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Biomedical subjects

G M Tyce

Publications and source records attributed to G M Tyce.

At least 55 records · Page 3Linked to original sources

Catecholamine metabolic pathways and exercise training. Plasma and urine catecholamines, metabolic enzymes, and chromogranin-A.

BACKGROUND: Because acute exercise increases systemic catecholamines, we sought to determine whether exercise training would alter daily or exercise-related catecholamine release and inactivation. METHODS AND RESULTS: In 24-hour urine collections, catecholamines and metabolites provided indexes of overall oxidative deamination, sulfation, and O-methylation. Plasma catecholamines, the sulfoconjugates of each, and chromogranin-A were determined at rest and during exercise in 10 well-trained male subjects and nine minimally trained male subjects (maximal oxygen uptake 55.2 and 42.5 ml/kg/min, respectively), and levels of activities of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAO-B), and thermolabile phenolsulfotransferase (TL-PST) were also determined. Plasma-free catecholamines showed minimal differences between the two groups at submaximal exercise (4 minutes) but large differences at maximal exercise, reflecting the different exercise levels attained. Inactivation of plasma catecholamines by sulfation across rest and exercise tended to be greater in the well-trained group, with small increases in both plasma sulfoconjugated dopamine and sulfoconjugated norepinephrine. In the well-trained group, urinary metabolites demonstrated trends toward increased dopamine release (p less than 0.07) and small increases in the daily release of epinephrine and its sulfoconjugated metabolites. Indexes of deamination, sulfoconjugation, and O-methylation, with the exception of a reduced deamination of dopamine and the activities of COMT, MAO-B, and TL-PST were not different in the two groups. CONCLUSIONS: Despite considerable differences in the exercise activities per week between well-trained and minimally trained individuals, there were minimal differences in the release and metabolism of catecholamines at rest or during exercise.

Adult↗

Renal denervation enhances the phosphaturic effect of parathyroid hormone.

Hyperventilation/hypocapnia increases renal phosphate reabsorption and decreases the phosphaturic effect of parathyroid hormone (PTH). Recent studies suggest that the blunted phosphaturic effect of PTH in hyperventilated/hypocapnic rats may be mediated by the stimulation of renal beta-adrenoreceptors. In the present study, no differences in plasma catecholamine levels were detected in hyperventilated/hypocapnic rats as compared to hyperventilated/normocapnic rats. Therefore, studies were performed to determine the role of the renal nerves in the blunted phosphaturic effect of PTH in hyperventilated/hypocapnic rats. In clearance experiments in acutely thyroparathyroidectomized male Sprague-Dawley rats, PTH infusion increased the fractional excretion of phosphate (FEPi) in the denervated left kidney of hyperventilated/hypocapnic rats (n = 8), from 2.4 +/- 1.1 to 18.6 +/- 2.7%, as compared to 1.0 +/- 0.3 to 9.1 +/- 2.1% in the contralateral innervated kidney. Denervation of the left kidney in hyperventilated/normocapnic rats (n = 8) also significantly increased the phosphaturic response to PTH by 2.5 +/- 1.5 to 26.9 +/- 3.0% as compared to 0.9 +/- 0.5 to 18.6 +/- 2.6% in the contralateral innervated kidney. The phosphaturic responses to PTH were similar when comparing the denervated kidney in hyperventilated/hypocapnic rats with the innervated kidney of hyperventilated/normocapnic rats. Thus, renal denervation enhanced the phosphaturic effect of PTH in both hyperventilated/hypocapnic and hyperventilated/normocapnic rats. These results suggest that renal nerves play a role in the modulation of the phosphaturic effect of PTH.

Animals↗

MAO and L-dopa treatment of Parkinson's disease.

