Prevention by guanethidine analogues of output of noradrenaline induced by sodium reduction in rabbit ventricular slices

1 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(aminoethylether)N,N,N′,N′ tetra-acetic acid (EGTA) or by an increase in the calcium concentration to 10 mM 30 min before sodium deprivation. 2 Guanethidine 4 × 10-6 and 4 × 10-5 M and 4-7-exo-methylene-hexahydroisoindoline-ethyl guanidine (No. 865-123) 4 × 10-5 to 8 × 10-4 M inhibited, in a dose-dependent manner, increases in output of noradrenaline induced by reduction of sodium to 18 mM, while guanethidine 8 × 10-5 M and high doses of bretylium produced no inhibition: the latter two released noradrenaline. 3 The inhibitory actions of guanethidine 4 × 10-5 M and No. 865-123 4 × 10-4 M were prevented by tetracaine 3.3 × 10-4 M, which per se did not modify the output of noradrenaline induced by 18 mM sodium. 4 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 × 10-4 M did not prevent the accumulation of guanethidine 4 × 10-5 M and No. 865-123 1.1 × 10-6 to 4 × 10-4 M. 5 The guanidine derivatives appear to increase the permeability of adrenergic nerve endings to sodium ions.