Mechanism of the Positive Inotropic Responses to Bretylium and Guanethidine

Bhagat, B.; Shideman, F. E.

doi:10.1111/j.1476-5381.1963.tb01296.x

Cited by 23 publications

(17 citation statements)

References 15 publications

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“…Many of the original studies on the acute effects of bretylium indicated that this drug had no effect on the tissue content of noradrenaline at a time when adrenergic neurone blockade was evident (Brodie & Kuntzman, 1960;Cass & Spriggs, 1961;Bhagat & Shideman, 1963;Bhagat & Gilliam, 1965;Spriggs, 1966;Chang, Chang & Su, 1967; Krauss, Kopin & Weise, 1970). The exception to this generalization was provided by Cession-Fossion (1965) who showed that bretylium initially produced an increase and later a decrease in the noradrenaline content of rat heart.…”

Section: Introductionmentioning

confidence: 99%

The effects of bretylium on the subcellular distribution of noradrenaline and on adrenergic nerve function in rat heart

Abbs

Pycock

1973

British J Pharmacology

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Summary1. The effects of bretylium were investigated on the content and subcellular distribution of noradrenaline in the rat heart and on the response to stimulation of the sympathetic nerves supplying the heart. 2. In most experiments bretylium produced no change in the total noradrenaline content of the heart but significant changes were produced in the subcellular distribution of noradrenaline. 3. Treatment with amphetamine both prevented and antagonized the bretylium-induced adrenergic neurone blockade and most of the accompanying changes in the subcellular distribution of noradrenaline. 4. There was a temporal correlation between the bretylium-induced depletion of noradrenaline from the microsomal (P2) fraction and adrenergic neurone blockade. 5. The onset of adrenergic neurone blockade was also accompanied by an elevation of the noradrenaline content in the low-speed coarse (PWA) fraction and in the mitochondrial (P1.) fraction; this elevation was prevented by pretreatment with a-methyl-p-tyrosine. 6. It is concluded that although the elevation of the noradrenaline content of the P1A and P,B fractions and a depletion of amine from the P2 fraction are associated with the onset of adrenergic neurone blockade only the depletion from the P2 fraction is required for its maintenance. This conclusion supports the hypothesis that only a small portion of the noradrenaline content of an adrenergically-innervated organ is associated with the release of transmitter, for when this small 'store' is depleted, by agents like bretylium, the nerves fail to function.

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Section: Introductionmentioning

confidence: 99%

The effects of bretylium on the subcellular distribution of noradrenaline and on adrenergic nerve function in rat heart

Abbs

Pycock

1973

British J Pharmacology

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“…Effect of monoamine oxidase inhibitors on the concentration of cardiac catecholamines in rats exposed to cold Monoamine oxidase inhibitors have been shown to block the release of catecholamines by reserpine (Bhagat, 1963) and by guanethidine (Bhagat & Shideman, 1963). Therefore, it was considered of interest to determine whether or not monoamine oxidase inhibitors antagonize the release of cardiac catecholamines associated with cold.…”

Section: Resultsmentioning

confidence: 99%

Factors involved in maintenance of cardiac catecholamine content: relative importance of synthesis and re‐uptake

Bhagat

Friedman

1969

British J Pharmacology

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. When animals were exposed to a temperature of 4° C for 6 hr, endogenous catecholamines remained unaltered or reduced slightly depending upon the strain of rats used. In contrast, labelled noradrenaline declined rapidly, but the decline was inhibited when animals were pretreated with monoamine oxidase inhibitors. . Increased sympathetic nervous activity associated with cold resulted in a four‐fold increase in rate of synthesis of noradrenaline. . Reduction in endogenous and labelled catecholamine levels associated with cold was exaggerated by pretreatment with cocaine, imipramine or phenoxy‐benzamine—drugs known to inhibit the uptake of noradrenaline into the nerve terminal. . Cocaine and imipramine in higher doses inhibited the release of both endogenous and labelled noradrenaline, suggesting a dual action: in small doses they increased the depletion of catecholamines by blocking the reincorporation, while in higher doses they inhibited the release of noradrenaline. . It is concluded that, under normal conditions, the re‐uptake mechanism may not play a significant role in the maintenance of normal cardiac catecholamine levels and that such levels are maintained by synthesis alone. However, when the heart is subjected to high impulse nerve activity, synthesis is not sufficiently accelerated to compensate for impulse‐induced massive release and may require the support of an additional mechanism, such as the partial reincorporation of released transmitter. In fact, the re‐uptake mechanism is enhanced during high impulse activity.

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“…The depleting action of reserpine on the catecholamine stores is very large (3-6), and 90% depletion of rat heart occurred 4 hours after a single dose of reserpine (10).…”

Section: Discussionmentioning

confidence: 99%

“…Other workers (10) showed that maximal depletion of cardiac catecholamine occurred 4 hours after a single dose of reserpine to the rat, and the normal level was not regained until about 10 days after the dose.…”

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confidence: 94%