Adrenal medullary transplantation into the brain for treatment of Parkinson's disease: clinical outcome and neurochemical studies

Transplantation of adrenal medulla into the caudate nucleus as treatment for Parkinson's disease was performed in eight patients. Although our previous 6-month follow-up revealed early modest improvement, an extension of that follow-up to 1 year disclosed no additional gains in any patient. At the end of 1 year, only one patient could be categorized as moderately improved; three patients were mildly improved, and four patients were unimproved. The rationale for transplanting adrenal medulla was to reestablish a physiologic source of dopamine to the striatum. We measured cerebrospinal fluid (CSF) and plasma catecholamines and metabolites before and after transplantation. Conjugated dopamine (the predominant form of dopamine found in the CSF) and homovanillic acid (the major dopamine metabolite) were modestly and inconsistently increased in the CSF. Conjugated and free epinephrine and norepinephrine, as well as 3-methoxy-4-hydroxyphenylglycol concentrations were not increased in CSF after graft placement, an indication that the adrenal chromaffin cells were no longer producing high levels of these nondopamine catecholamines and metabolites. CSF cortisol concentrations were not increased after transplantation, compared with values from controls, consistent with low numbers of functioning adrenal cortical cells contaminating the graft (or poor survival). Posttransplantation CSF did not induce a neurotrophic effect in cell cultures of 15-day embryonic rat dorsal root ganglion or PC12 (rat pheochromocytoma) cell lines. Survival of samples of patients' adrenal medullary tissue for 2 weeks in tissue culture attested to the viability of the graft at the time of transplantation. The relative concentrations of dopamine to epinephrine or norepinephrine increased in these cultured adrenal medullary cells, presumably because of loss of the glucocorticoid influence on catecholamine synthesis. A wide variety of factors could have contributed to our failure to replicate the earlier impressive results of adrenal-to-brain transplantation reported by others. Continued transplantation studies in animal models of parkinsonism are necessary for better elucidation of these factors.     

Free and conjugated catecholamines in patients with cirrhosis

A defect of conjugation may play a role in the elevated plasma free norepinephrine observed in patients with cirrhosis. Plasma free, sulfoconjugated, and glucuronoconjugated catecholamine concentrations were assessed in 15 patients with cirrhosis and in 15 age-matched control subjects. Plasma free norepinephrine and epinephrine levels were significantly higher in patients with cirrhosis (481 +/- 75 and 96 +/- 16 pg/ml, respectively) than in those of the control group (307 +/- 33 and 42 +/- 10 pg/ml, p less than 0.05 and p less than 0.01, respectively). Plasma free dopamine levels were similar in both groups. Sulfoconjugated catecholamines were the predominant form in plasma from both cirrhotic patients and control subjects. The ratio of conjugated to total catecholamines was similar in the two groups. Therefore, it is unlikely that a defect in conjugation of catecholamines is contributing to the excessive plasma free norepinephrine and epinephrine concentrations found in patients with cirrhosis. Moreover, in patients with cirrhosis, no significant relation was found between plasma conjugated catecholamines and the severity of liver disease. This study shows that cirrhosis does not induce alteration in conjugation of catecholamines and that hepatocellular function is not essential for conjugation of circulating catecholamines.     

Effect of metoclopramide on plasma catecholamine release in essential hypertension

The catecholamine (CA)-releasing action of metoclopramide (MCP) observed in patients with pheochromocytoma was tested in 20 subjects with essential hypertension and compared with the same effect of glucagon in 10 of them. We found that even in the absence of pheochromocytoma, MCP is a CA-releasing substance, moderately increasing systolic blood pressure and pulse rate. The release of CA is reflected by an increase in concentrations of free norepinephrine and total (free plus sulfated) epinephrine 3 minutes and of total dopamine and norepinephrine 10 minutes after the MCP bolus dose, whereas glucagon had an effect on the release of free epinephrine. Regional catheterization before and after MCP dosing in one subject showed a considerable increase in adrenal epinephrine and norepinephrine concentrations 45 seconds after the MCP bolus dose. MCP has a free CA-releasing potency much like that of glucagon. Because the released free CA is readily sulfoconjugated, the effect on CA release can be more easily detected when conjugated CA is determined. MCP should thus be used with caution in pheochromocytoma as well as in other forms of hypertension.     

