Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1323099 (sympathomimetic)
 2,957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Normally, the carrier of the neuronal noradrenaline uptake mechanism (uptake1) is involved nearly exclusively in the inward transport of substrates. However, an outward transport is induced by either of two mechanisms: a. by the decrease (or reversal) of the Na+ concentration gradient across the neuronal membrane or b. by the "facilitated exchange diffusion" due to the inward transport of substrates of this carrier. In rat vasa deferentia (preloaded with 3H-noradrenaline; vesicular uptake, MAO and COMT blocked) all substrates of the carrier induced an outward transport of 3H-noradrenaline, in strict correlation with their Km for uptake1. The inward transport of these substrates increases the availability of the carrier on the inside of the neuronal membrane. However, additional factors contribute to this release: inhibition of re-uptake and co-transport of Na+ and Cl-. When vesicular uptake and MAO are intact, the strict correlation between Km and releasing effect was not seen. This is attributable to the very low axoplasmic concentration of 3H-noradrenaline under these conditions (i.e. to lack of substrate for outward transport). However, if substrates of uptake1 are also substrates of vesicular uptake, they are able to "mobilize" vesicularly stored 3H-noradrenaline and, hence, to induce substantial outward transport. These "good" releasers are identical with the "indirectly acting sympathomimetic amines" (i.e. they are tyramine-like).
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PMID:Carrier-mediated outward transport of noradrenaline from adrenergic varicosities. 210 2

The 3H-noradrenaline-releasing effects of p- and m-tyramines and -octopamines, either deuterated or not, were studied in isolated vasa deferentia of the rat (COMT inhibited and calcium-free solution in all experiments). Km for uptake1 was higher for octopamines than for tyramines, but not increased by the introduction of deuterium in alpha-position, except for (probably contaminated) deuterated p-octopamine. Other tissues were preloaded with 3H-noradrenaline. After inhibition of vesicular uptake and MAO equi-releasing concentrations of the eight amines were strictly correlated with Km, they were 6 to 7 times higher for unsubstituted octopamines than for corresponding tyramines. When only MAO (but not vesicular uptake) was inhibited, this difference decreased to about 4-fold, but the releasing potency of the deuterated amines (relative to their parent amines) remained unchanged (except for p-octopamine). When vesicular uptake and MAO were intact, unsubstituted octopamines were only 1.5 to 2.2 times less potent than the corresponding tyramines. Analysis of the efflux of 3H-DOPEG confirmed that this gain in the relative potencies of octopamines is due to their increased ability to mobilize vesicular 3H-noradrenaline; moreover, deuterated amines as well were then better mobilizers than were their parent amines. It is concluded that, provided vesicular uptake is intact, the introduction of a beta-OH-group enhances the ability of indirectly acting sympathomimetic amines to mobilize vesicular noradrenaline; the introduction of deuterium in alpha-position, on the other hand, enhances this mobilizing effect exclusively when MAO is intact.
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PMID:The release of 3H-noradrenaline by p- and m-tyramines and -octopamines, and the effect of deuterium substitution in alpha-position. 250 Jun 4

The adrenergic nerve endings of vasa deferentia of either untreated or reserpine (R) and/or pargyline (P) pretreated rats were loaded with 3H-noradrenaline; COMT was inhibited by U-0521 (U). After 100 min of wash-out with Ca2+-free solution, the efflux of tritium (and of 3H-noradrenaline) from the tissue was largely of neuronal origin and remained constant with time (when expressed as fractional rate of loss; FRL). After 110 min of wash-out the effect of inhibition of the Na+,K+-ATPase (by low K+ or ouabain) on basal and on sympathomimetic amine-induced efflux of tritium (or 3H-noradrenaline, under the condition U) was studied in paired experiments. Inhibition of the Na+,K+-ATPase caused a time-dependent increase in the efflux of tritium (or 3H-noradrenaline) which was inhibited by desipramine. Inhibition of the Na+,K+-ATPase also caused a time-dependent reduction of the initial rate of neuronal uptake of 3H-noradrenaline. The effectiveness of the sympathomimetic amines tyramine and amphetamine in inducing "release" (i.e., outward-transport) of noradrenaline depended on the experimental condition: it was most pronounced under the condition RPU, followed by the condition PU and lowest under the condition U (i.e., in tissue of untreated rats). Inhibition of the Na+,K+-ATPase caused an early and transient enhancement of the "release" of noradrenaline induced by tyramine or amphetamine. This enhancement was seen already within the first min after inhibition of the ATPase, i.e., before a pronounced inhibition of uptake (of noradrenaline) and before a pronounced increase of the basal efflux was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of co-transported sodium in the effect of indirectly acting sympathomimetic amines. 301 Jan 39

