Accumulation Of Catecholamines Research Articles

Differential regulation of neuropeptide Y and catecholamine production in superior cervical ganglion cultures

Primary cultures of newborn rat superior cervical ganglion (SCG) neurons grown in complete serum-free medium have been used to study the regulation of catecholamine and neuropeptide Y (NPY) production. The levels of mRNA for preproNPY and for tyrosine hydroxylase were determined, and the rates of synthesis and accumulation of NPY and catecholamines were measured. Drugs which effectively blocked accumulation of newly synthesized catecholamines (tyramine, reserpine) had no effect on NPY synthesis and accumulation. The catecholamine uptake blocker desipramine and the α 2-adrenergic receptor agonist clonidine inhibited accumulation of newly synthesized catecholamines, but only after prolonged exposure to drug; NPY synthesis and accumulation were unaltered by these treatments. The α 2-adrenergic receptor antagonist yohimbine had no effect on catecholamine or NPY synthesis or accumulation, regardless of the time of treatment. The net synthesis and accumulation of catecholamines and NPY decreased in parallel in response to treatment with phorbol esters, and increased in parallel in response to treatment with glucocorticoids; there was no change in the mRNA levels for tyrosine hydroxylase or preproNPY following either treatment. The levels of tyrosine hydroxylase or preproNPY mRNA were increased following treatment with dibutyryl cyclic AMP, with no change in the net synthesis and accumulation of catecholamines or NPY. Thus, the levels of mRNA for preproNPY and tyrosine hydroxylase are not faithful indicators of the rate of catecholamine or peptide production under several treatment conditions. The complex pattern of regulation of catecholamine and NPY production in SCG neurons grown under closely controlled conditions provides an ideal system in which to examine neuronal regulation of neurotransmitter and neuromodulator production.

Partial Purification and Characterization of the Vacuolar H+‐ATPase of Mammalian Synaptic Vesicles

Several major proteins of synaptic vesicles from rat or cow brain sediment as a large complex on sucrose density gradients when solubilized in nonionic detergents. A vacuolar H(+)-ATPase identified by sensitivity to bafilomycin A1 appears to be associated with this oligomeric protein complex. Two subunits of this complex, synaptic vesicle proteins S and U, correspond to the 57-kDa (B) and 39-kDa accessory (Ac39) subunits, respectively, of bovine chromaffin granule vacuolar H(+)-ATPase as shown by Western immunoblot analysis. The five subunits of the oligomeric complex constitute approximately 20% of the total protein of rat brain synaptic vesicles. Taken together, these results strongly suggest that the abundant, multisubunit complex partially purified from brain synaptic vesicles by density gradient centrifugation is a vacuolar H(+)-ATPase. Bafilomycin A1 completely blocks proton pumping in rat brain synaptic vesicles as measured by [14C]methylamine uptake and also blocks catecholamine accumulation measured by [3H]dopamine uptake. Moreover, ATPase activity, [14C]methylamine uptake, and [3H]dopamine uptake are inhibited by bafilomycin A1 at similar I50 values of approximately 1.7 nmol/mg of protein. These findings indicate that the vacuolar H(+)-ATPase is essential for proton pumping as well as catecholamine uptake by mammalian synaptic vesicles.

Differential accumulation of catecholamines, proenkephalin- and chromogranin A-derived peptides in the medium after chronic nicotine stimulation of cultured bovine adrenal chromaffin cells

We have used an antiserum to a synthetic peptide fragment of bovine chromogranin A (ChrgA)[Tyr o] bovine ChrgA (306–313): YLSKEWEDA, together with antibodies to proenkephalin-derived peptides, to measure the release of immunoreactive peptides from nicotine-stimulated cultured bovine adrenal chromaffin cells. Over a period of 6 hr the accumulation of YLSKEWEDA immunoreactivity and Met-enkephalin Arg 6Gly 7Leu 8 (MERGL) immunoreactivity in the medium of 10 μM nicotine-stimulated cells was shown to be biphasic; the initial phase occurred in the first 15–30 min and the second phase reached a peak after 4 hr. In contrast, catecholamine release occurred monophasically over the initial 15–30 min. Investigation of the second phase of peptide accumulation revealed that it was due in part to nicotine-evoked exocytosis and in part to extracellular processing of high molecular weight precursor proteins.