Distribution of free and conjugated catecholamines between plasma, platelets and erythrocytes: different effects of intravenous and oral catecholamine administrations

Plasma, platelet and erythrocyte contents of free and conjugated norepinephrine, epinephrine and dopamine were determined by radioenzymatic assay in 12 resting healthy volunteers. Mean platelet/plasma concentration ratios were 533 for free norepinephrine, 502 for free epinephrine and 149 for free dopamine. Corresponding erythrocyte/plasma ratios were 1.04, 1.13 and 4.5, respectively. The presence of conjugated catecholamines in platelets and erythrocytes could be confirmed; however, their relative proportion within these cells, particularly in platelets, was lower than that in plasma. Upon intravenous infusion of dopamine for 3 hr at 5 micrograms kg-1 min-1, concentrations of free dopamine in plasma increased rapidly (280-970-fold), whereas conjugated dopamine only reached maximal values (14-19-fold increase) at 30 to 60 min after cessation of the infusion. The relative distribution of unconjugated dopamine in whole blood between plasma, platelets and erythrocytes changed from mean values of 1:0.33:3.7 at rest to 1:1.1:0.5 at the end of the infusion. As a result of the subsequent rapid decrease of dopamine in plasma and erythrocytes, this distribution was 1:17:1 shortly thereafter and remained constant up to the end of the investigation period. The relative distribution for conjugated dopamine of 1:0.001:0.5 at rest changed to about 1:0.2:0.1 at the termination of the infusion. Oral administration of norepinephrine and dopamine led to increases in the plasma concentrations of these amines in their conjugated forms only, whereas epinephrine concentrations remained constant. These elevations were not accompanied by corresponding increases in platelet and erythrocyte norepinephrine, epinephrine and dopamine contents.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human liver and conjugation of catecholamines

To investigate the role of the liver in conjugation of catecholamines we measured the concentrations of free and conjugated norepinephrine, epinephrine, and dopamine in plasma of patients with severe liver disease who were undergoing liver transplantation. Comparisons were made with catecholamine levels in plasma of euhepatic patients who were undergoing abdominal aortic aneurysmectomy. We were also able to determine the importance of the liver in conjugation of exogenous dopamine because this compound was given to both groups of patients. The concentrations of conjugated amines were within the normal range in the patients undergoing liver transplantation, and administered dopamine was conjugated to a similar extent in the two groups of patients. The data suggest that the liver is not indispensable for the conjugation of circulating catecholamines.     

The role of adrenal medulla in endogenous dopaminergic inhibition of aldosterone secretion

Evidence has accumulated that aldosterone secretion is under endogenous dopaminergic inhibition. To examine potential sources of the dopamine thus inhibitorily acting in the adrenal zona glomerulosa, the responsiveness of aldosterone, plasma renin activity, prolactin, and plasma catecholamines to haloperidol, a dopaminergic antagonist, was studied in rats 6 weeks after unilateral adrenalectomy (Group B), 6 weeks after unilateral adrenal demedullation followed by contralateral adrenalectomy 5 days later (Group C), and in controls without any pretreatment (Group A). In Group C, there were increases in basal levels of norepinephrine (P less than 0.01), prolactin (P less than 0.02), and aldosterone (P less than 0.01). Basal plasma renin activity was also increased (P less than 0.05), epinephrine concentrations were decreased. Two hours after haloperidol 1 mg/kg b.wt. i.p., aldosterone levels were increased in Groups A + B (P less than 0.01) but unresponsive in Group C. Haloperidol-induced stimulation of prolactin and norepinephrine was not impaired by the surgical procedures. Epinephrine levels were increased by haloperidol only in groups A + B (P less than 0.002). In none of the groups were plasma renin activity or dopamine levels influenced by haloperidol. It is concluded that dopaminergic inhibition of aldosterone production is brought about neither by circulating dopamine nor by potential dopaminergic nerves accompanying arterial blood supply of the adrenal cortex but by dopamine originating directly in adrenal medulla.     

