[Pharmacology of local anesthetics]. / De farmacologie van lokale anaesthetica.

Over the past fifty years, many synthetic local anaesthetics have been developed with fewer side effects, increased specificity of action and a higher margin of safety than cocaine, the first local anaesthetic in clinical medicine. Although the route of administration may affect pharmacokinetics and pharmacodynamics, the present paper focuses on the general pharmacology of these useful compounds.

Morphological, neurochemical, and behavioral studies on serotonergic denervation and graft-induced reinnervation of the rat hippocampus.

A procedure was developed to conduct simultaneously immunocytochemical and neurochemical studies on the serotonergic system in adjacent 300-micron-thick slices of rat hippocampus. This procedure was applied to correlate morphological (innervation pattern and density), neurochemical (5-hydroxytryptamine and 5-hydroxyindolacetic acid levels and [3H]5-hydroxytryptamine uptake and release) and behavioral (spatial learning) effects of neurotoxin-induced denervation and reinnervation by grafting fetal mesencephalic raphe cells. Intracerebroventricular injections of a low dose of 5,7-dihydroxytryptamine caused a discrete serotonergic denervation of the hippocampus. Eleven months after lesioning, 5-hydroxytryptamine and 5-hydroxyindolacetic acid levels and [3H]5-hydroxytryptamine uptake capacity were decreased by 50-60%. By this time, the residual fibers displayed an enhanced vulnerability towards K(+)-induced depolarization. Grafting of a fetal raphe cell suspension resulted in a reinnervation of the host hippocampus. The pattern of reinnervation was comparable to control innervation and the density was supranormal at the level of the graft. As observed semiquantitatively, the innervation density decreased with distance from the core of the graft. Neurochemical studies showed that the fibers were capable of synthesizing, metabolizing and releasing 5-hydroxytryptamine. The turnover of 5-hydroxytryptamine in both the denervated and the reinnervated hippocampus was comparable to that in control tissue. Previous behavioral testing of the denervated and of the denervated and implanted animals did not reveal any effect on spatial learning, either in an individual or in a social test paradigm. The latter data substantiate the notion that interference with the hippocampal serotonergic innervation does not hamper adequate spatial learning.

Alpha 2-adrenoceptor mediated inhibition of the release of radiolabelled 5-hydroxytryptamine and noradrenaline from slices of the dorsal region of the rat brain.

Possible local interactions between noradrenergic and serotonergic systems in the dorsal raphe region of the rat were investigated by studying the effects of various drugs on depolarization (20 mmol/l K+)-induced release of [3H]5-hydroxytryptamine (5-HT) and [3H]noradrenaline (NA) in vitro using a superfusion method. Exogenous 5-HT did not influence the release of [3H]NA. However, NA (in the presence of 10 mumol/l desipramine) as well as the selective alpha 2-adrenoceptor agonists clonidine and oxymetazoline strongly inhibited [3H]5-HT release. The selective alpha 1-adrenoceptor agonists phenylephrine and methoxamine did not affect the release of either [3H]5-HT or [5H]NA. The inhibition by NA of both [3H]5-HT and [3H]NA release was not affected by the beta-adrenoceptor antagonist sotalol nor by the selective alpha 1-adrenoceptor antagonist prazosin. However, phentolamine and the selective alpha 2-adrenoceptor antagonists yohimbine and rauwolscine competitively antagonized the inhibitory effect of NA on [3H]NA release (respective pA2-values 7.5 and 8.3) and on [3H]5-HT release (respective pA2-values 7.7 and 8.2). Moreover, the release of [3H]NA and also, but to a lesser extent, that of [3H]5-HT were increased by the antagonists. It is concluded that the release of both 5-HT and NA in the dorsal raphe region may be subject to presynaptic inhibition by NA via activation of alpha 2-adrenoceptors.

Role of prostaglandins in tone and effector reactivity of the isolated rat stomach preparation.

The influence of indomethacin (2 mug/ml) on the tone and on the response to ACh, 5-HT and tryptamine of the stomach strip preparation from normal and Essential Fatty Acid Deficient (EFAD) rats was examined. The pD2 value of ACh and 5-HT, but not of tryptamine, was significantly lower on the preparations obtained from EFAD rats than on those from normal rats. Contradictory results were obtained with respect to the influence of indomethacin on the pD2 value of ACh, 5-HT and tryptamine. No significant difference in initial tone and contractility of the stomach strips of both groups of rats was observed. However, the tone of the strips from normal rats increased with time. Preparations from EFAD rats showed a gradual decrease of the tome with time. Pre-incubation with indomethacin reduced the tone of strips from both groups of rats to a comparable extent. Thus further support is provided for the proposed role of prostaglandins in the maintenance of the tone of isolated smooth muscle. The possibility is raised that prostaglandins might not be predominantly involved in the generation of the initial tone and also not substantially contribute to the effector reactivity of the organ.

Analysis of ergotamine - 5-HT interaction on the isolated rat stomach preparation.

The effect of ergotamine on the isolated rat stomach and its influence on the response to ACh and 5-HT were investigated. The log dose-response curve of ergotamine was bell-shaped. Extension of the incubation time of ergotamine resulted in a parallel shift to the left of the curve. The response to ergotamine was inhibited by methyserigide and piperoxan. Incubation with ergotamine resulted in a decrease of the pD2-value of 5-HT together with a marked suppression of the maximum of the 5-HT curve. The response to ACh was affected in accordance with the prediction of an action of ACh and ergotamine on different receptors. The prolonged receptor stimulation by 5-HT or ACh resulted in a decrease of the apparent affinity towards their receptors. Incubation with ACh resulted in a parallel shift to the right of the 5-HT curve. However no inconsistency with the theoretical prediction of an action on separate receptors was observed with the ACh curve in the presence of 5-HT. It is concluded that ergotamine is a partial agonist on the D-tryptamine receptors of tbe isolated rat stomach. The marked decrease of the maximum of the 5-HT curve by ergotamine is probably caused by the slowly reversible character of its antagonism. The parallel shift to the left of the ergotamine curve with the extension of the incubation time and the persistence of its antagonism both are probably caused by a slow diffusion into and from the biophase.