The Role of Catecholamines in Ischemia

In myocardial ischemia, sympathetic activity of the heart is closely connected with the progression of cell injury and the incidence of malignant arrhythmias. Adrenergic stimulation of the ischemic myocardium is due to increased local norepinephrine concentrations in the heart, whereas the plasma catecholamine levels are of minor relevance. During the first few minutes of ischemia. efferent sympathetic nerves are activated. Excessive accumulation of norepinephrine, however, is prevented since adenosine, formed in the ischemic myocardium, suppresses exocytotic norepinephrine release, and released norepinephrine is rapidly removed as long as catecholamine reuptake is functional. With progression of ischemia to more than 10 min, the myocardium is no longer protected against excess catecholamine accumulation in the interstitial space because local metabolic release mechanisms become increasingly important. This release, which is independent of central sympathetic activity and extracellular calcium, occurs in two steps: first, norepinephrine escapes from its intracellular storage vesicles and accumulates in the cytoplasma of the neuron; in a second, rate-limiting step, norepinephrine is transported across the plasma membrane into the interstitial space, using the neuronal uptake carrier in reverse of its normal transport direction. Studies using acute and chronic sympathetic denervation and antiadrenergic agents demonstrate that this local metabolic, rather than centrally induced, norepinephrine release is critically involved in the progression of ischemic cell damage and the occurrence of ventricullar fibrillation in early ischemia. As a consequence of local metabolic catecholamine release, extracellular norepinephrine reaches 1,000 times the normal plasma concentration within 20 min of ischemia. Myocardial ischemia results in a temporary supersensitivity to catecholamines of the myocytes. This is due to a twofold increase in alpha1- and a 30% increase of beta-adrenergic receptor number at the cell surface. The sensitization of adenylate cyclase during the first 20 min of total ischemia is followed by a rapid inactivation of the enzyme that also includes the coupling protein Gs. The deleterious combination of extremely high norepinephrine concentrations with an at least temporarily enhanced responsiveness of the tissue to catecholamines is thought to accelerate the propagation of the wavefront of irreversible cell damage in the ischemic myocardium. Moreover, the inhomogenous distribution of catecholamine excess within the heart is considered to promote malignant arrhythmias by unmasking and enhancing electrophysiological disturbances in early ischemia.

Differential accumulation of catecholamines and of proenkephalin A- and chromogranin A-derived peptides during chronic nicotine stimulation of cultured bovine adrenal chromaffin cells

Differential accumulation of catecholamines and of proenkephalin A- and chromogranin A-derived peptides during chronic nicotine stimulation of cultured bovine adrenal chromaffin cells

Contrasting time course of catecholamine accumulation and of spontaneous discharge in experimental neuromas in the rat

Catecholamine-containing sympathetic axons in rat sciatic nerve-end neuromas were visualized histochemically. Within a few hours of ligating and sectioning the nerve, axons began to accumulate catecholamine histofluorescence. Density of labelled fibers peaked 2-5 days postoperative, then declined rapidly so that little or no label was observed beyond 12 days. Sympathectomy eliminated staining; neonatal treatment with capsaicin had no effect. Accumulation and dissipation of histofluorescence preceded the rise and fall of electrical hyperexcitability in neuromas by several days respectively.