Conjugated catecholamines in human plasma: where are they coming from?

The origins of conjugated catecholamines remain poorly known. The aim of the present study was to see whether a major contribution comes from the sympathetic nervous system. We have assumed some kind of parallelism between the activity of the sympathetic nervous system, the amount of catecholamines released and taken up, and the amount of conjugated catecholamines circulating in plasma. Accordingly, an increase in sympathetic activity should be followed by an increase in the plasma level of conjugated catecholamines. The plasma levels of sulfoconjugated and glucuroconjugated catecholamines were measured in 10 patients with mental disease resistant to drug treatment, before and after electroconvulsive therapy. As expected, blood pressure, norepinephrine concentration, and epinephrine concentration in plasma were transiently increased. Neither sulfoconjugated nor glucuroconjugated catecholamines were significantly changed. Conjugated catecholamines were measured in 10 volunteers before and at the nadir of insulin-induced hypoglycemia. As expected, plasma levels of norepinephrine and epinephrine were drastically increased. Plasma levels of sulfoconjugates were decreased and glucuroconjugates increased; these were narrow but statistically significant variations. Data reported in the present article do not support a major role for the activity of the sympathetic system in fixing the level of conjugated catecholamines in human plasma. This is a negative, but nonetheless important, observation. In human subjects, currently available information suggests an important role for the intestinal wall and renal function in determining the level of circulating sulfoconjugates.     

Catecholamines in critical care

Catecholamines (norepinephrine, epinephrine, and dopamine) are released into circulation in response to stress and injury and as part of the body's attempt at vasoregulation in response to circulatory failure. Norepinephrine is released from sympathetic nerve terminal, and epinephrine and dopamine are released from the adrenal medulla. Plasma levels of these catecholamines have been reported to be elevated in various clinical settings: congestive heart failure, myocardial infarction, cardiopulmonary bypass, diabetic ketoacidosis, hypoxia, hemorrhage, and septic shock. These amines have both beneficial and detrimental effects on survival. Both norepinephrine and dopamine are often employed in the critically ill to selectively increase cardiocerebral and renal blood flow, respectively.     

Ethanol-induced adrenomedullary catecholamine secretion in LS/Ibg and SS/Ibg mice

Ethanol, administered i.p., produced a dose-dependent increase in plasma norepinephrine and epinephrine concentrations in LS/Ibg (LS) but not in SS/Ibg (SS) lines of mice. Ethanol-induced elevations of plasma epinephrine in LS mice were approximately 10-fold greater than those observed in SS mice. Plasma epinephrine and norepinephrine attained peak concentrations at 20-min post-ethanol administration at doses ranging from 2.8 to 4.1 g/kg. Plasma catecholamines remained elevated for approximately 1 hr and returned to basal values 2 hr after ethanol administration. Significant correlations were obtained between blood ethanol (r = 0.99), plasma epinephrine (r = 0.92) and plasma glucose (r = 0.98) as a function of ethanol dose in LS mice. Chlorisondamine (3 mg/kg), a ganglionic blocker, abolished completely the ethanol-induced increase in plasma catecholamines. These results confirm previous suggestions that the response is centrally mediated through an increased sympathetic outflow rather than by a direct effect on the adrenal medulla. The increase in plasma epinephrine and associated hyperglycemia produced by ethanol was not observed with pentobarbital or halothane anesthesia. Ethanol-induced hypothermia was diminished markedly (47%) by an elevated ambient temperature (28 degrees C) without reducing the hyperglycemic response to ethanol. These results suggest that ethanol-induced hypothermia does not mediate ethanol-induced adrenomedullary catecholamine secretion and concomitant hyperglycemia. It is proposed that the differential ethanol-induced secretion of adrenomedullary catecholamines in LS and SS mice is due to differential central nervous system sensitivities to ethanol.     