The aim of this study was to determine whether there were differences in the oxidative deamination of dopamine in patients with Parkinson's disease who demonstrated a long-duration response (LDR) to treatment with dopa and carbidopa and in patients who demonstrated only a short-duration response (SDR) to the drugs. The patients who demonstrated LDR had received dopa and carbidopa for a shorter time (3.4y) than had the SDR patients (9.5y). The concentrations of dopamine and 3-methoxytyramine and their deaminated metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were measured in 24-h urine samples collected from patients in both groups. The ratios of homovanillic acid to 3-methoxytyramine and dopamine were greater in SDR than in LDR patients suggesting increased oxidative deamination of dopamine in this group. Increased oxidative deamination could be caused by an increase in MAO activity as Parkinson's disease progresses or by the treatment with L-dopa.

Aged↗

The secretion of catecholamines, chromogranin A and neuropeptide Y from the adrenal medulla of the cat via the adrenolumbar vein and thoracic duct: different anatomic routes based on size.

Secretion of the adrenal medulla was stimulated in nine cats by insulin-induced hypoglycemia. Levels of catecholamines (mol. wt 153-183), neuropeptide Y (mol. wt 4254) and chromogranin A (mol. wt 48,000) were measured in concurrently collected samples of adrenolumbar venous blood and thoracic duct lymph for up to 4 h following insulin administration. Insulin-induced hypoglycemia elicited an increase in the secretion of catecholamines, which reached peak levels in the adrenolumbar venous plasma at 1.5-2 h and in the lymph at 2.5 h. Although catecholamines were the most numerous measured molecules in the lymph, levels of norepinephrine and epinephrine were 75-250-fold less than those found in the adrenolumbar venous plasma. Neuropeptide Y in the adrenolumbar venous plasma reached peak levels between 1 and 1.5 h; at this time approximately 20% of the peak venous amount was detected in the lymph. Chromogranin A was found in approximately equal amounts in both plasma and lymph; the peak level in the plasma occurred at 1.5-2 h, while that in the lymph was reached at 2-3 h. We suggest that the size of a molecule influences the route it takes following exocytosis from the chromaffin vesicle. Smaller molecules such as catecholamines may pass directly into the circulation, while larger molecules such as chromogranin A may be temporarily sequestered in the interstitial space before passing into the lymph, and hence into the circulation.

Adrenal Medulla↗

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.

Activities of Daily Living↗

ANP inhibits Na(+)-H+ antiport in proximal tubular brush border membrane: role of dopamine.

Infusion of ANP to rats results in an inhibition of Na(+)-H+ antiport and Na(+)-Pi symport in brush border membrane vesicles (BBMV) prepared from kidneys of these animals (J Clin Invest 75:1983). iIn the present study we investigated the intrarenal mechanism by which infused ANP elicits these changes in proximal tubular transport systems. As in rats, infusion of ANP to rabbits resulted in a diuresis, natriuresis, and increase in GFR; however, unlike in rats, the fractional excretion of phosphate (Pi) was not changed. In BBMV prepared from cortices of ANP-infused rabbits, the rate of Na(+)-H+ antiport was decreased (delta -27%), but Na+ gradient-dependent uptakes of Pi and L-proline were not different from controls. Incubation of rabbit cortical tubule suspension in vitro with ANP 10(-7) M alone had no inhibitory effect on Na(+)-H+ antiport in BBMV prepared from these tubules, whereas incubation with other hormonal agents, 1 U/ml PTH (delta 61%) or with dopamine (DA) 10(-4) M (delta -34%), did inhibit the rate of Na(+)-H+ antiport in BBMV from the same pool of tubules. However, when tubules were incubated in the presence of (10(-5) M) DA, the addition of 10(-7) M ANP did cause a significant (delta -21%) decrease in Na(+)-H+ antiport activity in BBMV. In contrast, ANP did not show similar inhibitory effect in the presence of submaximal inhibitory doses of PTH. To explore whether ANP may act on proximal tubules in vivo indirectly, via mediation of DA, we evaluated the effect of ANP on some parameters of catecholamine system in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effects of intrathecal morphine, clonidine, and midazolam on the somato-sympathoadrenal reflex response in halothane-anesthetized cats.