O-60 - Staurosporine, a protein kinase inhibitor, potentiates neurite outgrowth and catecholamine accumulation in PC12D cells

O-60 - Staurosporine, a protein kinase inhibitor, potentiates neurite outgrowth and catecholamine accumulation in PC12D cells

Catecholamine depletion and accumulation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) in adrenal medullary chromaffin cells

Cultures of bovine adrenal medullary chromaffin cells converted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to 1-methyl-4-phenylpyridinium (MPP(+)) by a pargyline-sensitive mechanism. Both MPTP and MPP(+) accumulated in these cells. Upon subcellular fractionation, distribution of MPP(+) paralleled that of catecholamines, suggesting storage in chromaffin vesicles. In contrast, MPTP was found in both soluble and particulate fractions, but not in chromaffin vesicles. MPTP produced a rapid depletion of 20-25% of chromaffin cell catecholamines, an action blocked by the nicotinic antagonist d-tubocurarine but not by the monoamine oxidase inhibitor pargyline. This depletion was not mimicked by MPP(+). Addition of > OR = 50 microM MPTP to chromaffin cell cultures caused additional, progressive catecholamine loss from 1 to 6 days of drug exposure that was mimicked by MPP(+) and not blocked by pargyline or d-tubocurarine. Cultures of bovine adrenal cortical cells also converted MPTP to MPP(+) and accumulated both of these drugs, but at a slower rate and to a lesser extent than chromaffin cells. Although chromaffin cells form MPP(+) from MPTP and store MPP(+), these studies suggest that catecholamine depletion in these cells results from the actions of MPTP and MPP(+) which are not stored in chromaffin vesicles. MPTP evokes catecholamine secretion from chromaffin cells via nicotinic acetylcholine receptors. MPTP and free MPP(+) are also toxic to the cells, probably through blockade of metabolic processes. These findings suggest that cells with a high capacity for MPP(+) uptake but limited vesicular storage capacity, i.e. sustained high cytoplasmic drug levels, would be susceptible to the toxic actions of this drug.

This issue

A series of biochemical and behavioral experiments tested the hypothesis that anisomycin (ANI), a protein synthesis inhibitor, produced decrements in long-term memory by raising free tyrosine levels and by the accumulation of catecholamines (CAs) rather than by its primary effect on protein synthesis. We compared the effects of ANI and three catecholamine synthesis inhibitors (CAIs)—diethyldithiocarbamic acid, alpha-methyl-p-tyrosine, and tetrabenazine—on cerebral concentrations of tyrosine and CAs and on the rate of accumulation of CAs. ANI had a relatively small effect, whereas the CAIs resulted in large reductions. When ANI and a CAI were used in combination, effects on CA levels were determined mainly by the CAI. The amnestic effects of ANI and the CAIs were also compared across seven experimental paradigms. Pretraining administration of any of the four drugs could result in amnesia for passive avoidance training, but only when training was weak. With an increase in training strength, a series of three injections of ANI (one pre- and two post-training) caused amnesia, but a similar series of CAI injections did not. Substituting one CAI injection for the second of three successive ANI injections did not cause amnesia, but substituting cycloheximide, another protein synthesis inhibitor, resulted in amnesia. With an active avoidance test, ANI caused amnesia while AMPT did not; d-amphetamine blocked the amnestic effect of ANI but caused amnesia in AMPT injected mice. Whereas ANI lengthened the temporal gradient over which electroconvulsive shock produced amnesia, AMPT or DDC did not. DDC caused only transient amnesia for passive avoidance training, while the amnestic effect of ANI remained constant at 24-hr and 1-week retention tests. We conclude that ANI and CAIs have distinctly different abilities to produce amnesia. These experiments provide additional support for the hypothesis that protein synthesis is required for formation of long-term memory.

Effects of different monoamine oxidase inhibitors on the metabolism of L-dopa in the rat brain

The influence of monoamine oxidases A and B on the metabolism of dopamine or the expanded dopamine pool following L-dopa administration remains unclear. This study found that treatment of Sprague-Dawley rats with monoamine oxidase inhibitors strongly affected L-dopa metabolism in the brain, but the influence varied with each individual inhibitor. In animals pretreated with pargyline or clorgyline, L-dopa administration led to huge accumulations of dopamine and significantly raised central norepinephrine concentrations. In contrast, similar L-dopa injections in deprenyl-pretreated rats caused only a moderate rise in dopamine and no change in norepinephrine. There seems to be little relationship between the degree of monoamine oxidase inhibition and the accumulation of catecholamines and their metabolites in the rat brain. The effects of monoamine oxidase inhibitors on dopamine accumulation appeared to occur outside the catecholaminergic neurons since in the animals pretreated with 6-hydroxydopamine, which decreased significantly the content of brain catecholamines, dopamine accumulation following L-dopa administration still remained considerable. On the other hand, the influence of monoamine oxidase inhibitors on brain norepinephrine concentrations seemed to originate in the noradrenergic neurons because norepinephrine increase was greatly reduced in rats treated with 6-hydroxydopamine but was restored when the treatment with 6-hydroxydopamine was accompanied by desimipramine which specifically protects noradrenergic stores.