Dopa in plasma increases during acute exercise and after exercise training

Plasma dihydroxyphenylalanine (dopa) has been shown to originate in sympathetic neurons, and it has been suggested that plasma level reflects activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. In this study, we measured the effects of acute exercise and exercise training on the levels of dopa and catecholamines in the plasma of healthy, older individuals. Venous blood was drawn from 19 men, from 52 to 75 years of age, at rest, at a standard submaximal work load, at peak exercise, and 3 minutes after exercise on a cycle ergometer. Ten of 12 men then completed 12 to 16 weeks of supervised training, and seven continued normal activity. All 17 men were then retested. The seven control subjects subsequently underwent exercise training as above and were retested again. Levels of dopa and catecholamines in plasma samples were measured by high-performance liquid chromatography with electrochemical detection. Dopa levels at rest were considerably higher than free dopamine, epinephrine, and norepinephrine. During short-term exercise, levels of dopa and catecholamines increased. The absolute increase in dopa was greater than the increase in epinephrine or dopamine but was not greater than that in norepinephrine. After the training period, basal dopa levels increased significantly and correlated with the increase in peak oxygen uptake. There was no change in basal conjugated norepinephrine or dopamine levels with exercise or training, but the level of conjugated epinephrine decreased slightly. No changes occurred in levels of dopa or catecholamines in the untrained group. Free dopamine, norepinephrine, and epinephrine levels at peak exercise were increased after exercise training.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitative analysis of the contribution of pulmonary and hind limb circulation to the clearance of exogenous catecholamines

The contribution of pulmonary and hind limb circulation to the clearance of exogenous catecholamines was analyzed quantitatively. During infusion of clinical doses of norepinephrine, epinephrine and dopamine in dogs, the plasma level of catecholamine and the plasma flow were measured simultaneously. Percentage of contribution was calculated from the following equation; transorgan difference of plasma catecholamine (nanograms per milliliter) X plasma flow (milliliters per minute) X 100/dose (nanograms per minute). This value means the percentage of the amount of catecholamine cleared by an organ to the amount of catecholamine administered into the body. Small but significant transpulmonary gradients of plasma levels of norepinephrine, epinephrine and dopamine and large translimb gradients of plasma levels of these catecholamines were observed. The plasma flow of pulmonary circulation was increased by infusion of epinephrine and dopamine, whereas it remained unchanged by infusion of norepinephrine. The plasma flow of hind limb circulation showed no significant change by infusion of catecholamines. The calculated contribution values indicate that pulmonary circulation clears 35.7% of norepinephrine (at 0.2 ng X kg-1 X min-1), 27.1% of epinephrine (0.2 ng X kg-1 X min-1) and 21.5% of dopamine (10 micrograms X kg-1 X min-1) administered exogenously, and that the corresponding figures for hind limb circulation are 8.2, 7.8 and 4.5%.     

High plasma levels of catecholamines during insulin-induced hypoglycemic stress do not cause beta-adrenergic receptor sequestration.

In the present investigation insulin-induced hypoglycemia was used as a powerful stimulus to rapidly release epinephrine from the adrenal medulla. Insulin injection raised epinephrine 16-fold and doubled norepinephrine plasma levels. The aim of this attempt was to induce beta-adrenergic receptors (beta-ARs) sequestration in vivo on mononuclear leukocytes (MNLs). The number of total and surface beta-ARs was significantly increased 30 minutes after insulin administration, with only partial recovery at 90 minutes. No detectable receptor sequestration was observed: surface receptors were about 90% of total receptors in all the conditions examined. Isoproterenol-stimulated cyclic adenosine monophosphate (cAMP) accumulation was also increased after 30 minutes (+66%) and 90 minutes (+65%) of insulin injection. Basal and forskolin-stimulated intracellular cAMP values were unchanged. We conclude that, even after a strong release of catecholamines, beta-AR redistribution cannot be demonstrated on MNLs.     

Potential role of the renal tubule in fixing the level of plasma sulfoconjugated catecholamines in the dog.

