Masakatsu Nozaki

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)

Platelet aggregation response in schizophrenia and prostaglandin E1.

Platelet aggregation response to various stimulants was examined in 18 unmedicated schizophrenic patients, 13 medicated patients, and 13 control subjects. Platelet aggregation response to epinephrine decreased only in unmedicated schizophrenic patients. Clinical improvement in seven patients after neuroleptic medication was significantly correlated with an increase in platelet aggregation response to arachidonic acid, and nonsignificantly to epinephrine, dopamine, and serotonin. The inhibitory effect of prostaglandin E1 on platelet aggregation response to adenosine diphosphate was investigated in seven unmedicated schizophrenic patients, six medicated patients, and eight controls. The inhibitory effect of prostaglandin E1 on platelet aggregation response to adenosine diphosphate was significantly reduced in all unmedicated schizophrenic patients. Neuroleptic medication had some effect in normalizing aberrant sensitivity to prostaglandin E1 in those patients, although acute medication induced an adverse reaction in the controls.

Effect of salicylates on acute inflammation.

It is generally accepted that anti-inflammatory drugs (NSAID) act by inhibiting the synthesis of prostaglandin (PGs) . However, salicylic acid, the most ancient of these drugs, is an ineffective cyclooxygenase inhibitor, but is equipotent with aspirin in antiinflammatory activity, we have now investigated the effect of such salicylates as aspirin (ASA), salicylic acid (SA), methyl salicylate (MS) and glycol salicylate (GS) on experimental acute inflammation.On rat paw edema induced by carrageenin, all salicylates showed the inhibitory effect in oral administration that was weak at 1 hr, but potent after 2 hrs. In local injection, all salicylates did not show the significant inhibition on paw edema, but in skin application as ointment, these drugs inhibited signi-ficantly the paw edema. The order of inhibitory activity on edema was ASA>SA≥MS≥GS. On guinea pig skin erythema induced by UV irradiation and arachidonic acid, all salicylates inhibited significantly only in early phase, but did not inhibit PGE2-induced erythema in all phase. The order of inhibitory activity on erythema was ASA>SA>GS≥MS.This mode of action of salicylates was the same as that of general NSAID of cyclooxygenase inhibitors. Collagen- or arachidonic acid-induced aggregation of rat platelets and acute death of rabbits by arachidonic acid i.v. injection were inhibited by aspirin, whereas other three salicylates were inactive. A23187-, fMLP- and zymosan-induced active oxygen generation of rat leucocytes was not inhibited by all salicylates.It may be suggested from these results that except a partial action of ASA, salicylates act as SA in viva and the anti-inflammatory activity of SA is due to inhibition of PGs production, and the mechanisms are not the inhibition of the platelets and leucocytes functions, but the unknown action.

A ROLE OF LIPID IN OPIATE-RECEPTOR INTERACTION

The interaction between opiates and lipids vesicle was studied by fluoripolarimetric method to examine a rotational freedom of bound opiates using the intrinsec fluorescence of opiates. Among the selected combinations of the lipid-opiate system tested, phosphatidyl inositol showed the highest affinity to morphine and its analogues, resulting in a strong immobilization of bound opiates, whereas the other phospholipids and cerebroside sulfate did not alter the dynamic property of the opiates even certain interaction was expected from the change in fluorescence intensity. Phosphatidyl serine which quenched the opiate fluorescence, also showed a slight immobilization of some opiates. On the contrary, the endogenous opioids were not immobilized even by phosphatidyl inositol.