Release of tritiated noradrenaline from perfused rat hearts by sympathomimetic amines

Abstract

The hypothesis that the limiting factor controlling the noradrenaline-releasing activity of a sympathomimetic amine is the ability of the nerve ending to take up the amine, i.e. the affinity of the amine for the postulated amine carrier in the sympathetic nerve ending, was tested on perfused rat hearts labelled with tritiated noradrenaline (NA). Experiments were done to determine whether cocaine and desmethylimipramine (DMI) would block the releasing action of sympathomimetic amines (SMA) and to determine whether the ranking order of the releasing activity of a series of SMA corresponds to the order of affinity for the amine carrier as reported by Iversen. The releasing activity of NA was found to be a saturable process, reaching a maximum rate estimated to be 2.6% of the amount present in the heart per minute. In addition, cocaine and DMI competitively blocked the releasing activity of infused NA, adrenaline, and dopamine, but this inhibition could be overcome by increasing the dose of the SMA. The ranking order of releasing activity of this series of amines was l-noradrenaline, dopamine, l-adrenaline, p-tyramine, d-noradrenaline, d-adrenaline, l-isoproterenol, phenylethylamine, d-isoproterenol, which was approximately the same as their order of affinity for the amine carrier. Our results indicate that uptake by a membrane carrier is probably the limiting factor in the releasing activity of SMA which are catechols and have a β-OH group. However, those amines studied which do not have these structural properties, i.e. dopamine, tyramine, and phenylethylamine, are further limited in their releasing activity, possibly owing to a less rapid exchange at the binding site on the storage granule.

Sympathomimetic Amine-Induced Release of Norepinephrine-³H from Different Intraneuronal Storage Compartments

“…Patou [1975] demon strated lhat AMPH was a more potent in ducer of 3H release than NE, TY and PHNE in reserpine and monoamine oxidase inhibi tor-treated guinea pig atria. In the perfused rat heart [Nash et al, 1968] and in the mouse heart in vivo [Daly et al, 1966] in which the neuronal storage granules were functional, AMPH was a less potent depleting agent than NE, TY and PHNE. More recent in vivo studies performed by Simpson [1980] dem onstrated a potentiation of AMPH-induced increases in blood pressure after acute reser pine treatment without alteration of postsynaptic receptor sensitivity.…”

Effects of Dopamine, Dobutamine, Amrinone and Milrinone on Regional Blood Flow in Isoflurane Anesthetized Dogs

“…It has been reported DA constricts peripheral vasculature at high dose through activation of α adrenergic receptor, partially releasing endogenous NE [25], while DB induces rather vasodilatation through activation of β adrenergic receptor [4,27]. AM and ML decrease AP through the vasodilatation by inhibition of PDEIII [1,13] overcoming the increase in cardiac output.…”

Dobutamine: development of a new catecholamine to selectively increase cardiac contractility.

“…These experiments indicated that dobutamine had the attenuated chronotropic and vascular effects we were seeking. We then made certain that dobutamine did not retain the norepinephrine-releasing action of dopamine (2,10,11), which is undesirable for two reasons. First, norepinephrine is arrhythmogenic.…”