Shimonaka H

Antinociception by epidural and systemic α2-Adrenoceptor agonists and their binding affinity in rat Spinal cord and brain

This study was designed primarily to relate the antinociceptive and hemodynamic effects of clinically available &agr;2-adrenoceptor agonists to their binding affinity for &agr;2-adrenoceptors in the spinal cord and brain. In rats with chronic indwelling epidural catheters, the percentage maximal possible effect on tail-flick latency was measured after epidural or IM dexmedetomidine (DXM), clonidine (CL), or tizanidine (TZ) administration. To examine their binding affinities, isolated spinal cord and brain membranes with an &agr;2 agonist were incubated with 3H-UK14304, a selective &agr;2 agonist, and the radioactivity in the reaction mixtures was measured by liquid scintillation spectrometry. Epidural DXM (0.5–10 &mgr;g), CL (10–500 &mgr;g), and TZ (5–500 &mgr;g) all produced dose-dependent antinociceptive effects; the rank order of potencies was DXM > CL > TZ, the same as for their systemic administration. The antinociceptive effects were blocked by epidural yohimbine. The receptor binding affinities expressed as the concentration that inhibits 50% for spinal cord and brain, respectively, were 0.25 and 1.3 nM (DXM), 10.8 and 12.5 nM (CL), and 48.2 and 96.8 nM (TZ). The changes in arterial blood pressure and heart rate evoked by antinociceptive doses did not correlate with the rank order of antinociceptive potencies. The relative antinociceptive potencies of epidural &agr;2 agonists may depend on their binding affinities to &agr;2-adrenoceptors in the spinal cord, but their cardiovascular effects may result from actions both inside and outside the central nervous system. Implications Spinal antinociception caused by the epidural administration of &agr;2 agonists is well correlated with their binding affinity to spinal &agr;2-adrenoceptors.

The Inhibitory Effects of Local Anesthetics on Superoxide Generation of Neutrophils Correlate with Their Partition Coefficients

Lidocaine and tetracaine suppress superoxide anion (O2 sup -) generation of neutrophils. We examined the effects of eight local anesthetics on O2- generation in human neutrophils and searched for a potential relationship between the biological activities and the physicochemical properties of presently available eight local anesthetics. Human neutrophils incubated with local anesthetic and a Cypridina luciferin analog as a O2--specific chemiluminescence probe were stimulated by phorbol ester. The chemiluminescence development based on O2- generation was monitored by a luminometer. All of the tested local anesthetics suppressed O2- generation in a concentration-dependent manner. The concentration of each of eight local anesthetics that produced 50% inhibition of peak chemiluminescence (IC50) had a rank order of dibucaine < tetracaine < bupivacaine < ropivacaine < procaine < mepivacaine < lidocaine = prilocaine. A linear relationship was obtained between IC50 values and the values of logarithm of partition coefficient (log P) of eight local anesthetics; log (IC50 in molarity) = -1.252 - 0.514 x log P, r2 = 0.891, P < 0.001. Unlike with staurosporine, which inhibits protein kinase C (PKC), no effect was observed on the O2- generation in the presence of tetrodotoxin (TTX), veratridine (VTD), or amiloride. These results suggest that the inhibitory effects of local anesthetics on O2- generation of neutrophils are predicted by physicochemical properties of the drugs, especially partition coefficients. (Anesth Analg 1997;84:405-12)

Mechanisms of dexmedetomidine-induced cerebrovascular effects in canine in vivo experiments

Dexmedetomidine decreases cerebral blood flow without significantly affecting cerebral oxygen consumption in anesthetized dogs.To assess the direct cerebrovascular effects of dexmedetomidine, we investigated the responses of vasomotor tone to topical application of dexmedetomidine to pial vessels in vivo, using a parietal cranial window. Forty-one dogs were anesthetized with pentobarbital. In 20 dogs, we topically applied six concentrations of dexmedetomidine solution (10-8, 10-7, 10 (-6), 10-5, 10-4, 10-3 M) and directly measured pial arterial and venous diameters. In 10 dogs, the inhibitory effects of pretreatment of pial vessels with 10-5 M yohimbine were examined after the application of 10-5 M dexmedetomidine. In the remaining 11 dogs, the effects of 10-3 M dexmedetomidine were evaluated in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME), glibenclamide, or propranolol. Dexmedetomidine significantly constricted pial arteries and veins in a concentration-dependent manner (10-7 M to 10-4 M; P < 0.05). Yohimbine blocked dexmedetomidine-induced constriction of pial vessels (both large and small arteries and large veins P < 0.0001; small veins P < 0.005). However, when the highest concentration of dexmedetomidine (10-3 M) was administered under the window, pial vessel diameter was not significantly altered. In the presence of glibenclamide, 10-7 and 10-3 M dexmedetomidine induced a significant decrease in pial arterial diameter compared with 10-7 and 10-3 M dexmedetomidine solution alone, respectively (P < 0.05). L-NAME or propranolol did not affect the dexmedetomidine-induced constriction. Although yohimbine, glibenclamide, or propranolol did not change pial vascular diameter, L-NAME significantly constricted both pial arteries and veins (P < 0.05). Our study demonstrates that topical application of dexmedetomidine constricts both pial arterial and venous vessels in a concentration-dependent manner. The vasoconstrictor effects of dexmedetomidine appear to be mediated via activation of alpha2-adrenoceptors, although this action is accompanied by activation of adenosine triphosphate sensitive K+-channels as a counterbalancing vasodilatory effect. The present results also suggest that the resting tone of pial arteries and veins does not depend on alpha (2-and) beta-adrenergic control, but is influenced by nitric oxide. (Anesth Analg 1995;81:1208-15)

