Biomedical subjects

R Stull

Publications and source records attributed to R Stull.

At least 19 recordsLinked to original sources

PubMed1989

Effects of a peripherally acting alpha 2-adrenoceptor antagonist (L-659,066) on hemodynamics and plasma levels of catechols in conscious rats.

L-659,066 is a new alpha 2-adrenoceptor antagonist which does not enter the central nervous system after systemic administration and therefore can be used to examine effects of blockade of peripheral alpha 2-receptors on hemodynamics and plasma levels of catechols. After i.v. administration to conscious rats, L-659,066 produced dose-related, small decreases in mean arterial pressure (MAP) and large increases in heart rate (HR), arterial plasma levels of norepinephrine (NE), and levels of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG). After administration of L-659,066, HR, but not MAP, was strongly correlated with NE levels (r = 0.93, P less than 0.001). Levels of DHPG and dihydroxyphenylalanine (DOPA) also were strongly correlated with NE levels (r = 098 and r = 0.71). After comparison with responses during hypotension induced by the vasodilator, nitroprusside, the results indicated that L-659,066 increases sympathetically mediated NE release and catecholamine turnover due to inhibition of presynaptic alpha 2-receptors as well as due to reflexive sympathetic activation related to blockade of alpha 2-receptors on arterial smooth muscle cells.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Patterns of plasma levels of catechols in neurogenic orthostatic hypotension.

Patients with neurogenic orthostatic hypotension can have deficits in sympathetic neural function at any of several levels of the sympathetic neuraxis. We determined whether patterns of plasma levels of dopa, norepinephrine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid would distinguish patients with orthostatic hypotension associated with multiple system atrophy, pure autonomic failure, or deficiency of dopamine-beta-hydroxylase. Plasma levels of catechols were normal in most patients with multiple system atrophy, consistent with relatively intact peripheral sympathetic neurons; in contrast, most patients with pure autonomic failure had decreased levels of all four catechols, consistent with degenerative loss of sympathetic nerve endings. Patients with deficiency of dopamine-beta-hydroxylase had increased levels of dopa and dihydroxyphenylacetic acid and markedly decreased levels of norepinephrine and dihydroxyphenylglycol, suggesting compensatory increases in sympathetic nerve activity in the absence of norepinephrine biosynthesis. Subgroups of patients with pure autonomic failure or multiple system atrophy had low levels of norepinephrine with normal levels of dopa, dihydroxyphenylglycol, and dihydroxyphenylacetic acid, consistent with normal catecholamine biosynthesis and decreased postganglionic sympathetic nerve traffic or decreased exocytotic release from sympathetic nerve endings. The results demonstrate the value of examining patterns of plasma levels of catechols to elucidate mechanisms of neurogenic orthostatic hypotension.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Plasma levels of catechols during reflexive changes in sympathetic nerve activity.

Relationships between changes in levels of catechols and directly recorded sympathetic nerve activity were examined using simultaneous measurements of renal sympathetic nerve activity and arterial and renal venous concentrations of norepinephrine (NE), dihydroxyphenylalanine (dopa), and dihyroxyphenylglycol (DHPG) during reflexive alterations in renal sympathetic nerve activity in anesthetized, adrenal-demedullated rats. Nitroprusside infusion increased renal sympathetic nerve activity by 90%, arterial levels of dopa by 96%, NE by 326%, and DHPG by 141%. Phenylephrine infusion increased arterial DHPG levels by 81% and decreased renal sympathetic nerve activity by 37% and NE levels by 26%; arterial dopa levels were unchanged. Ganglionic blockade by chlorisondamine (with concomitant phenylephrine infusion to maintain MAP) decreased renal sympathetic nerve activity by 65% and NE concentrations by 37%; arterial dopa concentrations were unchanged, and DHPG concentrations increased by 60%. Proportionate responses of arterial levels of NE were strongly related to proportionate changes in renal sympathetic nerve activity. Clearance of DHPG from arterial plasma was prolonged by phenylephrine-induced hypertension and by nitroprusside-induced hypotension. The results suggest that changes in arterial NE levels reflect changes in sympathetic activity; changes in dopa levels reflect changes in catecholamine biosynthesis; and changes in DHPG levels depend on reuptake of released NE and on hemodynamic factors affecting DHPG clearance.