Modulatory effects of spinal opioid, alpha-adrenergic, and benzodiazepine receptors on the somato-sympathoadrenal reflex response, evoked by supramaximal bilateral sciatic nerve stimulation (50 times minimal motor threshold) were evaluated in halothane-anesthetized cats. Group 1 (n = 8) served as a control; group 2 (n = 7) received intrathecally (it) the opioid receptor agonist morphine (500 micrograms); group 3 (n = 7), the alpha 2-adrenergic agonist clonidine (200 micrograms it); and group 4 (n = 7), the benzodiazepine receptor agonist midazolam (1 mg it). Plasma samples were collected from the adrenal vein at baseline, after it drug administration, and during sciatic nerve stimulation for the measurement of norepinephrine, epinephrine, and dopamine. In control cats (group 1), sciatic nerve stimulation evoked significant increases in adrenal vein catecholamine plasma levels, blood pressure, and heart rate. Morphine (group 2) did not have any effect on spontaneous hemodynamics and adrenal secretion. During stimulation (group 2), there were no significant increases in adrenal norepinephrine and epinephrine concentrations, whereas dopamine concentrations, blood pressure, and heart rate rose significantly. Clonidine (group 3) led to a decrease in heart rate and adrenal vein norepinephrine and epinephrine concentrations at baseline. During sciatic nerve stimulation in this group (3), significantly lower concentrations were observed in adrenal vein catecholamines compared with control, whereas the hemodynamic response was not suppressed. Midazolam suppressed baseline and stimulation-evoked adrenal vein catecholamine concentrations, but hemodynamics were not significantly affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

Precursors and metabolites of norepinephrine in sympathetic ganglia of the dog.

3,4-Dihydroxyphenylalanine, dopamine, epinephrine, 3,4-dihydroxyphenylglycol, and 3,4-dihydroxyphenylacetic acid as well as norepinephrine were measured in dog lumbar sympathetic ganglia. The responses of these compounds to several classes of stimuli were investigated using an isolated time-resolved superfusion system. Nonselective (i.e., amphetamine and high K+) and receptor-mediated selective (oxotremorine) stimuli were used to evoke releases. The overflows of all compounds were measured by HPLC with electrochemical detection. The efficiency of each stimulus was estimated by normalizing the amount of evoked release to the total neurotransmitter pool when the stimulus was applied; i.e., fractional release was calculated. Overflows of all compounds except 3,4-dihydroxyphenylalanine were enhanced by a 10-min 100 microM amphetamine stimulus, and each of the catecholamine pools (dopamine, norepinephrine, and epinephrine) was affected to the same degree. By contrast, the 3,4-dihydroxyphenylalanine and dopamine pools were more readily releasable than the norepinephrine pool with a 10-min 80 mM K+ stimulus, and these releases were Ca2+ dependent. Epinephrine was released in preference to norepinephrine by a 10-min 1 mM oxotremorine stimulus. The data suggest the existence of at least three types of neurons in dog lumbar ganglia and are consistent with previous histological observations.

Animals↗

Origin and metabolism of serotonin.

A brief review is given of the distribution of serotonin in tissues. The enzymatic steps in the biosynthesis and metabolism of serotonin are described, and factors involved in the regulation of the in vivo metabolism of serotonin are reviewed.

Animals↗

Measurement of lumbar CSF levels of met-enkephalin, encrypted met-enkephalin, and neuropeptide Y in normal patients and in patients with Parkinson's disease before and after autologous transplantation of adrenal medulla into the caudate nucleus.

