Comparison of Bretylium and Guanethidine: Tolerance, and Effects on Adrenergic Nerve Function and Responses to Sympathomimetic Amines

Abstract

Bretylium depresses the slope of regression lines relating frequency of sympathetic nerve stimulation to magnitude of contractions of the cat nictitating membrane. In contrast, guanethidine and reserpine preferentially abolish responses to low rates of nerve stimulation and cause a roughly parallel shift of the regression lines. The hypersensitivity of the nictitating membranes of cats to intravenous adrenaline or noradrenaline is far greater after a series of small daily doses of bretylium or guanethidine than after single large doses. The maximal sensitivity produced was similar to that after postganglionic sympathetic nerve section and exceeded that produced by ganglion blockade. The development of hypersensitivity to catechol amines is accompanied by some return of responses of the nictitating membranes to sympathetic nerve stimulation despite continued daily administration of bretylium or guanethidine. In cats given bretylium daily, responses to low rates of nerve stimulation become greater than in controls unless the dose of bretylium given subcutaneously is 50 mg/kg or more. When marked hypersensitivity to catechol amines has been produced by giving bretylium or guanethidine daily for 7 or 14 days, the sympathomimetic effects of these compounds are greater. Responses to intravenous dimethylphenylpiperazinium are also increased and the results suggest that even large daily doses of adrenergic neurone blocking agents do not appreciably impair the functioning of the adrenal medulla. The pressor effects of intravenous adrenaline, noradrenaline and dimethylphenylpiperazinium iodide increase less than the corresponding nictitating membrane responses. These results are discussed in relation to tolerance to adrenergic neurone blockade, and differences between the effects of bretylium and guanethidine found in man. Bretylium and guanethidine depress the slopes of the dose-response curves for the pressor and nictitating membrane contracting effects of tyramine. When single doses or a short series of daily doses were given, guanethidine caused more depression of the slopes than did bretylium, but nevertheless large depressions of slope were found after giving bretylium daily for several weeks. The magnitude of the responses can be greater or less than in controls depending on the dose of the sympathomimetic amine, the dose of the adrenergic neurone blocking agent and the duration of its administration. The results suggest that injection of tyramine produces a progressively smaller release of adrenaline or noradrenaline during the daily administration of bretylium (or guanethidine) but that in some test situations this is more than compensated for by the development of hypersensitivity to the catechol amine released. Some corresponding changes in responses to amphetamine and ephedrine are also described.

The Mode of Hypotensive Actions of 2-(2,6-Dighlorophenyl-L-Amino)-Imidazoline in the Rabbit

“…The initial pressor and the subsequent depressor response to ST-155 were not affected within 60 minutes after intravenous injection of 15 mg/kg of guanethidine, when the adrenergic neuron blockade has been reported to occur (10). Pretreatment of rabbits with 15 mg/kg of guanethidine, whose tissue catecholamines are markedly depleted (11), did not significantly affect the blood pressure level (94±8 mmHg, N=4).…”

Effects of clonidine and guanethidine on peripheral sympathetic nerve function in the pithed rat

“…Blockade of only the lower rates of adrenergic nerve transmission, both centrally and peripherally, would also explain why postural and exertional hypotension is minimal with this drug. An analogous suggestion has previously been put forward in more detail to account for differences in the prominence of these effects occurring between the peripheral sympathetic blocking agents bretylium and guanethidine (Boura & Green, 1962).…”

Ventricular Tachyarrhythmias

“…The duration of action varies between 6 and 24 hours depending on dose. 59 The major cardiovascular effects are biphasic with an initial sympathomimetic effect (tachycardia and increased cardiac output) followed by a sympatholytic response (brachycardia and hypotension), the latter being more marked.60 Bretylium differs from quinidinelike drugs in that it lacks local anesthetic properties and is devoid of significant effect on the transmembrane resting or action potential, overshoot, membrane responsiveness, or conduction velocity.6'…”