Animals↗

PubMed1989

Plasma levels of catechols after fasting in intact or adrenal-demedullated rats.

We compared arterial plasma levels of catechols after a 24-h fast with levels after 24 h of an ad libitum diet in conscious rats. Epinephrine concentrations were significantly decreased after the fast; levels of norepinephrine, dopa, and dihydroxyphenylglycol were unaffected. Adrenal-demedullated rats had decreased levels of dopa regardless of dietary intake and lower levels of norepinephrine after fasting than during the usual diet. The results indicate that fasting decreases adrenomedullary activity in intact animals, with little or no effect on sympathoneural activity.

Adrenal Medulla↗

PubMed1989

Skin color, aging, and plasma L-dopa levels.

Although plasma levels of L-dopa are derived substantially from catecholamine-synthesizing tissues, melanocytes--which produce L-dopa as part of the melanin synthetic cascade--also may be a source of circulating L-dopa. We compared plasma L-dopa levels in albino subjects and in Caucasian and Black normal volunteers and patients with essential hypertension. DOPA levels were similar among the subject groups. Among Caucasian normal volunteers, L-dopa levels were negatively correlated with subject age (r = -0.30, P less than 0.05), whereas norepinephrine levels tended to increase with subject age (r = 0.25, 0.05 less than P less than 0.10), so that the L-dopa:norepinephrine ratio was highly negatively correlated with subject age (r = -0.50, P less than 0.01). Skin pigmentation does not contribute importantly to plasma L-dopa levels in humans. In contrast with levels of norepinephrine, L-dopa levels appear to decrease during normal aging.

Adolescent↗

PubMed1989

Urinary excretion of dihydroxyphenylalanine and dopamine during alterations of dietary salt intake in humans.

1. Urinary excretion of dopamine (DA) increases during dietary salt loading. The majority of urinary DA is derived from circulating dihydroxyphenylalanine (dopa). Whether the increase in urinary DA excretion during salt loading results from increased efficiency of uptake of dopa by proximal tubular cells of the kidney, facilitation of intracellular conversion of dopa to DA, or increased delivery of dopa to tubular uptake sites, has been unknown. 2. In 10 inpatient normal volunteers on a constant diet, daily excretion of dopa and DA was assessed during normal sodium intake (109 mmol/day) for 1 week, low sodium intake (9 mmol/day) for 1 week and high sodium intake (249 mmol/day) for 1 week. 3. Urinary DA excretion exceeded urinary dopa excretion by about tenfold, and the excretion of both DA and dopa increased by about twofold between the low and high salt diets, with similar proportionate changes. Plasma dopa was unchanged by dietary salt manipulation. 4. The results indicate that increases in urinary DA excretion during dietary salt loading can be accounted for by increased delivery of dopa to sites of uptake by proximal tubular cells. Since dopa is released into the bloodstream by sympathetic nerve endings and by the brain, and since interference with decarboxylation of dopa attenuates natriuretic responses, dopa may function indirectly as a neurohormone involved in homoeostatic regulation of sodium balance.

Adult↗

PubMed1989

Implications of plasma levels of catechols in the evaluation of sympathoadrenomedullary function.

This report summarizes new techniques for examining aspects of sympathoadrenomedullary function. Tracer pharmacokinetic methods are more accurate than measurements of antecubital venous norepinephrine (NE) in assessing sympathoneural responsiveness. During mental challenge (playing a video game), patients with essential hypertension had significantly larger increments of NE spillover into arterial blood than did normotensive control subjects, whereas responses of antecubital venous and even arterial NE did not differ significantly between the groups. The rate of neuronal reuptake of endogenous NE can be measured in vivo using plasma levels of NE and of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG). Regional production of dihydroxyphenylalanine (DOPA) may reflect catecholamine biosynthesis, and DOPA may be an indirectly acting natriuretic neurohormone. Positron emission tomography after injection of positron-emitting fluorodopamine may allow in vivo, noninvasive assessments of regional sympathetic function.

