On the Mechanism of Action of Guanethidine and Bretylium

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.

Section: Resultssupporting

confidence: 82%

Prevention by Guanethidine Analogues of Output of Noradrenaline Induced by Sodium Reduction in Rabbit Ventricular Slices

Hosotani

Misu

1978

“…creased V,,,,, and action potential height. The guanethidine molecule is apparently too large to pass through sodium channels in an ionized form, as suggested by Hille's experiments (1971) (Schanker & Morrison, 1965;Brodie et al, 1965). Membrane depolarization after transient excitation in adrenergic nerve endings seems to be mainly responsible for the blockade, because the adrenergic neurone blocking action in rabbit hearts depends upon the external sodium concentrations (Kubo & Misu, 1974).…”

Section: Effects Ofpretreatment With a Low Dose Of Tetrodotoxin On Gumentioning

confidence: 94%

“…Many hypotheses have been advanced concerning the mechanism by which adrenergic neurone blocking drugs prevent the release of noradrenaline (Boura & Green, 1965;Brodie, Chang & Costa, 1965;Burn & Welsh, 1967;Abbs & Dodd, 1974;Kubo & Misu, 1974;Giachetti & Hollenbeck, 1976). Kubo & Misu (1974) demonstrated that guanethidine-induced blockade of adrenergic transmission in rabbit hearts is attenuated when nerves are stimulated during perfusion with a low sodium solution and accentuated during perfusion with a high sodium solution.…”

Section: Introduction Methodsmentioning

confidence: 99%

Action of Guanethidine on Rabbit Atrial Membranes

Misu

Nishio

1978

Intracellular potentials were recorded in driven left atria from reserpine‐treated rabbits. Guanethidine 2 × 10−5m slightly increased Vmax and shortened the total duration (TD) of the action potential (AP) without causing hyperpolarization. For the first 30 min after 4 × 10−4m, Vmax increased without hyperpolarization and AP height increased slightly. Thereafter, Vmax and height decreased with a slight and gradual depolarization. This depolarization was irreversible. TD was increased after 15 minutes. Guanethidine 2 × 10−3 M initially decreased Vmax and height before causing depolarization. Pretreatment with tetrodotoxin (TTX) 1.6 × 10−7m prevented or reversed the initial increases in Vmax, height and TD induced by guanethidine (4 × 10 −4m). TTX 3.1 to 6.2 × 10−6m, added 15 or 30 min after guanethidine 4 × 10−4m, delayed or prevented depolarization by guanethidine. Ouabain 10−5m incubated for 20 and 90 min greatly inhibited Na+, K+‐adenosine triphosphatase and K+‐phosphatase activities; guanethidine was without effect. Guanethidine probably increases resting sodium permeability after the promotion of increases in sodium permeability during the AP. High doses of the drug decrease sodium permeability during the AP.

“…Our results are in agreement with previous findings of Kirpekar & Furchgott (1964) who showed that cocaine antagonizes the inotropic effect of bretylium on normal guinea-pig left atrium. Brodie, Chang & Costa (1965) have shown that bretylium uptake by rat heart in vivo decreases by about 32% in animals previously treated with cocaine. Although our results on restoration of tyramine response do not allow us to measure exactly the degree of blockade of bretylium uptake, the fact that cocaine when present during bretylium treatment completely abolished the restoration of the response to tyramine, suggests that blockade must be appreciable.…”

Section: Discussionmentioning

confidence: 99%

Influence of Cocaine and Sodium on Bretylium Uptake by Reserpine‐treated Guinea‐pig Left Atrium

Garcı́a¹,

Sánchez‐García²

1975

1The effects of cocaine and sodium on bretylium uptake into sympathetic nerve terminals were investigated in the reserpine-treated guinea-pig left atrium. The ability of bretylium pretreatment to increase the retention of noradrenaline was used as an index of bretylium uptake. Such increased retention has been assessed both by direct measurement and by the ability of tyramine to produce an inotropic response. 2 The restoration of the response to tyramine after incubation with noradrenaline was abolished when the atrium was pretreated with bretylium in the presence of cocaine. When bretylium was added before cocaine, or when ca-methyl-noradrenaline (not a substrate for monoamine oxidase) was used for incubation, the responses to tyramine were restored in the normal way. 3 Bretylium greatly enhanced the retention of [3 HI-noradrenaline; when bretylium was added in the presence of cocaine, [3HI -noradrenaline retention was severely impaired. 4 Pretreatment with bretylium in a low-sodium (25 mM) or sodium-free medium significantly decreased the retention of [ 3HI -noradrenaline, as compared with the control.5 Potassium deprivation did not modify the enhanced retention of [3 H I -noradrenaline induced by bretylium pretreatment. 6 Bretylium was released from the nerve terminals by exposure of the preparation to a sodium-free medium or to a solution containing calcium 50 mM, leading to a considerable decrease in 3H I -noradrenaline retention.7 The results are consistent with the view that both cocaine and sodium deprivation block the uptake of bretylium by the adrenergic nerve terminals, and that bretylium is probably taken up by a mechanism similar to or identical with the uptake system for noradrenaline and other amines.