Studies on Mg2+-dependent ATPase in bovine adrenal chromaffin granules. With special reference to the effect of inhibitors and energy coupling.

The Mg2+-ATPase activities of bovine adrenal chromaffin granules were studied in highly purified preparations of granule ghosts and in intact organelles. The overall ATPase activity (150-250 nmol ADP min-1 mg-1) of the granule ghost preparations was inhibited less than 5% by the bathophenanthroline chelate of Fe(II), a potent inhibitor of mitochondrial F1-ATPase. This small inhibition can be accounted for by a very minor contamination with mitochondria or mitochondrial fragments. The overall ATPase activity of native granule ghosts was inhibited about 75% by N-ethylmaleimide, with half-maximal inhibition at about 20 microM. The titration curve was slightly shifted towards higher concentrations as compared to the inhibition curve for the proton pump activity, which was completely inhibited at 25 microM. N,N'-Dicyclohexylcarbodiimide inhibited the overall ATPase activity by 75-80% at 1.1 mumol/mg protein, a concentration that completely abolished the proton pump activity. Low concentrations (10 microM) of vanadate inhibited the overall ATPase activity by about 15% but had no effect on the proton pump activity, which was partly inhibited only at higher vanadate concentrations. Our attempts to assign a function to the vanadate-sensitive and N-ethylmaleimide-insensitive ATPase have so far been unsuccessful. In particular, our assay for ATP diphosphohydrolase activity was negative, although the chromaffin granule ghosts revealed a low Mg2+-ADPase activity (11.8 nmol AMP min-1 mg-1 protein). In intact chromaffin granules the specific Mg2+-ATPase activity (50-70 nmol ADP min-1 mg-1) was stimulated 2-fold by uncouplers, as compared to 1.6-1.7-fold in granule ghosts. The degree of energy coupling was rather independent of the external pH (6.5 less than pH less than 8.0) and temperature (20-45 degrees C). As expected, partial inhibition (about 15%) of the overall ATPase activity by 10 microM vanadate increased the ATPase control ratio. ADP was found to be a potent inhibitor of the proton pump activity with MgATP as the substrate, and the effect can partly be explained by a competitive type of inhibition of the hydrolytic reaction. This effect of ADP explains some of the kinetic data reported for MgATP-dependent (H+-ATPase-dependent) reactions in this organelle, notably the energy-dependent accumulation and storage of catecholamines.

Relationship between plasma and platelet epinephrine concentrations in humans.

Nine healthy humans received sequential 80-min infusions of saline and epinephrine (EPI) at 0.55 and 2.75 micrograms X min-1 X m-2 to determine whether increases in arterialized venous plasma EPI within the physiological range affect platelet EPI levels. The platelet EPI concentration was significantly higher than basal levels only during the 2.75 micrograms X min-1 X m-2 EPI infusion (P less than 0.02). To assess the role of platelets in EPI clearance from plasma, four human subjects underwent a 2.75 micrograms X min-1 X m-2 EPI infusion during beta-adrenergic blockade with propranolol. Propranolol decreased plasma EPI clearance (P less than 0.01) and increased both the plasma and platelet EPI concentrations (P less than 0.01) during the EPI infusion. To determine the changes in plasma and platelet EPI during and after EPI infusion, seven subjects received an 80-min EPI infusion at 2.75 micrograms X min-1 X m-2. After discontinuation of the EPI infusion, plasma EPI levels returned to base line within 30 min, whereas platelet EPI levels were significantly elevated above base line for 120 min (P less than 0.02 vs. base line). Platelets concentrate EPI during increases in plasma EPI, which are similar to the plasma levels seen in physiological and pathophysiological states in humans. The accumulation of catecholamines by platelets may be an additional mechanism in the regulation of plasma catecholamine levels in humans.