Catechols↗

PubMed1989

Cardiac norepinephrine kinetics in hypertrophic cardiomyopathy.

We examined the uptake and release of norepinephrine in the cardiac circulation and other regional vascular beds in 11 patients with hypertrophic cardiomyopathy (HCM) and in 10 control subjects during simultaneous infusion of tracer-labeled norepinephrine and isoproterenol. Cardiac neuronal uptake of norepinephrine was assessed by comparing regional removal of tracer-labeled norepinephrine with that of tracer-labeled isoproterenol (which is not a substrate for neuronal uptake) and by the relation between production of dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, and regional spillover of norepinephrine. Cardiac extraction of norepinephrine averaged 59 +/- 17% in the patients with HCM, significantly less than in the control subjects (79 +/- 13%, p less than 0.05), whereas cardiac extraction of isoproterenol was similar in the two groups (13 +/- 23% versus 13 +/- 14%), indicating that neuronal uptake of norepinephrine was decreased in the patients with HCM. The cardiac arteriovenous difference in norepinephrine was significantly larger in the patients with HCM than in the control subjects (73 +/- 77 versus 13 +/- 50 pg/ml, p less than 0.05), as was the product of the arteriovenous difference in norepinephrine and coronary blood flow (7.3 +/- 7.3 versus 0.8 +/- 3.0 ng/min, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Plasma dihydroxyphenylalanine and total body and regional noradrenergic activity in humans.

Dihydroxyphenylalanine (DOPA) is the immediate product of the rate-limiting step in catecholamine biosynthesis, hydroxylation of tyrosine. This study examined whether plasma concentrations of DOPA are related to tyrosine hydroxylase activity. Plasma concentrations of DOPA, norepinephrine, and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in arterial blood and blood draining the heart, brain, and forearm of 21 patients undergoing cardiac catheterization. Rates of entry of norepinephrine into arterial plasma and plasma draining the heart were estimated using infusions of radioactive norepinephrine. Arterial plasma DOPA correlated positively with arterial plasma DHPG (r = 0.63), MHPG (r = 0.47), norepinephrine (r = 0.67), and the rate of entry of norepinephrine into arterial plasma (r = 0.62). There were significant arteriovenous increments in plasma DOPA: 28% across the heart, 18% across the brain, and 32% across the forearm. Arteriovenous increments in plasma DOPA across the brain correlated positively with increments in plasma DHPG (r = 0.83), but not with increments in norepinephrine or MHPG. In the arm, where MHPG was the major metabolite, arteriovenous increments in DOPA correlated positively with increments in MHPG (r = 0.52) and with the combined increments in MHPG, DHPG, and norepinephrine (r = 0.60). In the heart, where DHPG was the major metabolite, arteriovenous increments in DOPA correlated positively with increments in DHPG (r = 0.72) and the combined increments in DHPG, MHPG, and norepinephrine (r = 0.62). The rate at which norepinephrine entered the great cardiac venous plasma from tissues of the heart correlated positively with the rate at which DOPA overflowed from the heart into the systemic circulation (r = 0.56). The relationships between plasma DOPA and norepinephrine metabolism and the rates of norepinephrine entry into plasma support the view that plasma DOPA reflects tyrosine hydroxylase activity.

Arteries↗

PubMed1989

Epinephrine suppresses stress-induced increases in plasma immunoreactive beta-endorphin in humans.