The mechanism of action of indirectly acting sympathomimetic amines was studied in the rat vas deferens, after inhibition of vesicular uptake (by reserpine), of MAO (by pargyline) and of COMT (by U-0521). 1. Km-values for the neuronal uptake of 12 substrates were determined as the IC50 of the unlabelled substrate inhibiting the initial rate of neuronal uptake of 0.2 mumol/l 3H-(-)-noradrenaline. The IC50 ranged from 0.35 mumol/l (for(+)-amphetamine) to 44.3 mumol/l (for 5-HT). The Vmax (determined for 8 substrates) was substrate-dependent. 2. Tissues were loaded with 0.2 mumol/l 3H-(-)-noradrenaline and then washed out with amine-free solution. All 12 substrates of uptake1 induced an outward transport of 3H-noradrenaline, and equieffective concentrations were positively correlated with Km. Moreover, the EC50 for release greatly exceeded Km. It is proposed that this discrepancy between EC50 and Km is indicative of the fact that at least four factors (each one in strict dependence on Km) contribute to the initiation of outward transport of 3H-noradreanline: a) the appearance of the carrier on the inside of the axonal membrane (facilitated exchange diffusion), b) the co-transport of Na+, c) the co-transport of Cl- (both lowering the Km for 3H-noradrenaline at the inside carrier), and d) inhibition of the re-uptake of released 3H-noradrenaline (through competition for the outside carrier). 3. At least for amezinium, Vmax appears to limit the maximum rate of outward transport. 4. For some substrates (especially for the highly lipophilic ones) bell-shaped concentration-release curves were obtained.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The mechanism of the 3H-noradrenaline releasing effect of various substrates of uptake1: multifactorial induction of outward transport. 344 77

The mechanism of action of indirectly acting sympathomimetic amines was studied in vasa deferentia of unpretreated rats (COMT inhibited), preloaded with 3H-noradrenaline. 1. Concentration-release curves were obtained for 12 unlabelled indirectly acting amines. From differences between these results and those in an accompanying report (involving tissues from rats pretreated with reserpine and pargyline), it is concluded that a "mobilisation" of vesicular 3H-noradrenaline is required for high and sustained rates of outward transport of 3H-noradrenaline from intact adrenergic varicosities. 2. Experiments with a reserpine-like compound (Ro 4-1284) supported the view that a "mobilisation" of vesicular 3H-noradrenaline is required for substantial release. 3. An atypical time course of release and abnormally high rates of release were observed in the presence of excessive concentrations of (+)-amphetamine. Such atypical effects are ascribed to the of basic amines to increase the intravesicular pH. 4. Analysis of the ratio NA/DOPEG (rate of efflux of 3H-noradrenaline/rate of efflux of 3H-DOPEG) indicated that the inward transport (by uptake) of substrates of MAO fails to achieve axoplasmic concentrations which saturate MAO. Inhibition (or saturation) of MAO is not a prerequisite for the initiation of outward transport. 5. A larger fraction of vesicular 3H-noradrenaline is accessible to equireleasing concentrations of (+)-amphetamine (an inhibitor of MAO) than of tyramine (a substrate of MAO). 6. From the present and the accompanying report it is concluded that "substantial and sustained indirect sympathomimetic effects" are to be expected for substrates of uptake which additionally mobilise vesicular noradrenaline. However, this "mobilisation" does not seem to involve a change in intravesicular pH, except at excessive concentrations.
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PMID:The mechanism of the 3H-noradrenaline releasing effect of various substrates of uptake1: role of monoamine oxidase and of vesicularly stored 3H-noradrenaline. 344 78

The effects of a wide range of Prostacyclin (PGI2) concentrations on the Isometric Developed Tension (IDT) of isolated left auricles driven at different frequencies (0.8, 1.6 or 3.3 Hz) were explored. A comparison of the positive inotropism of PGI2, norepinephrine (NE), tyramine and phenylephrine (Phenyl) indicated that PGI2, NE and tyramine enhanced peak tension significantly less at slow (0.8 and 1.6 Hz) than at higher rates (3.3 Hz); whereas Phenyl augmented equally the IDT at all of these three driving frequencies. The positive inotropism evoked by PGI2 was inhibited by (-)-propranolol and also by a treatment with 6-OHDA. Cocaine, normetanephrine and U-0521, augmented the positive inotropic influence of PGI2 on atria paced at a slow rate (0.8 Hz) but not at a faster one (3.3 Hz). These results suggest that the action of PGI2 on atrial contractions is apparently indirect and mediated by the release of tissue catecholamines. In addition the effect of PGI2 and NE at slow and fast rates appears associated with a different relative relevance of the processes which terminate the action of added sympathomimetic agonists, namely, neuronal or extraneuronal uptake as well as metabolization via COMT. These mechanisms seen to be more prominent at slower driving frequencies and could explain the diminished effect of PGI2 and NE on slowly paced atria.
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PMID:Inotropic effect of prostacyclin (PGI2) on isolated rat atria at different contraction frequencies. 699 66