose of this study was to examine and compare the effects of both SNP and ATP on general coronary hemodynamics, myocardial O2 consumption, and circulating catecholamines. Twelve dogs were anesthetized with 1.0% halothane and given either SNP or ATP by controlled infusion to reduce their systemic blood pressure by 50% for a 2-h period followed by a (blood pressure) recovery period. The ATP-induced hypotension was rapid, easily controlled, not accompanied by tachyphylaxis over the 120 min studied, and resulted in an increase in coronary sinus blood flow (CSBF), which plateaued at 260% above control. The increase in CSBF was almost immediate and remained at this elevated level for the duration of the induced hypotension. During the ATP-induced hypotension, there was no change in heart rate or circulating catecholamines. A 60% reduction in myocardial O2 uptake was observed, presumably from the cardiac unloading. In contrast, SNP-induced hypotension required a marked increase in dose over time, did not significantly increase CSBF, did increase heart rate, and resulted in large increases in circulating plasma catecholamines. Neither agent affected cardiac output. ATP-induced hypotension resulted in no change in cardiac lactic acid uptake, while SNP caused lactic acid production, indicating possible cardiac ischemia or cyanide toxicity.

A rabbit model for evaluation of surgical anesthesia and analgesia: characterization and validation with isoflurane anesthesia and fentanyl analgesia.

PurposeWith a clamp test, quantitative estimation of the level of surgical anesthesia/analgesia is not easy. We have developed a rabbit pain model allowing for quantitative evaluation of the level of surgical anesthesia/analgesia using both electrical and mechanical stimuli as simulated surgical stimuli. We evaluated whether this model allows for accurate tracing of dynamically changing levels of surgical anesthesia/analgesia induced by isoflurane and fentanyl.MethodsEight rabbits tracheotomized and vascularly cannulated under 3% isoflurane anesthesia were placed on a sling that allowed for free movement of the head and extremities. After the isoflurane concentration was reduced stepwise to 1.5% and then to 0%, four graded doses of fentanyl (5, 10, 20, and 40 µg·kg−1) were injected intravenously at intervals of 120 min. At each dose, anesthetic/analgesic end-point variables were determined, including the number of animals behaviorally unresponsive to clamping the forepaw (nonresponders) and the threshold voltage of subcutaneous electrical stimulation (2, 5, and 50 Hz) required to evoke the head lift (HLT: pain detection/arousal threshold: sedative/hypnotic index) and the escape movement (EMT: pain tolerance threshold: analgesic index).ResultsWith increasing doses of isoflurane and fentayl, HLTs and EMTs, especially those at 5 Hz, increased dose-dependently and proportionately to increases in the number of nonresponders to clamping the forepaw, a standard indicator of the anesthetic/analgesic level.ConclusionUsing the HLT and EMT, especially at 5 Hz, combined with a clamp test, this rabbit model allows for repeated, quantitative, and distinctive evaluation of the dynamically changing levels of both sedative/hypnotic and analgesic components of surgical anesthesia/analgesia.

Aminophylline reversal of prolonged postoperative sedation induced by propofol.

Propofol is frequently used for intravenous sedation or anesthesia in ambulatory and office-based anesthesia. Although awakening is usually rapid, there are instances of delayed recovery from propofol anesthesia. It has been reported that aminophylline antagonizes the sedative effects of several anesthetic and analgesic drugs. The case reports presented here demonstrate that intravenous aminophylline effectively reversed prolonged propofol-induced sedation/anesthesia in the postoperative period. There were no side effects or delayed re-sedation after the administration of aminophylline. Our study suggests that aminophylline could be a clinically useful propofol antagonist.

Analgesic effect of intravenous ATP on postherpetic neuralgia in comparison with responses to intravenous ketamine and lidocaine.

PurposeNo study has been performed on the analgesic effect of adenosine 5′-triphosphate (ATP) on postherpetic neuralgia (PHN). We conducted an open-label trial of ATP in patients with PHN, and compared ATP with ketamine and lidocaine.MethodsTwelve patients with PHN were studied. On separate days, ketamine (0.3 mg·kg−1), lidocaine (2 mg·kg−1), and ATP (100 µg·kg−1·min−1 or less for 120 min) were administrated intravenously. The intensity of spontaneous pain as well as tactile allodynia was assessed using a visual analog scale (VAS). When the VAS score for spontaneous pain was decreased by more than 50%, the patient was classified as a responder.ResultsFive, 6, and 6 patients responded to ketamine, lidocaine, and ATP, respectively. In 6 ATP responders, pain relief developed slowly and lasted for 9 (median) h (range: 3–72 h). All 5 ketamine responders and only 1 of 7 ketamine nonresponders responded to ATP (5/5 vs 1/7, P < 0.05, χ2 test) whereas 2 of 6 responders to lidocaine and 4 of 6 nonresponders to lidocaine responded to ATP (2/6 vs 4/6, P > 0.05). The ketamine responders responded to ATP more often than did the lidocaine responders (5/5 vs 2/6, P < 0.05).ConclusionIntravenous ATP exerted slowly developing and long-lasting analgesic effects in half of patients with PHN. Patients with ketamine-responsive PHN were likely to respond to ATP.

The Characteristics of Intravenous Adenosine-Induced Antinociception in a Rabbit Model of Acute Nociceptive Pain: A Comparative Study with Remifentanil

BACKGROUND:Adenosine and remifentanil are potent IV analgesics with ultrashort half-lives. The antinociceptive effect of IV adenosine has not been clearly characterized. We compared the antinociceptive effects of adenosine and remifentanil in rabbits. METHODS:Sixteen rabbits, placed on a sling allowing reasonably free movement, received IV adenosine (400 &mgr;g · kg−1 · min−1) or remifentanil (0.4 &mgr;g · kg−1 · min−1) over 240 min. RESULTS:Both drugs produced profound antinociception, as assessed by the number of animals unresponsive to clamping the forepaw and the electrical stimulation threshold of escape movement. With remifentanil, the antinociceptive effect increased rapidly, reaching its peak at 60 min, and then began to decline despite continued infusion. After stopping the infusion, it decreased rapidly and disappeared within 30 min. The vasodilating effect of IV adenosine was immediate in onset and ultrashort in duration. The antinociceptive effect of adenosine increased slowly but progressively during the infusion, reaching its peak only when the infusion ended. Then it decreased slowly over the following 360 min after terminating the infusion. CONCLUSION:Remifentanil had a rapid onset and short duration of action, and probably showed signs of tolerance development, whereas the antinocieptive effect of adenosine was slow in onset and long-lasting, despite its ultrashort plasma half-life and the immediate on–off profiles of its vasodilating effect.

Intravenous administration of large dosages of adenosine or adenosine triphosphate with minimal blood pressure fluctuation

Hemodynamic responses, blood gas, and metabolic changes were assessed when large dosages of a pre-mixed solution of adenosine or adenosine triphosphate (ATP) with catecholamine were intravenously administered in the conscious, spontaneously breathing rabbit. The present study offers a simple and effective approach to enabling safe administration of large doses of the potent vasodilators, adenosine or ATP with minimal cardio-respiratory and metabolic changes.