The present study evaluated the hypothesis that increased plasma levels of epinephrine (EPI) stimulate immunoreactive beta-endorphin (i beta END) secretion in humans experiencing a mild stress. The stressor consisted of intraoral injections of a local anesthetic solution (with or without EPI) just before the surgical extraction of impacted third molars in 26 awake unsedated patients. The EPI group experienced a 30-fold increase in plasma EPI levels by 2 min after injection; these concentrations were physiologically active, as evidenced by increased pulse rate and systolic blood pressure. However, compared to a no EPI control group the EPI group had a significantly reduced i beta END response to the stressor, as evaluated by comparison of plasma levels at individual time points, maximal increases in plasma i beta END levels, and areas under the time-response curve. Whereas there was no association between plasma levels of EPI and i beta END in the EPI group (r = 0.119; P = NS), EPI and i beta END levels were strongly related in the no EPI group (r = 0.82; P less than 0.001). These results do not support the hypothesis of a stimulatory effect for EPI on i beta END release and, instead, suggest that an inhibitory relationship may exist in humans experiencing stress. The association between EPI and i beta END responses observed in the control group during this form of stress appears to be due to activation of a common central neural element.

Anesthetics, Local↗

PubMed1989

Tumor necrosis factor: immune endocrine interaction.

Tumor necrosis factor (TNF), a peptide produced by macrophages in response to endotoxin, has been implicated as a mediator of septic shock. This study examined the effects of injections of recombinant (r) human TNF on circulating levels of metabolic substrates and hormones in conscious, unrestrained rats and the effects of TNF on cortisol secretion from human adrenocortical cells in vitro. Sublethal doses of rTNF--doses that did not produce hemodynamic changes in previous work--produced rapid (1 hour), significant increases in blood levels of glucose, lactate, and triglycerides and decreases in plasma levels of branched chain amino acids. Plasma levels of glucagon, corticosterone, ACTH, norepinephrine, and dihydroxyphenylglycol were also increased significantly. Incubation of adrenocortical cells with either 0.15 or 1.5 micrograms of rTNF increased cortisol secretion to the same extent as did 10(-10) mol/L ACTH. Administration of TNF produces a variety of metabolic and neuroendocrine effects including stimulation of anterior pituitary, adrenal cortical, and pancreatic secretion, and sympathoneural activation. These changes, and the in vitro results, are consistent with the view that immune cells can interact with endocrine cells through release of TNF.

Adrenocorticotropic Hormone↗

PubMed1988

Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine.

STUDY OBJECTIVE: To determine the efficacy and toxicity of combination chemotherapy in patients with advanced, malignant pheochromocytoma. DESIGN: Nonrandomized, single-arm trial. SETTING: Governmental medical referral center. PATIENTS: Fourteen patients with malignant pheochromocytoma confirmed by histologic tests. All patients had metastatic disease and elevated urinary catecholamine secretion. INTERVENTIONS: After optimization of antihypertensive therapy, patients received cyclophosphamide, 750 mg/m2 body surface area on day 1; vincristine, 1.4 mg/m2 on day 1, and dacarbazine, 600 mg/m2 on days 1 and 2, every 21 days. MEASUREMENTS AND MAIN RESULTS: Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine produced a complete and partial response rate of 57% (median duration, 21 months; range, 7 to more than 34). Complete and partial biochemical responses were seen in 79% of patients (median duration, more than 22 months; range, 6 to more than 35). All responding patients had objective improvement in performance status and blood pressure. Toxicity included expected hematologic, neurologic, and gastrointestinal effects of chemotherapy without serious sequelae. There were four minor hypotensive episodes and one minor hypertensive episode. CONCLUSIONS: Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine is effective for advanced malignant pheochromocytoma. Urinary catecholamines are useful to ascertain biochemical response to therapy.

Adolescent↗

PubMed1988

Sympathoadrenomedullary hyper-responsiveness to yohimbine in juvenile spontaneously hypertensive rats.