Plasma levels of sulfoconjugated catecholamines in human subjects and in dogs are usually much higher than those of native amines. Their origins and the mechanism(s) involved in fixing their plasma concentrations are not well known; however, several lines of clinical evidences indicate a major role for the kidney. Thus this study was undertaken to measure the renal fractional excretion--used as an overall index of kidney mechanisms involved in the handling of catecholamines and their sulfoconjugates in the dog--and to look for any possible relationships between plasma concentration and urinary excretion. This was carried out in 36 anesthetized hydropenic mongrel dogs. The mean values of the renal fractional excretion of sulfoconjugated dopamine, norepinephrine, and epinephrine were shown to be statistically greater than 100%, suggesting a predominant secretion by the renal tubules of hydropenic dogs. Statistically significant correlations between plasma concentration and urinary excretion of sulfoconjugates--independent of blood pressure, cardiac output, clearance of para-aminohippuric acid, glomerular filtration rate, and sodium excretion are reported. Thus any change in the tubular handling of sulfoconjugates is likely to have a direct consequence in the fixation of their plasma concentrations.     

Increased conjugated dopamine in plasma after exercise training

To evaluate the effect of endurance exercise on plasma catecholamines, we exercise trained eight dogs (group T) by treadmill running for 8 weeks. Six sedentary dogs constituted a nontrained control group (group NT). Heart rate response to a graded submaximal stress test was reduced in group T dogs (p less than 0.05), but mean resting aortic blood pressure (NT, 84 +/- 5 mm Hg; T, 82 +/- 4 mm Hg) and heart rate (NT, 87 +/- 1 bpm; T, 84 +/- 2 bpm) were unchanged by exercise, and no cardiac hypertrophy occurred after exercise. Plasma norepinephrine and epinephrine levels were reduced in group T at rest and during a fixed exercise workload. Plasma conjugated dopamine showed a marked increase in group T dogs (NT, 1398 +/- 130 pg/ml; T, 11346 +/- 1291 pg/ml; p less than 0.01) at rest, and no change in conjugated dopamine occurred in either group after short-term exercise stress. No intergroup differences were noted in resting coronary flow or coronary arteriovenous oxygen, or in myocardial oxygen consumption. The data verify previous findings of lower plasma levels of norepinephrine and epinephrine after training, and indicate that a marked rise in conjugated dopamine occurs after training. These findings suggest that norepinephrine and epinephrine metabolism is shifted toward conjugated dopamine by exercise training, thereby reducing active catecholamines in plasma, but retaining a large pool of usable metabolite.     

Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase

This is a reversed-phase liquid-chromatographic method, with electrochemical detection, for simultaneously measuring, in plasma, the concentrations of the catecholamine precursor dihydroxyphenylalanine (DOPA); the endogenous catecholamines norepinephrine, epinephrine, and dopamine; and the deaminated catecholamine metabolites dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG). We used this method to assess effects of monoamine oxidase (EC 1.4.3.4) inhibition in humans. Plasma DHPG concentrations as determined by the present method (mean 826, SEM 61 ng/L) were similar to those found by other methods. Inhibition of monoamine oxidase (by administering deprenyl or tranylcypromine) decreased plasma DHPG by greater than 65%, plasma DOPAC by greater than 50%, and plasma DOPA by about 20%, without consistently affecting norepinephrine or epinephrine. Simultaneous measurement of DOPA, catecholamines, and DHPG may be useful for examining the synthesis, release, and intraneuronal metabolism of norepinephrine. The assay method is rapid, reliable, and simple, and it provides a more comprehensive assessment of noradrenergic nervous function than does measurement only of catecholamines.     