The levels in lumbar cerebrospinal fluid (CSF) of neuropeptide Y (NPY), methionine enkephalin (Enk), and Enk contained in amino- and carboxy-terminus extended forms (X-Enk) were examined in nine control patients undergoing elective surgical procedures and in eight patients with advanced Parkinson's disease, before and after the autologous transplantation of adrenal medullary fragments into the right caudate nucleus. The levels of CSF Enk and X-Enk before surgery in patients with Parkinson's disease were significantly less than those observed in control patients (Enk, 166 +/- 38 vs 264 +/- 44 pg/ml; X-Enk, 794 +/- 416 vs 1497 +/- 153 pg/ml). NPY levels did not differ (221 +/- 25 vs 193 +/- 23 pg/ml). After surgery, lumbar CSF samples were taken at 6 weeks, 12 weeks, 6 months, and 9 months. Placement of adrenal medullary fragments into the striatum had no effect on the levels of NPY or Enk at any time point. The levels of X-Enk were significantly enhanced only at 12 weeks (1138 +/- 140 pg/ml) but were at presurgical levels again by 6 months. These data suggest that the transplant was not functionally contributing to the CSF levels of these peptides.

Adrenal Medulla↗

Decreased catecholamine content in parkinsonian adrenal medullae.

Autopsy specimens of adrenal medullae from parkinsonian and nonparkinsonian patients were analyzed for free catecholamines by high-performance liquid chromatography with electrochemical detection. The total free catecholamine content (nanomoles free catecholamine per milligram protein) was significantly lower in the parkinsonian patients than in the control population when the values were corrected for age and time from death to organ harvest. It is not established whether this decreased catecholamine content in the adrenals of parkinsonian patients is a concomitant of the disease itself or whether it is secondary to drug therapies used to treat the symptoms of Parkinson's disease.

Adrenal Medulla↗

Decreased adrenal medullary catecholamines in adrenal transplanted parkinsonian patients compared to nephrectomy patients.

Adrenal medullary catecholamines were measured in tissue samples from eight patients who underwent autologous transplantation of the adrenal medulla to the caudate nucleus as a treatment for Parkinson's disease. These adrenal catecholamine levels were compared to a group of patients of similar age who underwent unilateral nephrectomy for renal cell carcinoma. The levels of each catecholamine, expressed as nanomoles per milligram wet weight tissue, were significantly lower (P less than or equal to 0.005) in the parkinsonian patients than in the nephrectomy patients. These observations support data reported previously from autopsy specimens and suggest that the adrenal medullae of parkinsonian patients may be a compromised source of dopamine-producing tissue; this may limit its effectiveness in eliciting maximum clinical improvement following transplantation.

Adrenal Medulla↗

Cerebrospinal fluid indices of blood-brain barrier permeability following adrenal-brain transplantation in patients with Parkinson's disease.

Cerebrospinal fluid (CSF) and serum or plasma concentrations of albumin, IgG and carbidopa were measured before and after adrenal-brain transplantation in patients with Parkinson's disease to indirectly assess blood-brain barrier (BBB) integrity. Previous studies in animals have suggested that the BBB is compromised by cerebral transplantation. CSF and plasma levodopa was also measured to permit comparison with the carbidopa values, recognizing that levodopa readily crosses the BBB via facilitated transport. Our patients underwent adrenal-brain transplantation in accordance with the method of Madrazo et al. (I. Madrazo, R. Drucker-Colin, V. Diaz, J. Martinez-Mata, C. Torres, and J. J. Becerril, 1987, N. Engl. J. Med. 316: 831-834) in which adrenal medullary pieces are implanted in the head of the caudate nucleus, in contact with the cerebrospinal fluid. All patients were maintained on oral carbidopa/levodopa therapy after surgery. CSF albumin/serum albumin and CSF IgG/serum IgG ratios were initially elevated above the preoperative baseline 6 weeks after the surgery; however, these values returned to the preoperative baseline by 6 months following the operation in six of seven patients. This suggested that the BBB was sufficiently intact to exclude these larger protein molecules from the CSF of these six patients. On the other hand, exogenously administered carbidopa, which normally is largely excluded from the cerebrospinal fluid by the BBB, was modestly increased in the CSF in four of the five patients in which it was measured. This suggests that the transplant BBB might be partially patent to small molecules for at least 6 months after the surgery. Whether increased passage of carbidopa into CSF and perhaps the transplant is of clinical significance has yet to be determined. Median CSF levodopa did not increase after surgery, probably because a limited defect in the BBB would be likely to be overshadowed by the effects of facilitated transport. CT scans performed following intravenous iothalamate meglumine contrast failed to reveal enhancement (dye leakage) near the transplantation site; however, artifact from the metal surgical clips used in the Madrazo procedure prevented good visualization of the area.

