The multifunctionality of FGF-2 in the adrenal medulla

 Chromaffin cells of the adrenal medulla and their tumor counterparts, the pheochromocytoma (PC12) cells, are well-established model systems in neurobiology. The development of sympathoadrenal progenitor cells to chromaffin cells can be studied with regard to developmental signals which trigger the differentiation. With regard to potential treatments of neurological disorders like Parkinson’s disease chromaffin cell grafting can be used as one therapeutical approach. The beneficial effect of chromaffin cell grafts is possibly not only related to the release of dopamine but may also be linked to the release of growth factors. One of the growth factors that is synthesized by chromaffin and PC12 cells is basic fibroblast growth factor (FGF-2). The experimental data available so far, are in agreement with different functional roles of FGF-2. This article summarizes the putative physiological functions of FGF-2 in the adrenal medulla. Three differential functional roles of FGF-2 are discussed: (1) as a differentiation factor for sympathoadrenal progenitor cells; (2) as a target-derived neurotrophic factor for preganglionic sympathetic neurons which innervate adrenal medullary cells; (3) as an auto-/paracrine factor in the adrenal medulla. Accepted: 21 August 1996     

Sympathoadrenal response of postmenopausal women prior and during prolonged administration of estradiol

Objective: Cardiovascular disease seems to increase after the menopause and is thought to be reduced by estrogen replacement therapy. Among the many studies which have tried to define the multifactorial mechanisms of estrogens cardiovascular prevention, very few have focused on their possible modulation of adrenergic activity. In the present study we investigated whether prolonged estradiol replacement via transdermal patches is able to modulate cardiovascular and adrenergic responses to stimuli. Methods: Baseline and responses to a cold stimulus and to the upright position of catecholamines (epinephrine and norepinephrine), heart rate, systolic and diastolic blood pressure were investigated in 15 healthy volunteer postmenopausal women both prior to and after 2 months of treatment with patches rated to deliver 50 μg/day of estradiol. Results: Basal norepinephrine levels (P<0.005), as well as their integrated responses to the cold stimulus (P<0.02) were lower during estradiol. By contrast, responses of norepinephrine to the upright test, as well as basal and responses to stimuli of epinephrine and circulatory parameters were not different before and during estradiol. Conclusions: Estradiol replacement at low doses significantly decreases overall sympathetic output, both in basal conditions and under specific stimuli. These effects whether maintained or magnified in the long term may play a role in the prevention of the postmenopausal cardiovascular risk.     

Attenuated adrenergic responses to exercise in women with fibromyalgia – A controlled study

The pathogenesis of widespread pain and fibromyalgia (FM) is unknown. Altered responses from the hypothalamus–pituitary–adrenal axis, sympathetic nervous system and muscular system have been suggested as being of importance. The present study was undertaken to determine: (i) whether the sympathoadrenal response to repetitive isometric contractions until exhaustion is altered in patients with FM, and (ii) whether sympathoadrenal responses are associated with muscle fatigue and pain during exercise. Nineteen women with FM, and 19 healthy women matched for age, smoking and self‐reported physical activity, participated. Maximal voluntary contraction (MVC), repetitive isometric contractions (6s contraction and 4s resting phases) were performed with both quadriceps muscles at 30% of MVC until exhaustion. Muscle activity was recorded from the quadriceps muscles by surface electromyography (EMG). Plasma adrenalin (Adr), noradrenalin (NAdr) and cortisol were measured and perceived exertion and pain reported during exercise. Attenuated Adr responses (p<0.001) with normal plasma NAdr and cortisol (p>0.19) responses were found during exercise in the FM group compared with the control group. Significantly higher EMG amplitude (%EMG_max) during the contraction phases (p=0.001) was found in the FM than in the control group. Perceived exertion and pain responses to exercise were higher in the FM group than in the controls (p<0.001), without relationship to the sympathoadrenal responses. In conclusion; the exercise was perceived as being more painful and strenuous in the FM group. Muscle performance was altered with increased muscle activity during the exercise. Women with FM showed an attenuated Adr response to repetitive isometric exercise.     

Cells of the sympathoadrenal lineage: Biological properties as donor tissue for cell-replacement therapies for Parkinson's disease

