Activation Of Sympathoadrenal System Research Articles

W08-P-033 The thrombocyte dysfunction and the sympathoadrenal system activity in the dynamics by using therapy in patients with the metabolic syndrome

W08-P-033 The thrombocyte dysfunction and the sympathoadrenal system activity in the dynamics by using therapy in patients with the metabolic syndrome

Psychosocial Stress‐Induced Activation of Salivary Alpha‐Amylase: An Indicator of Sympathetic Activity?

Assessment of sympathoadrenal medullary system (SAM) activity is only possible to date via measurement of catecholamines in blood plasma or via electrophysiological methods. Both ways of measurement are restricted to endocrinological or psychophysiological laboratories, as both require either immediate freezing of blood samples or complex recording devices. Efforts have therefore been undertaken to find a method comparable to salivary cortisol measurements, in which noninvasive samples can be taken at any place and stored at room temperature for sufficient time before later analysis in the laboratory. Salivary alpha-amylase (sAA) is a candidate that may prove useful in this context. We show here that sAA activity is increased by acute psychosocial stress (Trier Social Stress Test) and that increases in sAA correlate with increases in norepinephrine. We further report that sAA exhibits a stable circadian pattern that mirrors that of salivary cortisol. In conclusion, the current data show that salivary alpha-amylase may serve as an easy-to-use index for SAM activity. However, some questions remain to be answered; for example, what impact does salivary flow rate exert on stress-induced sAA activity?

Salsolinol, an antagonist of prolactoliberine, induces an increase in plasma catecholamine levels in the rat

It has been recently observed that salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a putative endogenous prolactin-releasing factor is a potent inhibitor of stress-induced release of epinephrine and norepinephrine. The prolactin release caused by salsolinol was inhibited by 1-methyl-3,4-dihydroisoquinoline (1MeDIQ). Therefore, the aim of our present studies was to investigate the effect of 1MeDIQ on plasma catecholamine levels. It has been found that 1MeDIQ is able to induce a massive increase in plasma catecholamine levels. Pretreatment of the animals with a ganglionic blocker, chlorisondamine, could completely abolish the effect of 1MeDIQ on plasma norepinephrine, and plasma epinephrine levels were only significantly attenuated. Spinal cord transection between cervical and thoracic segments eliminated 1MeDIQ induced increase in epinephrine, whereas increase in plasma norepinephrine was not affected. Hence, this effect of 1MeDIQ on sympathoadrenal system activity is most probably mediated through the level of sympathetic ganglia or partially at more centrally located sites of the nervous system. These results suggest that elevation of plasma catecholamines is involved in the mechanism of action of 1MeDIQ inhibiting the biological effect of salsolinol.

Different effects of novel stressors on sympathoadrenal system activation in rats exposed to long-term immobilization.

Activation of the sympathoadrenal system, evaluated by plasma levels of epinephrine (E) and norepinephrine (NE) after exposure of rats to various stressors, is well documented. However, response of rats exposed long-term to a homotypic stressor and then exposed once to a heterotypic novel stressor is poorly understood. In the present study, we examined changes in plasma levels of catecholamines (CA) and corticosterone (COR) of rats after a single (2-h) or long-term repeated immobilization (41 times, 2 h daily) and in rats adapted to long-term immobilization exposed once to the novel stress of cold exposure or insulin or 2-deoxy-D-glucose (2DG) administration. Long-term immobilization produced a significant elevation of basal plasma COR but not NE and E levels. Long-term immobilized rats exposed to insulin or 2DG showed significant elevation of plasma CA and COR levels in comparison to the administration to control rats. Exposure of long-term immobilized and control rats to cold stress increased plasma NE and COR, whereas plasma E was not significantly changed. The exposure of long-term immobilized rats to a further single immobilization (2 h) increased plasma CA levels, but, in naive control rats, the single immobilization produced more pronounced increases. These data suggest that rats exposed to homotypic long-term immobilization are able to respond to heterotypic stressors by higher activation of the sympathoadrenal system as compared with the control, previously unstressed rats. Reduced plasma CA levels in long-term immobilized rats exposed to homotypic stressor are most probably due to an adaptation at the level of brain regulatory centers.

