The Effect of Calcium in Removing the Blocking Action of Bretylium and Guanethidine

Summary The uptake of guanethidine by adrenergic neurones has been studied indirectly by testing the ability of various procedures to prevent or reverse adrenergic neurone blockade in the periarterially stimulated isolated ileum preparation. Adrenergic neurone blockade was prevented but not reversed by equilibration with guanethidine (3·3 × 10−6m) at low temperatures (10° C), in the absence of sodium or in the presence of tetrodotoxin (0·3 × 10−6m) or noradrenaline (1·2 × 10−3m). Calcium (5 × 10−2m) both prevented and, to some extent, reversed the adrenergic neurone blocking action of guanethidine. Equilibration with guanethidine in the presence of mersalyl (0·6 × 10−7m) or in the absence of potassium or calcium could neither prevent nor reverse adrenergic neurone blockade.

Section: Resultssupporting

confidence: 72%

Factors affecting the action of guanethidine on adrenergic neurones

Gulati

Jaykar

1971

“…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.

“…This retention, which amounted to only 13% of controls (column A), was comparable to that in the preparation initially treated with bretylium in the absence of sodium (column B). Burn & Welsh (1967) showed that bretylium blocked the inhibition of the movements of the rabbit ileum induced by stimulation of the periarterial nerves; when the calcium concentration was raised the bretylium block was removed. In order to test the possibility that high calcium could also reverse the enhanced retention of [3H]-noradrenaline induced by bretylium, a group of 8 experiments was carried out in which bretylium (20 lAg/ml, for 5 min) was administered in normal Krebs to both halves of a reserpinized atrium; the medium of one preparation was then changed to Krebs containing calcium 50 mM for 40 min and then back to normal Krebs 20 min before [3H]-noradrenaline (10,Ci for S min) incubation started.…”

Section: Effect Of Potassium Deprivation On the Abili7 Of Bretylium mentioning

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.