Free and conjugated catecholamines in human plasma during physical exercise.

To investigate changes of free and sulfoconjugated catecholamines in response to alterations in sympatho-adrenal activity, free and conjugated noradrenaline, adrenaline and dopamine were determined radioenzymatically in plasma of 49 subjects. During brief vigorous bicycle exercise (8 min, maximal heart rate: 177 beats/min) mean free noradrenaline and adrenaline values of 2.0 and 0.51 nmol/l at rest, increased to 6.7 and 2 nmol/l (P less than 0.001) respectively, at the maximal workload of 200 watt, whereas conjugated noradrenaline and adrenaline decreased from 3.4 and 0.8 nmol/l to 2.1 and 0.4 nmol/l (P less than 0.001) respectively. In the tenth min of the recovery period basal free and conjugated noradrenaline and adrenaline levels were measured. The moderate stress of a steam bath (20 min, maximal heart rate: 131 beats/min) doubled free noradrenaline and adrenaline levels. However, conjugated noradrenaline and adrenaline concentrations remained unchanged. The increase in free catecholamine values during an exhausting cross-country march over 20 km was associated with an accumulation of sulfated catecholamines. After a rest of 30 min free noradrenaline and adrenaline reached basal values, whereas conjugated noradrenaline and adrenaline remained elevated by 64 and 70% respectively, compared to pre-exercise concentrations. It was concluded that conjugated noradrenaline and adrenaline may be used as pools for free noradrenaline and adrenaline during brief vigorous exercise. In addition, they may also be indicators of chronic activation of the sympatho-adrenal system.

Inhibitory effects of desmethylimipramine, metanephrine and normetanephrine on the neuronal and extraneuronal accumulation of catecholamines in fish spleen.

The effect of desmethylimipramine, metanephrine and normetanephrine on the neuronal and extraneuronal accumulation of radiolabelled adrenaline and noradrenaline were studied in the perfused spleen of the teleost fish, Atlantic cod, Gadus morhua. Desmethylimipramine was found to be a potent inhibitor for the neuronal accumulation of both adrenaline and noradrenaline in the cod spleen, suggesting similarities with the neuronal uptake mechanism in mammals. Metanephrine was found to inhibit the extraneuronal accumulation of noradrenaline, though not that of adrenaline, while normetanephrine did not change the extraneuronal accumulation of any of the catecholamines. Both metanephrine and normetanephrine were more potent neuronal uptake blockers than extraneuronal. Metanephrine inhibited only the neuronal accumulation of adrenaline, while normetanephrine inhibited neuronal accumulation of both catecholamines. It is concluded that adrenaline and noradrenaline accumulate differently in the adrenergic neurons of the cod spleen as was suggested earlier for noradrenaline and tyramine (Nilsson & Holmgren 1976). It is also evident from the study that the uptake mechanisms or accumulation of catecholamines in lower vertebrates such as fish may be different from corresponding mechanisms in mammals.

Temperature effects on catecholamine accumulation in neuronal and extraneuronal compartments in the cod spleen.

The effects of temperature on the accumulation of radiolabelled adrenaline and noradrenaline were studied in the perfused spleen of the Atlantic cod, Gadus morhua. A decrease in temperature from 20-24 to 10 degrees C showed a corresponding decrease in the neuronal and extraneuronal accumulation of both adrenaline and noradrenaline. The Q10-values for the neuronal accumulation of adrenaline and noradrenaline were 3.6 and 2.1, respectively. This indicates that adrenaline is accumulated neuronally by an active process. An increased perfusing time resulted in an even more pronounced difference in the neuronal accumulation between the two amines. The extraneuronal accumulation of both amines was only slightly affected by a 10 degree C decrease in temperature, and with increasing perfusion time, the accumulation increased as in a passive diffussion. There are strong indications that adrenaline and noradrenaline not only accumulate differently from each other in the adrenergic neurons of the cod spleen, but also that the adrenaline uptake mechanism neuronally might resemble the characteristic mammalian catecholamine uptake while noradrenaline seems to accumulate by a more primitive mechanism, not sensitive to a reduction in temperature. This might be physiologically important for the cod, since the spleen can synthetize adrenaline from noradrenaline and the uptake of adrenaline from the circulation is therefore less important.