Effects of real and simulated microgravity on response of sympathoadrenal system to various stress stimuli.

Changes in plasma levels of epinephrine (EPI) and norepinephrine (NE) were investigated in humans exposed to physical exercise (WL), to psychic stressor (mental arithmetic test, MAT), and to oral glucose administration (oGTT) before and during a stay in microgravity (real space flight, SF) or in simulated microgravity (head-down bed rest, HDBR). A permanent cannula inserted into the cubital vein and a special appliance, Plasma-03, were used for blood collection, plasma separation, and freezing of samples during SF. Plasma EPI, NE, dihydroxyphenylglycol (DHPG), and dihydroxyphenylalanine (DOPA) levels were measured by the high-pressure liquid chromatography (HPLC) method. Basal plasma EPI, NE, DHPG, and DOPA levels were found within the range of control values during SF. Preflight WL produced high increase in plasma NE and moderate elevation of plasma EPI, DHPG, and DOPA levels. Exaggerated exercise induced increases in plasma NE, DHPG, EPI, and DOPA levels were demonstrated in real microgravity. A return to preflight responses of sympathoadrenal system was seen after the landing. Plasma EPI, NE, and DHPG responses to MAT were relatively small, but increased during SF. During the oGTT the plasma EPI levels were slightly reduced in microgravity. Similarly as in SF, WL in HDBR was followed by significantly exaggerated responses of plasma catecholamines. These results show that both somatic and psychological stressors are able to induce an increased activation of sympathoadrenal system during SF or simulated microgravity in HDBR.

Renal dysfunction after chronic blockade of nitric oxide synthesis.

The effects of the chronic inhibition of nitric oxide (NO) on renal hemodynamics and tubular function were studied in rats treated for 8 weeks with the NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg/day). In addition, the effect of L-NAME administration on vasoactive systems (renin-angiotensin system, aldosterone, catecholamines, endothelin, and thromboxane A(2)) was evaluated. Chronic inhibition of NO significantly elevated blood pressure, reduced glomerular filtration rate and renal blood flow, blunted the pressure-diuresis-natriuresis response, and increased protein urine excretion. All these changes were associated with blunted nitrite production in response to acetylcholine in glomeruli. No changes were observed in the plasma levels of either renin activity, aldosterone, or endothelin in L-NAME-treated rats. Similarly, no differences were observed in the urinary excretion of thromboxane B(2) between both group of animals. By contrast, plasma concentrations of both epinephrine and norepinephrine were elevated in rats treated with L-NAME. In summary, the results show that chronic blockade of NO produced not only alterations in renal function, but also renal damage, suggesting an important renoprotective role of NO. An activation of sympathoadrenal system could participate in these renal alterations.