Sympathoadrenal (SA) cell lineage encompasses neural crest derivatives such as sympathetic neurons, small intensely fluorescent (SIF) cells of sympathetic ganglia and adrenal medulla, and chromaffin cells of adrenal medulla and extra-adrenal paraganglia. SA autografts have been used for transplantation in Parkinson's disease (PD) for three reasons: (i) as autologous donor tissue avoids graft rejection and the need for immunosuppressant therapy, (ii) SA cells express dopaminotrophic factors such as GNDF and TGFβs, and (iii) although most of SA cells release noradrenaline, some of them are able to produce and release dopamine. Adrenal chromaffin cells were the first SA transplanted cells in both animal models of PD and PD patients. However, these autografts have met limited success because long-term cell survival is very poor, and this approach is no longer pursued clinically. Sympathetic neurons from the superior cervical ganglion have been also grafted in PD animal models and PD patients. Poor survival into brain parenchyma of grafted tissue is a serious disadvantage for its clinical application. However, cultured sympathetic cell grafts present a better survival rate, and they reduce the need for levodopa medication in PD patients by facilitating the conversion of exogenous levodopa. SA extra-adrenal chromaffin cells are located on paraganglia (i.e., the Zuckerkandl's organ), and have been used for grafting in a rodent model of PD. Preliminary results indicate that long-term survival of these cells is better than for other SA cells, exerting a more prolonged restorative neurotrophic action on denervated host striatum. The ability of SA extra-adrenal cells to respond to hypoxia, differently to SA sympathetic neurons or adrenal medulla cells, could explain their good survival rate after brain transplantation.     

The development of the chromaffin cell lineage from the neural crest

Chromaffin cells are neuroendocrine cells, which are highly specialized for the synthesis and release of multiple hormones. Like sympathetic neurons, which are essential, inter alia, for neural control of vascular tone, they are derivatives of the neural crest, a transient structure at the dorsal surface of the embryonic neural tube. Chromaffin cells and sympathetic neurons have many features in common, but are also distinct in several respects. This review provides a summary of similarities and differences regarding the development of chromaffin cells and sympathetic neurons, viewed from molecular and morphological perspectives. Two major, still not finally settled issues, are whether (1) the two related cell types arise from one common or two separate cell lineages of delaminating neural crest cells, (2) in the former case when does lineage segregation occur, and what are the molecules underlying their phenotypic diversification.     

Angiotensin converting enzyme-regulated,noncholinergic sympathoadrenal catecholamine release mediates the cardiovascular actions of human ‘new pressor protein’ related to coagulation beta-factor XIIa

BACKGROUND:

Human ‘new pressor protein’ (NPP), related to coagulation beta-factor XIIa (β-FXIIa), potently releases sympathoadrenal catecholamines in bioassay rats, with concurrent elevation of systolic and diastolic blood pressure (SBP/DBP) and heart rate (HR). Elevated plasma NPP/β-FXIIa levels in hypertensive anephric pediatric patients on hemodialysis associated with fluid status and blood pressure changes were previously reported, suggesting that NPP/β-FXIIa contributed to their hypertension.

OBJECTIVE:

To investigate the mechanism of action of NPP/β-FXIIa.

METHODS:

Hemodynamic and sympathoadrenal responses to NPP (20 µL plasma equivalent/rat) or coagulation β-FXIIa (300 ng/kg intravenously) were measured in rats treated with pentolinium (ganglion blockade [+GB]) and/or captopril (+CAP; angiotensin converting enzyme [ACE] inhibition).

RESULTS:

In controls not receiving GB or CAP (–GB–CAP), NPP/β-FXIIa raised plasma epinephrine (E) sixfold, SBP/DBP by 14/8 mmHg and HR by 15 beats/min. With blockade of the cholinergic pathway to the sympathoadrenal system (+GB), basal E, norepinephrine (NE), SBP, DBP and HR all dropped. However NPP/β-FXIIa remained capable of raising E 20-fold, NE fourfold, SBP/DBP by 27/11 mmHg and HR by 20 beats/min, suggesting that it acted through a ‘noncholinergic’ mechanism. With +CAP alone, NPP/β-FXIIa raised plasma E 18-fold, NE threefold, SBP/DBP by 29/8 mmHg and HR by 73 beats/min, implicating an ACE-regulated ‘peptidergic’ mechanism. Combining +GB with +CAP potentiated NPP/β-FXIIa actions further by raising E 50-fold, NE sevenfold, SBP/DBP by 55/20 mmHg and HR by 87 beats/min, strengthening the efficacy of this alternate pathway.

CONCLUSIONS:

The cardiovascular effects of NPP/β-FXIIa are considerably mediated by a noncholinergic (peptidergic) ACE-regulated mechanism for sympathoadrenal catecholamine release that is enhanced by +GB and/or +CAP. Under inflammatory procoagulant conditions, endogenously produced NPP/β-FXIIa may interfere with the antihypertensive effects of ACE inhibition therapy.     

Intraventricular alloxan impairs feeding to both central and systemic glucoprivation

Fourth ventricular alloxan injections impair the feeding response to systemically induced glucoprivation. However, the effect of alloxan on responses to centrally administered glucoprivic agents has not been assessed. Therefore, rats implanted with fourth ventricular cannulas were tested for feeding and glycemic responses to centrally administered 5-thioglucose (5TG, 120 micrograms/5 microliter) and subcutaneously administered 2-deoxy-D-glucose (2DG, 250 mg/kg, IP). Subsequently, alloxan (200 micrograms in 5 microliter), alloxan plus 3 M D-glucose, or the saline vehicle solution was injected into the fourth ventricle and the animals were then retested with systemic 2DG and intraventricular 5TG. Feeding responses to both centrally and systemically induced glucoprivic challenge were greatly impaired by alloxan treatment. Thus, feeding elicited by both centrally and systemically induced glucoprivation appears to be mediated by the same central neural substrate. The possibility that the alloxan-damaged cells are glucoreceptors is discussed. In contrast to glucoprivic feeding, the hyperglycemic response to glucoprivation was not impaired by alloxan. Therefore, the neural elements controlling this response may differ biochemically from those controlling feeding.     