Adrenal Medulla↗

Dihydroxyphenylglycol as an index of neuronal uptake in dog saphenous vein.

Dihydroxyphenylglycol (DOPEG), the metabolite of norepinephrine (NE) that arises intraneuronally, was measured together with NE in superfusates collected before, during, and after nerve stimulation and in extracts of dog saphenous vein after superfusion and electrical stimulation (ES). Different concentrations of NE in the synaptic clefts were achieved by treating tissues with corticosterone, corticosterone and yohimbine, corticosterone and cocaine, or by omitting drugs from the superfusate. NE and DOPEG were quantitated by liquid chromatography with electrochemical detection. The time courses of NE overflow and DOPEG efflux into superfusate were followed. The amounts of DOPEG in superfusates under basal conditions were two to four times higher than the amounts of NE and progressively increased during ES except in tissues with neuronal uptake inhibited. NE overflow reached a steady state within the first 6 min of ES. Increased NE concentrations in synaptic clefts resulted in increased DOPEG production except where neuronal uptake was inhibited. The increased DOPEG production during ES appears to reflect the increased rate of neuronal uptake, which results in more NE being available for intraneuronal metabolism. No evidence was found that newly formed DOPEG was delayed in leaving the tissue. Thus the increase in DOPEG production that occurs during ES may be useful as an index of neuronal uptake of NE in dog saphenous vein.

Animals↗

Plasma dopa and feeding.

Dopa is a normal constituent of plasma in man and experimental animals. Dopa concentrations in plasma have been used to reflect the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. However, it is not known to what extent plasma dopa is affected by feeding, since several foods contain dopa or tyrosine, the immediate precursor of dopa. In this study dopa and its major metabolites (3-O-methyldopa and free and conjugated catecholamines) were measured in plasma of dogs during 5 hr after feeding. Plasma dopa did not change significantly after feeding. This finding increases the value of plasma dopa as an index of tyrosine hydroxylase activity. Plasma norepinephrine decreased, and conjugated dopamine increased, after feeding; the other analytes did not change significantly.

Animal Feed↗

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)

Blood Specimen Collection↗

Adrenal vein catecholamines and met-enkephalin during staged hemorrhage and naltrexone administration in cats.

Concurrent levels of catecholamines and met-enkephalin in adrenal vein, femoral vein, and femoral artery were measured under baseline conditions and during staged hemorrhage in halothane (1 MAC)-anesthetized cats (Group II, n = 8) and compared to a nonbled control group (Group I, n = 5). In Group III (n = 14) an i.v. bolus of naltrexone in a range of different dosages (0.01 mg/kg to 10 mg/kg) followed by a continuous infusion was administered prior to induction of hemorrhage. In Group II, the loss of 25% of estimated total blood volume led to a significant decrease (-40 +/- 11 mmHg) in mean arterial blood pressure (MABP) without evoking adrenal stimulation. Hemorrhage to 50% of total blood volume was without a further significant fall in MABP, but led to a significant increase in catecholamine and met-enkephalin levels in the adrenal vein. Naltrexone-treated cats in Group III were not different from Group II in regard to hemodynamic and sympathoadrenal response during staged hemorrhage. We conclude that prophylactic administration of naltrexone has no effect on hemodynamic parameters during staged hemorrhage and that the concurrent adrenal secretion of catecholamines and met-enkephalin is not modulated by actions on opiate receptors in the halothane-anesthetized cat.

Adrenal Glands↗