Heart Remodeling in the Hereditary Hypertriglyceridemic Rat

The hereditary hypertriglyceridemic (hHTg) rat is characterized by insulin resistance, hypertension, and hypertriglyceridemia. Thus, we investigated whether (a) remodeling of the heart left ventricle (LV) is present under the given hypertensive situation and (b) whether this potential alteration could be influenced by an inhibition of the angiotensin converting enzyme (ACE) and/or by a blockade of nitric oxide production. Five groups of rats were investigated: control Wistar (C) rats, hHTg rats, hHTg rats given captopril (100 mg/kg/day) (hHTg + CAP) or NG-nitro-l-arginine methyl ester (L-NAME, 40 mg/kg/day) (hHTg + L-NAME), and hHTg rats given the combination of both drugs (hHTg + CAP + L-NAME) for 28 days. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography each week. After cervical dislocation, the relative weights of the left and right ventricles (LV/BW, RV/BW) were obtained, the LV nucleic acid concentrations were analyzed, and the fibrosis amount was quantified with aid of a semiquantitative histological technique. In the hHTg group, the increased SBP (141.7 +/- 4.4 vs. 117.2 +/- 3.1 mmHg in controls) was linked to hypertrophy of the LV (1.63 +/- 0.05 vs. 1.30 +/- 0.03 g/kg in controls) with only a minimum of fibrosis. DNA concentration in the LV was decreased (0.45 +/- 0.03 vs. 0.69 +/- 0.04 mg/g w.w. in controls) in the hHTg group. Captopril normalized SBP and decreased the LV/BW (1.44 +/- 0.04 g/kg). Chronic administration of L-NAME to the hHTg rats additionally enhanced (189.3 +/- 5.9 mmHg) the already raised SBP, stimulated fibrosis development, and increased DNA concentration (0.54 +/- 0.02 mg/g w.w.) in the LV compared to hHTg group, yet without additional weight increase of the LV. The combined treatment of the hHTg rats with CAP and L-NAME resulted in normal SBP and the development of LV hypertrophy, and fibrosis was substantially reduced. (a) The heart of hHTg rats carries signs of LV hypertrophy with minimal fibrosis. (b) Nevertheless, LV fibrosis was increased in the hHTg + L-NAME group. (c) Captopril normalized SBP and decreased the extent of LV hypertrophy in both the nontreated hHTg and the hHTg + L-NAME groups and (d) substantially reduced the development of LV fibrosis in the hHTg + L-NAME group. LVH in hHTg rats may be induced by sympathoadrenal system activation, circulating volume enlargement, and impairment of nitric oxide (NO) production rather than by activation of the renin-angiotensin-aldosterone system.

Intravenous cocaine increases plasma epinephrine and norepinephrine in humans

Cocaine has been shown to activate the sympathoadrenal system in both animal and human studies. Controlled human studies have found inconclusive results regarding whether acute cocaine treatment elevates plasma epinephrine and norepinephrine concentrations. The purpose of this study was to investigate whether commonly abused doses of cocaine increase plasma epinephrine and norepinephrine concentrations in humans, in a double-blind, placebo-controlled study. Five male cocaine users were given an intravenous injection of 0.46 mg/kg dose of cocaine or placebo, on two consecutive days. Plasma epinephrine and norepinephrine concentrations were significantly increased in response to cocaine injection compared to placebo. Peak plasma epinephrine and norepinephrine concentrations were reached 3 and 12 min after cocaine injection, respectively. While changes in epinephrine levels following cocaine were correlated with systolic blood pressure and heart rate changes, changes in plasma norepinephrine were correlated with diastolic blood pressure and heart rate changes following cocaine administration. These results suggest that plasma epinephrine and norepinephrine can be used as a measure for cocaine induced sympathoadrenal system activation.

Resting metabolic rate, fat-free mass and catecholamine excretion during weight loss in female obese patients

The reduction in resting metabolic rate (RMR) during weight loss exceeds that accounted for by changes in body composition by 15%, suggesting that factors other than fat-free mass (FFM) explain the metabolic adaptation during food restriction in obesity. Our study aimed to establish if changes in the sympathoadrenal system activity, as inferred from an integrated measure such as 24 h urinary excretion of catecholamines, may play a role in the RMR adaptation observed during dietary restriction in obese patients. Ninety-three obese female subjects consumed a low-energy diet (LED) (2930 kJ/d (700 kcal/d)) for a 3-week period. At the beginning and at the end of the study, 24 h urinary excretion of catecholamines, FFM and RMR were measured. The LED induced a significant reduction in body weight (-3.3 (SEM 0.4) kg; P < 0.01), FFM (-1.9 (SEM 0.7) kg; P < 0.01) and in the fat mass (-1.2 (SEM 0.5) kg; P < 0.01). Noradrenalin excretion (24 h) decreased during the LED from 264 (SEM 26) during a weight-maintenance period to 171 (SEM 19) nmol/24 h after consumption of the LED for 3 weeks (P < 0.001); mean 24 h adrenalin excretion did not change during the LED (22 (SEM 3) during the weight-maintenance period v. 21 (SEM 3) nmol/24 h after consumption of the LED for 3 weeks; NS). The LED induced a significant decrease in RMR (7300 (SEM 218) v. 6831 (SEM 138) kJ/24 h; P < 0.001). The only independent variable that significantly explained variations in RMR both before and after consumption of the LED for 3 weeks, was FFM (r2 0.79 and r2 0.80 respectively). Urinary noradrenalin excretion explained a further 4% of the variability in RMR, but only before the diet, so that a role of sympathoadrenal system on RMR seems to be present in obese patients in basal conditions but not at the end of the LED.