Depolarization effects on the peptidergic phenotypes of chick sympathetic and adrenal cells

Depolarizing stimuli are among the factors known to influence the phenotypic plasticity of nerve cells. In order to determine the prevalence of the depolarization effects in terms of cell and neuropeptide phenotypes, we have analyzed the effect of potassium (K⁺)-induced depolarization on the avian sympathoadrenal system. The expression of three peptidergic phenotypes, somatostatin (SS), neuropeptide Y (NPY) and enkephalin (Enk) by two cell types, adrenal and sympathetic, was studied under different depolarizing regimens. Cells from the sympathetic paravertebral ganglion and adrenal gland of 10–11-day chick embryos were cultured and the peptide levels were measured by radioimmunoassays. Chronic depolarization causes differential effects on the peptidergic phenotypes increasing NPY and Enk but decreasing SS in both adrenal and sympathetic cultures. However, shorter exposures to depolarizing stimuli revealed diverse effects on NPY and Enk phenotypes and even between adrenal and sympathetic cells. Moreover, the maintenance of the effects after removal of the depolarizing stimuli showed additional differences among the phenotypes. Our results are not compatible with a previously established hypothesis stating that depolarization increases the synthesis of whichever neurotransmitters a neuron is already producing. They provide evidence indicating that the depolarization effect is much more complex than originally thought, and serve to initiate an in depth probe into the effect of depolarization on cellular plasticity.     

Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in obsessive–compulsive disorder patients

Salivary α-amylase (sAA) serves as a marker of sympathoadrenal medullary system (SAM) activity. Salivary AA has not been extensively studied in obsessive–compulsive disorder (OCD) patients. In the current study, 45 OCD patients and 75 healthy volunteers were assessed with the Yale–Brown Obsessive–Compulsive Scale (Y–BOCS), the Profile of Mood State (POMS), and the State-Trait Anxiety Inventory (STAI). Measures of heart rate variability (HRV), sAA, and salivary cortisol were also obtained following the application of electrical stimulation stress. The Y–BOCS and POMS Tension–Anxiety, Depression–Dejection, Anger–Hostility, Fatigue, and Confusion scores were significantly increased in patients with OCD compared with healthy controls. In contrast, Vigor scores were significantly decreased in patients with OCD relative to scores in healthy controls. There was no difference in HRV between the patients and the controls. Salivary AA levels in female and male OCD patients were significantly elevated relative to controls both before and after electrical stimulation. In contrast, there were no differences in salivary cortisol levels between OCD patients and controls. The elevated secretion of sAA before and after stimulation may suggest an increased responsiveness to novel and uncontrollable situations in patients with OCD. An increase in sAA might be a characteristic change of OCD.     

Clonidine as a drug for intravenous conscious sedation

 Clonidine, an α₂-adrenoceptor agonist, was introduced to clinical practice in the 1960s because of its antihypertensive effect. It has several beneficial actions during the perioperative period, particularly for medically compromised patients. The objective of this study was to evaluate the effects of clonidine as a drug for intravenous conscious sedation. We assessed the effects of intravenous clonidine on the hemodynamic and sympathoadrenergic responses to nociceptive stimuli and we evaluated its sedative and analgesic effects. Twenty-five volunteers aged between 23 and 25 years were included in this study. They received clonidine intravenously at 2 μg/kg. Constant-current, square-wave stimuli were delivered as nociceptive stimuli to the median nerve of the arm. We measured blood pressure, heart rate, cardiac output, and plasma concentrations of noradrenaline, adrenaline, and cortisol. The sedative and analgesic effects were measured by visual analogue scales. Changes in heart rate and blood pressure were not significantly different between the clonidine and control groups. Cardiac output tended to decrease after clonidine administration. Clonidine exerted its greatest sedative effect 30 min after injection. Noradrenaline concentration reached its nadir 15 min after clonidine administration. The time course of adrenaline concentrations was similar to that of noradrenaline. The plasma concentration of cortisol decreased in both groups. The most common adverse effect was dry mouth. In conclusion, intravenous clonidine, at a dose of 2 μg/kg, did not induce significant bradycardia, hypotension, or severe side effects in the healthy volunteer. It attenuated the adrenergic response to electrical stimulation. The results suggested that clonidine is a useful drug for intravenous sedation. Received: October 17, 2000 / Accepted: May 21, 2002