We examined responses of arterial plasma levels of the sympathetic neurotransmitter, norepinephrine (NE), of the adrenomedullary hormone, epinephrine (E), and of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG), after intravenous administration of the alpha-2 adrenoceptor antagonist, yohimbine, in conscious, freely-moving juvenile (4-week old) or mature (12-week old) rats with spontaneous hypertension (SHRs) and their normotensive Wistar-Kyoto (WKY) controls. Mature SHRs and WKY rats had similar levels of plasma catechols at rest, whereas juvenile SHRs had significantly higher levels of NE (400 +/- 109 (SD) vs 233 +/- 62 pg/ml), E (371 +/- 168 vs 148 +/- 67 pg/ml), and DHPG (800 +/- 147 vs 589 +/- 54 pg/ml). After yohimbine, average responses of NE in the juvenile SHRs were more than 5 times, of E more than 7 times, and of DHPG more than 11 times those of the juvenile WKY rats. The responses of plasma catechols to yohimbine were not excessive in mature 12-week old SHRs. The results demonstrate increased sympathoadrenomedullary activity at rest and markedly enhanced sympathoadrenomedullary responsiveness to yohimbine in juvenile but not mature SHRs and are consistent with the hypothesis that early in the development of hypertension in this laboratory animal model there is an abnormal dependence on central neural alpha-2 adrenoceptors as part of an incompletely successful compensatory mechanism for limiting sympathetic outflow.

Adrenal Medulla↗

PubMed1988

Derivation of urinary dopamine from plasma dopa.

1. We estimated the extent to which circulating dopa (3,4-dihydroxyphenylalanine) is the source of urinary dopamine (DA; 3,4-dihydroxyphenethylamine). Tritiated dopa ([3H]dopa) was infused for 90 min into the left renal artery of seven anaesthetized foxhounds, and levels of labelled and unlabelled dopa and DA were measured in the ureteral urine and in the femoral arterial and left renal venous plasma. 2. Only a small percentage of [3H]dopa delivered to the kidneys was excreted as [3H]DA (0.59% from the left kidney, 0.68% from the right); however, the arterial concentration of endogenous dopa (1220 pg/ml) and the renal plasma flows (144 and 141 ml/min by p-aminohippurate clearances) were such that all of the urinary excretion of endogenous DA (about 1 ng/min from each kidney) could be accounted for by uptake and decarboxylation of circulating endogenous dopa. 3. Plasma dopa is the main source of urinary DA.

Animals↗

PubMed1988

Steady-state dopamine clearance in critically ill infants and children.

Little is known about dopamine pharmacokinetics in pediatric patients, especially in critically ill infants and children who often receive treatment with dopamine. Arterial plasma concentrations of dopamine were measured in 27 patients who were hemodynamically stable and received dopamine for at least one hour. The dopamine levels were measured using liquid chromatography with electrochemical detection. Dopamine clearance averaged 96.2 +/- 55.4 ml/kg.min in 13 patients in the neonatal ICU, and 58.8 +/- 51 ml/kg.min in 14 patients in the pediatric ICU. Six patients had renal (BUN greater than 25 mg/dl, or creatinine greater than 1.2 mg/dl) or hepatic (liver enzymes greater than 3 times normal) dysfunction. Dopamine clearance in these patients (25.1 +/- 17.2 ml/kg.min) was substantially lower than in the other patients (p less than .01). Neither postnatal nor gestational age correlated with dopamine clearance. Substantial interindividual variation was observed in steady-state dopamine clearance in critically ill infants and children, and plasma dopamine could not be predicted accurately from the dopamine infusion rate. Because of the more than three-fold prolongation of dopamine clearances in patients with hepatic or renal dysfunction, these patients may be more likely to suffer toxic effects of dopamine at the usual drug infusion rates.

Adolescent↗

PubMed1988

Levels of catechols in epileptogenic and nonepileptogenic regions of the human brain.

Recent reports about tyrosine hydroxylase and alpha 1-adrenoceptors in epileptic foci have suggested increased regional catecholaminergic activity, which may serve a compensatory, inhibitory role. We measured levels of catechols, including the precursor 3,4-dihydroxyphenylalanine (DOPA) and the catecholamines dopamine (DA) and norepinephrine (NE), in surgically removed foci identified by electrocorticography and in nonepileptogenic sites from 23 patients with intractable temporal lobe epilepsy. The following values (mean +/- 1 SD) were obtained: DOPA = 142 +/- 60 ng/g of protein in the focus vs. 115 +/- 39 ng/g in the nonfocus (p less than 0.01); DA = 168 +/- 85 vs. 106 +/- 54 ng/g (p less than 0.001); and NE = 267 +/- 117 vs. 181 +/- 80 ng/g (p less than 0.001). The results are consistent with increased catecholaminergic activity in epileptic foci.

