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The blocking activity and pH dependence of carbanilate local anaesthetics, carbisocaine and its homologues, were tested on isolated rat sciatic nerves at pH 6.0, 7.2 and 8.4. Carbisocaine blocked the compound action potential more strongly than the derivatives with shorter alkoxysubstituents. The blocking potency of shorter derivatives increased with the rise of external medium pH, whereas the activity of carbisocaine increased with decreasing external pH. Quaternary compounds applied in the external medium were able to block the action potential, but in higher concentrations and with a longer half-time than their tertiary analogues. The blocking potency of quaternary derivatives correlated well with the length of the alkoxysubstituent and thus also with their lipophilicity. Extracellular pH did not consistently change the inhibitory effect of quaternized derivatives. These observations support the view that the lipophilicity of local anaesthetics is one of the possible factors determining their anaesthetic activity and the pH dependence of their effect.

The action of newly synthesised basic esters of alkoxy-substituted derivatives of phenylcarbamic acid was compared with that of procaine and trimecaine in the guinea-pig small intestine. Some of the carbamate local anaesthetics, in concentrations high enough to markedly suppress cholinergic twitches, elicited regular rhythmic activity of the guinea-pig ileum. This effect of the carbamates was dependent on the position of the alkoxysubstituent and was independent of the basic group (pyrrolidine, piperidine or perhydroazepine) present. Only the ortho-substituted derivatives were active. It was also found that the rhythmic activity evoked was of myogenic origin, produced by rhythmic undulations of the sodium-pump activity, accompanied by a potential-dependent change in Ca2+ permeability. It is suggested that the mechanism by which carbamates reveal this endogenous rhythm in the guinea-pig ileum could be a selective block of noncholinergic, nonadrenergic innervation or the TEA-like activity of carbamates.

The paper presents a survey of the relationship in carbanilic acid derivatives between structure and local anaesthetic activity. By modifying the three parts of a typical local anaesthetic, i.e., the aromatic (lipophilic) part, the intermediate chain and the basic (hydrophilic) part, substances with high local anaesthetic activity have been obtained. The derivatives with alkoxy substituents with 5-7 carbon atoms in the ortho and meta positions have proved advantageous. The local anaesthetic activity is significantly influenced by the basic part, usually formed by secondary or tertiary amines, and particularly by the structure of the intermediate chain. Significant differences have been found to exist between the activity of individual geometrically, optically and conformationally fixed isomers. The results indicate that in the carbanilic acid derivatives studied, local anaesthetic activity depends on their structural arrangement and physicochemical properties, which have been found to play an important role regarding the presumed non-specific effect of these substances.

The effect of three newly synthesized local anaesthetics on platelet aggregation, serotonin release and integrity of platelets was investigated. Pentacaine, heptacaine and carbisocaine were found to be about 10 times more active than "classic" local anaesthetics. They inhibited platelet aggregation stimulated by collagen, thrombin and ADP at the concentrations of 0.01, 0.1 and 1 mmol/l respectively. At millimolar concentrations the test local anaesthetics liberated serotonin from platelets and disintegrated platelet membranes. Pentacaine was the most effective, followed by heptacaine and carbisocaine. The authors suppose that the perturbation induced in platelet membranes by local anaesthetics could be responsible for inhibition of platelet aggregation and release of serotonin.