Alteration of redox state of human serum albumin in patients under anesthesia and invasive surgery

Human serum albumin is a mixture of mercapt- (HMA, reduced form) and nonmercaptalbumin (HNA, oxidized form). We studied the mercapt<-->nonmercapt conversion of human serum albumin, which reflects the redox state of the extracellular fluids, in cardiac and other common surgical_ patients using high-performance liquid chromatography. Mean values of [(HMA)/(HMA+HNA)]+/-standard deviation, fHMA+/-sigma], for patients who received common surgery (group 1) and cardiac surgery (group 2) at the start of anesthesia were 0.636+/-0.050 (n = 83) and 0.615+/-0.062 (n = 14), respectively. fHMA values were markedly lower than those for healthy male adults of 0.750+/-0.028 (n = 28). fHMA values increased at 24 h after the start of anesthesia and decreased on the 4th postoperative day in most of the patients. These postoperative changes were prominent in cardiac surgical patients. Although fHMA values after the 7th postoperative day recovered to those at the start of anesthesia in almost all of common surgical patients, those in cardiac surgical patients never recovered even on the 21st postoperative day.

Mechanisms of vasodilation of cerebral vessels induced by the potassium channel opener nicorandil in canine in vivo experiments.

Background and Purpose Nicorandil, a potent antianginal agent characterized as a potassium channel opener, could produce cerebrovascular dilation in in vitro studies. Our aim was to investigate the pharmacologic response to the topical application of nicorandil on the vasomotor tone of pial vessels in vivo. To elucidate its mechanism, we also studied the inhibitory action of methylene blue and glibenclamide against nicorandil-induced vasodilation. Methods In 14 dogs prepared with a parietal cranial window, we administered five different concentrations of nicorandil solution (10−7, 10−6, 10−5,10−4, and 10−3 mol/L) under the window and measured pial arteriolar and venular diameters. After pretreating pial vessels with either 10−5 mol/L methylene blue or 10−5 mol/L glibenclamide, we examined inhibitory action after the application of 10−5 mol/L nicorandil. In additional experiments with 9 dogs, we evaluated the effects of nitroglycerin and cromakalim on pial vessels in the absence or presence of 10−5 mol/L methylene blue and 10−5 mol/L glibenclamide, respectively. Results Nicorandil produced significant, concentration-dependent dilation of pial vessels (P<.05). Methylene blue blocked nicorandil-induced dilation, whereas glibenclamide only attenuated such action of nicorandil. Nitroglycerin and cromakalim also produced a concentration-dependent increase in pial arteriolar and venular diameters (P<.05), and those effects were blocked in the presence of methylene blue or glibenclamide, respectively. Conclusions Our in vivo study demonstrates that topical application of nicorandil dilates both pial arterioles and venules in a concentration-dependent manner and suggests that the mechanisms of such action are most likely due to both cyclic GMP-mediated vascular smooth muscle dilation and the regulation of K+ flux.

Spinal Antinociceptive Effect of Epidural Nonsteroidal Antiinflammatory Drugs on Nitric Oxide-induced Hyperalgesia in Rats