Adult↗

PubMed1988

In vivo measurement of neuronal uptake of norepinephrine in the human heart.

Neuronal uptake (Uptake-1) of the sympathetic neurotransmitter norepinephrine from the circulation in the human heart was assessed in vivo with three techniques. 1) Cardiac removal of intravenously infused tracer-labeled norepinephrine was measured before and after Uptake-1 blockade with desipramine; 2) the difference between the fractional extraction of radioactive norepinephrine and of radioactive isoproterenol, which is not a substrate for neuronal uptake, was used to estimate the removal of norepinephrine by Uptake-1 in the heart compared with other vascular beds (arm, leg, brain, and lungs); and 3) regional arteriovenous differences in radioactive and endogenous dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, were compared in these beds. In untreated patients, cardiac removal of radioactive norepinephrine averaged 79%, whereas in desipramine-treated patients, cardiac removal of radioactive norepinephrine averaged 19%, a value similar to that of isoproterenol in untreated patients (14%), confirming that in the heart the non-neuronal removals of isoproterenol and norepinephrine were similar. In the heart, 69% of delivered norepinephrine was estimated to be removed by Uptake-1, a much higher percentage than that in the arm (14%), leg (7%), brain (10%), and lungs (4%). The cardiac arteriovenous increment in endogenous DHPG (137%) far exceeded that of the other beds (49%, 26%, 39%, and -19%, respectively), and radioactive DHPG in the great cardiac vein exceeded arterial levels by 113%, whereas in the other beds, arterial radioactive DHPG exceeded venous levels. The results indicate that the human heart is exceptionally dependent on neuronal uptake for in vivo removal of circulating norepinephrine.

Desipramine↗

PubMed1988

Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans.

We examined plasma levels of the sympathetic neurotransmitter norepinephrine (NE) and its deaminated metabolite dihydroxyphenylglycol (DHPG) during supine rest in healthy human subjects and in sympathectomized patients, during physiological (tilt) or pharmacological (yohimbine, clonidine) manipulations known to affect sympathetically mediated NE release, during blockade of neuronal uptake of NE (uptake-1) using desipramine, and during intravenous infusion of NE. Healthy subjects had a mean arteriovenous increment in plasma DHPG in the arm (10%, P less than 0.05), whereas sympathectomized patients had a mean arteriovenous decrement in DHPG in the affected limb (mean decrease 21%, P less than 0.05 compared with healthy subjects). Tilt and yohimbine, which stimulate, and clonidine, which inhibits, release of endogenous NE, produced highly correlated changes in plasma NE and DHPG (r = 0.94). Pretreatment with desipramine abolished DHPG responses to yohimbine while enhancing NE responses. To attain a given increase in plasma DHPG, about a tenfold larger increment in arterial NE was required during NE infusion than during release of endogenous NE. When plasma NE was markedly suppressed after administration of clonidine, plasma DHPG decreased to a plateau level of 700-800 pg/ml. The results indicate that (i) plasma DHPG in humans is derived mainly from sympathetic nerves; (ii) increments in plasma DHPG during stimulation of NE release result from uptake of NE into sympathetic nerve endings and subsequent intraneuronal conversion to DHPG; (iii) plasma DHPG under basal conditions probably is determined mainly by net leakage of NE into the axonal cytoplasm from storage vesicles; and (iv) increments in NE concentrations at neuronal uptake sites can be estimated by simultaneous measurements of DHPG and NE during NE infusion and NE release. Measurement of NE and DHPG provides unique clinical information about sympathetic function.

Administration, Oral↗