Neurochemical and behavioral effects of catecholamine and protein synthesis inhibitors in mice.

A series of biochemical and behavioral experiments tested the hypothesis that anisomycin (ANI), a protein synthesis inhibitor, produced decrements in long-term memory by raising free tyrosine levels and by the accumulation of catecholamines (CAs) rather than by its primary effect on protein synthesis. We compared the effects of ANI and three catecholamine synthesis inhibitors (CAIs)--diethyldithiocarbamic acid, alpha-methyl-p-tyrosine, and tetrabenazine--on cerebral concentrations of tyrosine and CAs and on the rate of accumulation of CAs. ANI had a relatively small effect, whereas the CAIs resulted in large reductions. When ANI and a CAI were used in combination, effects on CA levels were determined mainly by the CAI. The amnestic effects of ANI and the CAIs were also compared across seven experimental paradigms. Pretraining administration of any of the four drugs could result in amnesia for passive avoidance training, but only when training was weak. With an increase in training strength, a series of three injections of ANI (one pre- and two post-training) caused amnesia, but a similar series of CAI injections did not. Substituting one CAI injection for the second of three successive ANI injections did not cause amnesia, but substituting cycloheximide, another protein synthesis inhibitor, resulted in amnesia. With an active avoidance test, ANI caused amnesia while AMPT did not; d-amphetamine blocked the amnestic effect of ANI but caused amnesia in AMPT injected mice. Whereas ANI lengthened the temporal gradient over which electroconvulsive shock produced amnesia, AMPT or DDC did not. DDC caused only transient amnesia for passive avoidance training, while the amnestic effect of ANI remained constant at 24-hr and 1-week retention tests. We conclude that ANI and CAIs have distinctly different abilities to produce amnesia. These experiments provide additional support for the hypothesis that protein synthesis is required for formation of long-term memory.

Plasma clearance, metabolism, and tissue accumulation of 3H-labeled catecholamines in trout

Plasma clearance, metabolism, and tissue accumulation of [3H]norepinephrine (NE) and [3H]epinephrine (E) were measured after injection into the dorsal aorta of chronically catheterized trout, Salmo gairdneri. Sucrose, an inert volume marker, was injected with the catecholamines (CAs). Ion-exchange chromatography was used to separate unmetabolized CAs from deaminated and O-methylated metabolites in plasma. Both CAs are cleared from plasma at an exponential two-component rate. By 10 min postinjection, CA-specific extraction lowered plasma [3H]NE by 65% and [3H]E by 50%. Over 80% of the 3H remaining in plasma 10 min after injection was metabolized to O-methylated and deaminated products. Thus trout are able to quickly and efficiently lower circulating CA levels through tissue accumulation and metabolism. Kidney, liver, spleen, and atrium accumulate more CA than other tissues, although most tissues bind CA to some extent. Gills preferentially accumulate CAs over sucrose. Skeletal muscle has a low affinity for CAs but by virtue of its large mass may be an important organ in CA metabolism. NE is removed from the circulation faster, and more NE is bound to tissues than E. A blood-brain barrier for E but not NE was observed.

Explanted and implanted notochord of amphibian anuran embryos. Histofluorescence study on the ability to synthesize catecholamines.

