Abstract-Effectsof 4-7-exo-methylene-hexahydroisoindoline-ethyl-guanidine hemi sulfate , a new guanidine derivative, on adrenergic neurons and its local anesthetic activity were investigated in comparison with guanethidine. Both derivatives produced in a dose-dependent manner a progressive irreversible reduction of positive chronotropic and contractile responses to postganglionic sympathetic nerve stimulation in isolated rabbit atria. The time course of the reduction by No. 865-123 was somewhat slower. In dogs administered both agents, the pressor response to carotid occlusion was reduced and that to exogenous noradrenaline was potentiated with a slight decrease in blood pressure. Noradrenaline stores in the heart and spleen of rats were also depleted to a similar extent. In the guinea pig weal method, guanethidine acted as a potent local anesthetic with a slow onset and a prolonged action as compared to procaine. No. 865-123 revealed no more anesthetic activity than did saline. It is unlikely that the local anesthetic activity of the guanidine derivatives contributes to the adrenergic neuron blocking activity.Since bretylium and guanethidine were found to be effective in the treatment of hyper tension (1-3), a large number of adrenergic neuron blockers has been synthesized and pharmacologically investigated (4-7). The mechanism by which these drugs prevent the release of noradrenaline at adrenergic nerve endings is unknown. It has been suggested, however, that the mechanism related to bretylium and guanethidine could be explained by a selective local anesthesia of adrenergic nerve endings in combination with the high accumu lation of the blockers in these sites (4,8,9). On the other hand, Kubo and Misu (10) found that in isolated rabbit hearts, the adrenergic neuron blockade induced by guanethidine was restored by subsequent perfusion with a low sodium solution and accentuated with a high sodium solution. The present work revealed that a newly synthesized derivative produces a marked adrenergic neuron blocking activity which may be dissociated from its local anesthetic activity.
MATERIALS AND METHODSThe isolated sympathetic atria] preparation of rabbits was used to determine adrenergic Present address:
The prevention by guanethidine and related agents of the output of noradrenaline induced by low sodium was investigated in rabbit ventricular slices. When external NaCl was reduced, the output of noradrenaline into the medium collected at 30 min intervals, increased and the endogenous levels decreased. These changes induced by replacing sodium with sucrose or choline were not affected either by the omission of calcium and addition of 0.5 mm ethylene glycol‐bis(aminoethyl‐ether)N,N,N′,N′ tetra‐acetic acid (EGTA) or by an increase in the calcium concentration to 10 mm 30 min before sodium deprivation.
Guanethidine 4 × 10−6 and 4 × 10−5m and 4–7‐exo‐methylene‐hexahydroisoindoline‐ethyl guanidine (No. 865‐123) 4 × 10−5 to 8 × 10−4m inhibited, in a dose‐dependent manner, increases in output of noradrenaline induced by reduction of sodium to 18 mm, while guanethidine 8 × 10−5m and high doses of bretylium produced no inhibition: the latter two released noradrenaline.
The inhibitory actions of guanethidine 4 × 10−5m and No. 865‐123 4 × 10−4m were prevented by tetracaine 3.3 × 10−4m, which per se did not modify the output of noradrenaline induced by 18 mm sodium.
Accumulation of guanethidine and No. 865‐123 in ventricular slices was greater than that noted in striated muscle slices and was dose‐, time‐ and temperature‐dependent. Tetracaine 3.3 × 10−4m did not prevent the accumulation of guanethidine 4 × 10−5m and No. 865‐123 1.1 × 10−6 to 4 × 10−4m.
The guanidine derivatives appear to increase the permeability of adrenergic nerve endings to sodium ions.
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