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The effects of bretylium on the Mg(2+)-dependent ATP-hydrolytic action of myocardial Na(+)-K(+)-ATPase (EC 3.6.1.3) were studied in guinea-pig heart preparations in media containing various K+ concentrations. Under "standard" conditions (5 mM K+), bretylium inhibited the Na(+)-K(+)-ATPase activity in a concentration-dependent fashion in the range of 0.001-80 mM, with an IC20 value of 0.19 +/- 0.05 mM and an IC50 value of 1.38 +/- 0.11 mM. Reducing the K+ concentration from 5 to 2.5 mM enhanced the inhibitory action, shifting the effective (5-95% inhibition) concentration range to 0.0003-9.6 mM, with IC20 and IC50 values of 0.036 +/- 0.004 mM and 0.92 +/- 0.30 mM, respectively. On the other hand, increasing the K+ concentration to 10 mM shifted the range to 10-90 mM. The corresponding IC20 value was 0.48 +/- 0.02 mM and the IC50 was 2.24 +/- 0.36 mM. The results show that K+ plays an important role in the inhibition of myocardial Na(+)-K(+)-ATPase activity by bretylium. This is probably pertinent to the mode by which the drug may interfere with the electrogenic Na+/K+ pump activity of the enzyme, and, consequently, cause or aggravate cardiac arrhythmias.

Rat brain cortex slices preincubated with 3H-noradrenaline or 3H-serotonin were superfused, and the effects of bretylium and guanethidine on the electrically evoked 3H overflow were studied. Bretylium inhibited the evoked tritium overflow both from slices labelled with 3H-noradrenaline and from those labelled with 3H-serotonin (by 49 and 74%, respectively, at 10(-4)M bretylium); the inhibitory effect on slices preincubated with 3H-serotonin was only slightly attenuated by paroxetine, an inhibitor of the neuronal serotonin uptake. Guanethidine inhibited (and at 10(-5)M even abolished) the evoked 3H overflow from slices labelled with 3H-noradrenaline, but it did not impair the tritium overflow from slices preloaded with 3H-serotonin. It is concluded that bretylium inhibits not only noradrenaline release, but also produces an even more pronounced inhibition of serotonin release. By contrast, guanethidine preferentially blocks noradrenergic neurones and hence, may be used as a pharmacological tool for studying the involvement of noradrenergic neurones in functions of the central nervous system.

Effects of low concentrations of guanethidine, bretylium and tetracaine were comparatively studied with regard to inhibitory responses of rabbit ileum to periarterial nerve stimulation at 5, 10 and 20 Hz. Guanethidine 2 X 10(-7) to 10(-6) M and bretylium 3 X 10(-6) to 3 X 10(-5) M dose-dependently and preferentially reduced responses to lower frequencies, whereas tetracaine 10(-5) to 3 X 10(-5) M reduced responses, in a dose- and frequency-dependent manner. In conclusion, the mode of adrenergic neuron blocking action of guanethidine and bretylium differs from that of local anesthetics.

The ventricular fibrillation threshold (VFT) was determined by the electrical stimulation of the normal and the coronary artery-ligated myocardium in situ in anesthetized rats. A bilateral vagotomy lowered the VFT of the normal myocardium. After the coronary artery ligation in the vagotomized rats, VFT fell to a greater extent. Bretylium 20-40 mg/kg i.v. produced an elevation of VFT, hypotension and a decrease of the heart rate of rats with the normal or the ischemic myocardium. Lidocaine 10 mg/kg i.v. insignificantly affected the VFT of the normal and the ischemic myocardium. Nitroprusside 4 mg/kg i.v. elevated the VFT of the normal myocardium, and prevented a fall in the VFT of the ischemic myocardium. Adenosine 10 mg/kg or aspirin 20 mg/kg i.v. had no remarkable effect on the VFT of the normal myocardium, but prevented a fall in the VFT of the ischemic myocardium.

Transport of bretylium into adrenergic neurons was studied, using rabbit isolated periarterial nerve ileum preparations, by determining the effects of various incubation procedures, which inhibit noradrenaline uptake, to prevent or reverse the blockade. Adrenergic neuron blockade by bretylium 5 X 10(-5) (g/ml) was prevented but not reversed by incubation with sodium free and low temperature (10 degrees C) media. Ouabain 2.2 X 10(-8) and anoxia prevented bretylium-induced blockade. Noradrenaline 5 X 10(-6) and 8 X 10(-5) prevented and also reversed the blockade, but the reversing effect was transient. High calcium (totally 10 mM) readily reversed the bretylium-induced blockade, the recovery being complete and long-lasting. In light of the results, a sodium sensitive active transport of bretylium into adrenergic neurons is apparently necessary for development of adrenergic neuron blocking action in rabbit ilea.

A series of ortho-substituted N-alkyl-N-(2-chloroethyl)-benzylamines have been prepared. These compounds are structurally similar to the adrenergic neuron blocking agent bretylium. They were tested for neuron blocking activity using both the innervated rabbit jejunum and the vas-deferens-hypogastric nerve preparation of the guinea pig. Three compounds possessed some adrenergic neuron blocking activity of a prolonged nature, the most potent being N-(2-chloroethyl)-N-(0-bromobenzyl)-ethylamine.