The notochord of amphibian anuran embryos contains catecholamines during the early developmental stages. In order to determine if these catecholamines are synthesized in situ, the development of their specific histofluorescence was investigated in the notochord alone or the notochord combined with the lateral somitic mesoderm, both explanted at the neurula stage and cultivated in vitro or implanted into the ventral part of early neurulae endoderm. The histofluorescence evolution, on the other hand, was investigated in the notochord alone or combined with myotomes, both explanted after the beginning of catecholamine biosynthesis and cultivated in vitro for one hour, in order to determine the effect of explantation and culture on the accumulation of notochordal catecholamines. The comparative study of catecholamine histofluorescence in these different samples shows that: the notochord is able to perform, on its own, the entire biosynthesis of the catecholamines stored in it during the early developmental stages. The catecholamines generated from isolated notochords tend to diffuse into the culture medium, probably due to a deficiency in the vesicular storage system usually found in the catecholamine-synthesizing cells. This loss of catecholamines in vitro can be obviated by the presence round the notochord of any embryonal tissue (somitic mesoderm, endoderm).

The nitrefazole-ethanol interaction in man: cardiovascular responses and the accumulation of acetaldehyde and catecholamines.

The cardiovascular effects of ethanol ingestion after pretreatment with a new antialcohol drug, nitrefazole (2-methyl-4-nitro-1-(4-nitro-phenyl)imidazole, Altimol) were studied. Left ventricular function was examined by echocardiography and systolic time intervals in six healthy Finnish male volunteers who ingested 0.15-0.25 g of ethanol/kg, 24 hr after an 800 or 1600-mg peroral dose of nitrefazole. After ethanol ingestion, accumulation of acetaldehyde in blood (25-150 microM) was accompanied by a 1.5-2-fold increase in plasma noradrenaline, a 3-10-fold increase in plasma adrenaline, and a 0.5-2.0 degrees C rise in skin temperature. Heart rate increased by 70% and cardiac output by 107%. Diastolic blood pressure decreased by 30% and peripheral vascular resistance by 54%. Ejection fraction and maximum circumferential fiber-shortening velocity increased by 26 and 71%, respectively; the pre-ejection period/ejection time ratio decreased by 46%. An apparent vasovagal collapse was noticed in two nitrefazole-treated subjects after ethanol ingestion, and a third subject experienced a fainting attack shortly after the experiment. Thus, in subjects pretreated with nitrefazole, ingestion of rather small amounts of ethanol results in marked accumulation of acetaldehyde apparently due to aldehyde dehydrogenase inhibition. This causes elevation of plasma catecholamines and intense enhancement of cardiac performance. The marked cardiovascular changes demonstrate the potency of nitrefazole, suggesting that, particularly with alcoholics with occult myocardial diseases, its interaction with ethanol may be even more hazardous than that produced by other antialcohol drugs.

Catecholamine-blocking drugs injected at sites of amine accumulation reverse catecholamine degeneration associated deficits

It has been hypothesized that catecholamine (CA) accumulation in the axons of degenerating neurons may represent areas of functional neurotransmitter, and may be producing some of the consummatory and locomotory deficits which occur after central CA-depleting lesions. To test this hypothesis further, haloperidol (0.5 μl of a 7 nM sol.), propranolol (0.5 μl of a 175 nM sol.) or isotonic saline (0.5 μl) were injected 1.5 h, 24 h and 48 h after the injection of 6-hydroxydopamine (6-OHDA; 2 μl of 8 μg/μl) into the lateral hypothalamus (LH) of Sprague-Dawley rats to determine if the hypothermia, motor impairment and consummatory deficits could be reversed. Although haloperidol injection significantly enhanced the hypothermia seen 1.5 h after 6-OHDA injection, open field performance and consummatory responses were significantly improved after haloperidol was injected into the LH where accumulation is known to occur. Three consecutive days of intracerebral haloperidol treatment produced a recovery of body weight regulation lasting for 6 days. Treatment with propranolol enhanced open field performance 1 day after 6-OHDA injection but failed to enhance recovery of consummatory behaviour and body weight control. These results suggest that CA released from areas of accumulation act on adjacent CA receptors to participate in the production of behavioural deficits previously attributed only to the loss of functional neurotransmitter in terminal fields in the forebrain.