BACKGROUND Nonsteroidal antiinflammatory drugs (NSAIDs) suppress various hyperalgesia perhaps via inhibition of cyclooxygenase activity at the spinal cord. The present study aimed to examine whether epidural application of NSAIDs affects hyperalgesia induced by nitric oxide. METHODS The authors studied the antinociceptive effects of epidurally administered NSAIDs in rats with a chronically in-dwelling epidural catheter by three hyperalgesic models, including nitric oxide-induced hyperalgesia by nitroglycerin (10 microg) or l-arginine (100 microg), and the biphasic response in the formalin test. RESULTS Epidural, but not systemic, nitroglycerin induced hyperalgesia that was completely blocked by methylene blue but not by N(omega)-nitro-L-arginine methyl ester (L-NAME). Epidural l-arginine, but not d-arginine, also induced hyperalgesia that was completely blocked by L-NAME. Epidural S(+)ibuprofen (100-1,000 microg) suppressed the nitroglycerin- and l-arginine-induced thermal hyperalgesia and also the second phase response in the formalin test. Neither systemic S(+)ibuprofen nor epidural R(-)ibuprofen suppressed the hyperalgesia Epidural indomethacin (10-100 microg) or diclofenac (10-1,000 microg) dose-dependently suppressed nitroglycerin-induced thermal hyperalgesia The order of potency for this suppression (ID50 in microg) was indomethacin = didofenac > S(+)ibuprofen >> R(-)ibuprofen. CONCLUSIONS The antinociceptive action of epidurally administered NSAIDs could be the result of suppression of spinal sensitization, perhaps induced with nitric oxide in the spinal cord. The ID50 values for epidural indomethacin, diclofenac, and S(+)ibuprofen were about 10 times higher than those reported in other studies for intrathecal NSAIDs in hyperalgesia models. (Key words: Cyclooxygenase inhibitors; NO donor; NO precursor; optical isomers; neuroplasticity.)

Spinal antinociceptive action of Na+-K+ pump inhibitor ouabain and its interaction with morphine and lidocaine in rats

BACKGROUND The Na+,K+-adenosine triphosphatase is a ubiquitous enzyme system that maintains the ion gradient across the plasma membrane of a variety of cell types, including cells in the central nervous system. We investigated the antinociceptive effect of intrathecally administered ouabain and examined its potential interaction with spinal morphine and lidocaine. METHODS Using rats chronically implanted with lumbar intrathecal catheters, the ability of intrathecally administered ouabain, morphine, and lidocaine and of mixtures of ouabain-morphine and ouabain-lidocaine to alter tail-flick latency was examined. To characterize any interactions, isobolographic analysis was performed. The effects of pretreatment with intrathecally administered atropine or naloxone also were tested. RESULTS Intrathecally administered ouabain (0.1-5.0 microg), morphine (0.2-10.0 microg), and lidocaine (25-300 microg) given alone produced significant dose- and time-dependent antinociception, but systemic administration of ouabain did not produce such an effect. The median effective dose (ED50) values for intrathecally administered ouabain, morphine, and lidocaine were 2.3, 5.0, and 227.0 microg, respectively. Isobolographic analysis exhibited a synergistic interaction after the coadministration of ouabain and morphine. With ouabain and lidocaine, there was no such evidence of synergism. Intrathecally administered atropine, but not naloxone, completely blocked the antinociceptive effect of ouabain and attenuated its interaction with spinally administered morphine. CONCLUSIONS Intrathecally administered ouabain produces antinociception, at least in part, via an enhancement of cholinergic transmission in the spinal nociceptive processing system. The results of the interaction of ouabain with morphine and lidocaine suggest that modulation of Na+-,K+-electrochemical gradients and thus subsequent release of neurotransmitters in the spinal cord are likely to play important roles in the spinal antinociceptive effect of intrathecally administered ouabain.

Effects of anesthetics, dibucaine and methoxyflurane on the ATPase activity and physical state of Tetrahymena surface membranes

Abstract The effect was studied of a local anesthetic, dibucaine, and an inhalation anesthetic, methoxyflurane, on the ATPase activity and the membrane fluidity in the surface membrane, pellicle, of Tetrahymena pyriformis NT-I. Both anesthetics were observed to inhibit ATPase activity and to lower its transition temperature (28° → 21°). It was also found that these anesthetics exerted fluidizing and depression of the phase transition temperature and that the disordering effect by methoxyflurane was much greater than that by dibucaine. These results have demonstrated that the anesthetic-induced alterations in the physical property of the pellicular membrane lead to inhibition of ATPase activity bound to the membrane, thus providing evidence suggesting the relationship between the function and physical state of the biological membrane.

Oral high-dose midazolam premedication for infants and children undergoing cardiovascular surgery

Background:  The purpose of this study was to determine whether oral midazolam 1.5 mg·kg−1 is a safe and effective alternative to standard‐dose midazolam (0.5–1.0 mg·kg−1) premedication for infants and children with congenital heart disease.

Altered microviscosity of in vivo lipid-manipulated membranes inTetrahymena pyriformis: A fluorescence study

By determination using fluorescence polarization measurements with 1,6-diphenyl 1,3,5-hexatriene, ergosterolreplaced pellicle and microsome membranes ofTetrahymena cells become less fluid, whereas those membranes from chimyl alcohol-fed cells are more fluid, when compared with the control native membranes.