Modification of the cardiovascular effects of l-dopa by decarboxylase inhibitors

Intravenously infused L-dopa (0.3 mg/kg per min) produced hypertension and cardiac arrhythmias in halothane anesthetized dogs. Biochemical studies showed that the heart, kidney, and brain of these animals accumulated significant amounts of catecholamines formed from the administered precursor.Pretreatment of dogs with an extracerebral inhibitor of dopa decarboxylase [D,L-alpha-hydrazino-alpha-methyl-beta-(3.4-dihydroxyphenyl) propionic acid] prevented the development of hypertension and arrhythmias with infusion of L-dopa. Instead, these animals developed significant hypotension. The heart and kidney of these animals accumulated markedly reduced amounts of catecholamines formed from L-dopa compared with dogs receiving L-dopa alone: the amount of catecholamines accumulated in brain was unchanged. L-dopa, after extracerebral decarboxylase inhibition, appeared to produce hypotension by reducing peripheral vascular resistance without altering sympathetic nerve function. During hypotension, cardiac output was not altered and arterial pressure in perfused hindlimbs fell, even though flow was maintained. The pressor response to intravenous injections of norepinephrine and dopamine was unchanged. Hindlimb arterial pressure response to direct electrical stimulation of the lumbar sympathetic trunk was also unchanged.Pretreatment with a drug which inhibits brain as well as extracerebral dopa decarboxylase [D,L-seryl-2,3,4-trihydroxybenzylhydrazine hydrochloride] abolished all effects of L-dopa on blood pressure. In these animals, there was a marked reduction of catecholamine formation from L-dopa in the brain as well as the heart and kidney.It appears that L-dopa produces opposite effects on blood pressure depending on the site of accumulation of its metabolic products, dopamine and norepinephrine. If L-dopa is rapidly decarboxylated to catecholamines in peripheral organs, hypertension and cardiac arrhythmias occur. If peripheral dopa decarboxylase is selectively inhibited, a centrally mediated hypotensive effect, probably secondary to the accumulation of catecholamines in the brain, becomes apparent. If dopa decarboxylase is inhibited in the brain in addition to extracerebral organs, L-dopa has no effect on blood pressure.     

Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines

BACKGROUND: Measurements of plasma free metanephrines (normetanephrine and metanephrine) provide a useful test for diagnosis of pheochromocytoma and may provide other information about the nature of these tumors. METHODS: We examined relationships of tumor size, location, and catecholamine content with plasma and urinary metanephrines or catecholamines in 275 patients with pheochromocytoma. We then prospectively examined whether measurements of plasma free metanephrines could predict tumor size and location in an additional 16 patients. RESULTS: Relative proportions of epinephrine and norepinephrine in tumor tissue were closely matched by relative increases of plasma or urinary metanephrine and normetanephrine, but not by epinephrine and norepinephrine. Tumor diameter showed strong positive relationships with summed plasma concentrations or urinary outputs of metanephrine and normetanephrine (r = 0.81 and 0.77; P <0.001), whereas relationships with plasma or urinary catecholamines were weaker (r = 0.41 and 0.44). All tumors in which increases in plasma metanephrine were >15% of the combined increases of normetanephrine and metanephrine either had adrenal locations or appeared to be recurrences of previously resected adrenal tumors. Measurements of plasma free metanephrines predicted tumor diameter to within a mean of 30% of actual diameter, and high plasma concentrations of free metanephrine relative to normetanephrine accurately predicted adrenal locations. CONCLUSIONS: Measurements of plasma free metanephrines not only provide information about the likely presence or absence of a pheochromocytoma, but when a tumor is present, can also help predict tumor size and location. This additional information may be useful for clinical decision-making during tumor localization procedures.     

Effect of quinpirole, a specific dopamine DA2 receptor agonist on the sympathoadrenal system in dogs

The effects of quinpirole, a specific dopamine DA2 receptor agonist, were investigated on both cardiovascular responses in conscious dogs and catecholamine release from the adrenal medulla in anesthetized dogs. In conscious normal dogs, i.v. quinpirole (30 micrograms/kg) elicited a decrease in blood pressure and a marked increase in heart rate associated with a rise in plasma catecholamine levels. The increase in heart rate is due to both baroreflex and central mechanisms because a slight but significant positive chronotropic effect persists in sinoaortic denervated dogs (i.e., animals deprived of baroreflex pathways). The central origin of this excitatory effect was confirmed by two subsequent protocols: intracisterna magna injection of quinpirole (5 micrograms/kg) increased blood pressure, heart rate and plasma catecholamines; i.v. domperidone reversed the hypotensive effect of i.v. quinpirole into a pressor response. The rise in plasma catecholamines was associated with an increase in plasma vasopressin levels. In anesthetized dogs, i.v. quinpirole (10 micrograms/kg/min during 12 min), which also decreased blood pressure, failed to modify epinephrine (and norepinephrine) release from the adrenal medulla whatever the stimulation frequencies (1, 3 and 5 Hz) of the sectioned splanchnic nerve. Similar results were obtained with apomorphine (5 micrograms/kg/min during 12 min). These results show that two mechanisms are involved in the action of quinpirole: first, a peripheral depressor action (which elicits the decrease in blood pressure) and secondly, a central pressor component involving an increase in both sympathetic tone and vasopressin release. They also demonstrate clearly that peripheral DA2 receptors are not involved in the control of catecholamine release from the adrenal medulla under in vivo conditions.     

Regional changes in sympathetic nerve activity and baroreceptor reflex function and arterial plasma levels of catecholamines, renin and vasopressin during naloxone-precipitated morphine withdrawal in rats

The aim of the study was to examine regional changes in sympathetic nerve activity (SNA) and baroreceptor function and arterial plasma catecholamines, arginine vasopressin (AVP) and plasma renin activity during morphine withdrawal in chloralose-anesthetized rats. Dependence was induced by s.c. morphine base pellets. Adrenal, renal and splanchnic SNA and SNA from the lumbar sympathetic chain were recorded before and after i.v. injections of naloxone. Baroreceptor function was examined with phenylephrine-induced increases in mean arterial pressure. In separate experiments, arterial plasma norepinephrine, epinephrine, dopamine, plasma renin activity and AVP were measured before and after naloxone-precipitated withdrawal. Naloxone administration elicited an increase in mean arterial pressure and heart rate. Although renal SNA was inhibited by approximately 50%, adrenal SNA and lumbar SNA increased by approximately 400 and 80%, respectively. Splanchnic SNA did not change significantly. The baroreceptor-mediated inhibition of adrenal SNA was facilitated while that for renal SNA was attenuated. The arterial plasma level of norepinephrine was doubled and epinephrine increased almost 20-fold. AVP increased about 15-fold, whereas plasma renin activity showed only a minor increase after naloxone. This study shows that a marked differentiation of the SNA response occurs during morphine withdrawal in rats, which suggests an interaction between opioid receptors and the control of regional sympathetic output. Furthermore, large amounts of AVP and epinephrine are released, which probably contribute to the cardiovascular changes seen in the withdrawal phase.     

Does dopamine regulate aldosterone secretion in the rat?

This study investigated the role of dopamine in the control of adrenal steroidogenesis. Adrenaline, noradrenaline and dopamine have been measured in plasma and in the adrenal zona glomerulosa and medulla of rats fed low, normal and high sodium diets and in zona glomerulosa tissue of rats with adrenal regeneration hypertension (ARH). Adrenal concentrations (means +/- SE) of adrenaline, noradrenaline and dopamine in rats fed a normal diet were 1471 +/- 335, 527 +/- 75 and 51 +/- 12 nmol/g in the medulla, and 66 +/- 17, 18 +/- 9 and 6 +/- 1 nmol/g in the zona glomerulosa. The dopamine content of the zona glomerulosa was greater than could be accounted for by simple contamination from the medullary catecholamines and is commensurate with that of tissue with dopaminergic innervation. Adrenal noradrenaline and adrenaline concentrations and plasma catecholamine and corticosterone concentrations were not affected by dietary sodium intake. Plasma aldosterone concentrations were greater than 3030.4, 339.8 +/- 41.5 and 55.2 +/- 11.0 pmol/l in rats fed low, normal and high sodium diets respectively. Five weeks after right adrenalectomy and nephrectomy and left adrenal enucleation, ARH rat systolic blood pressure had increased by 47 mmHg. In the regenerated gland, the concentrations of noradrenaline and adrenaline were negligible but dopamine was present in amounts similar to that of a normal adrenal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)