Activity of sympathoadrenal system and myelokaryocyte death during aging in AKR/JY mice.

Accelerated bone marrow cell death and activation of the sympathoadrenal system were observed during aging of highly leukemic 2-7-month-old AKR/JY mice compared to that in (CBA/CaLacxAKR/JY)F1 strain. Close correlation was revealed between activity of the sympathoadrenal system and necrotic and apoptotic forms of cell death. This can promote tumor process, because maximum changes in hemopoietic cells occur during advanced stage of the disease.

Adrenomedullary function and its regulation in obesity.

Sympathoadrenal system (SAS) represents a major contributor to body homeostasis, regulating blood pressure heart rate, energy balance and intermediary metabolism. Thus, it is not unexpected that in last decades a consistent literature has been focused on the possible role of sympathoadrenal system in the pathogenesis of human obesity. There are, however, many factors confounding comparison of sympathoadrenal system activity between lean and obese subjects. Among these, one should be aware that SAS should be functionally separated into sympathetic nervous system (SNS) and adrenal medulla (AM), and that each of these two systems can be activated independently from the other by distinct physiological stimuli; this phenomenon in fact underlies the discordant pattern of findings for adrenomedullary and sympathetic activity in human obesity. While, in fact, obese subjects often display an increased basal SNS activity, there are numerous reports of blunted AM function in obese. Recent evidence suggests that this reduced adrenaline secretion is an acquired feature of human obesity, a finding that fits in well with the hypothesis that hormonal milieu, particularly sex steroids and cortisol, plays a role in the determination of blunted AM activity. Catecholamines have been recently demonstrated to play a role also in the regulation of whole energy balance. Adrenaline in fact acutely reduces both leptin mRNA as well as circulating leptin in human obese subjects, suggesting that catecholamines may influence the cross-talk between energy stores and the centrally mediated modulation of food intake. In summary, the study of adrenomedullary function and of possible mechanisms of its disturbances in human obesity, appears of great interest, and surely deserves further investigations.

Placental Biogenic Amine Transporters: In Vivo Function, Regulation and Pathobiological Significance

The biogenic amine transporters are part of a large family of plasma membrane transporters. These carriers mediate the re-uptake of neurotransmitters from the synaptic cleft and plasma compartments. Re-uptake process is inhibited by drugs like cocaine, fluoxetine and tricyclic antidepressants. There are specific transporters for norepinephrine, epinephrine, dopamine and serotonin. The placenta expresses the norepinephrine and serotonin transporters, which is unusual as they are otherwise expressed predominantly in neuronal tissue. Fetal catecholamine clearance rate is higher than under any other physiological conditions and is mediated in large measure by the placental transporters. The high intrauterine catecholamine secretion and clearance rates are part of the unique fetal neuroendocrine milieu. They condition the fetus to a high capacity for catecholamine secretion in the early postnatal period when elevated sympathoadrenal system activity is vital for postnatal survival. Because of the prominent catecholamine clearance rate, the fetus is vulnerable to the adverse effects of re-uptake inhibitors. Understanding the mechanisms of expression and regulation of placental biogenic amine transporters is important to the pathobiology of fetal conditions associated with elevated catecholamine levels or intrauterine exposure to uptake inhibitors like cocaine.

Multi-Component Physiological Response Mediates Therapeutic Benefits of Bright Light in Winter Seasonal Affective Disorder

The set of investigations was designed to determine whether bright light improves both psychic and physiological functions in patients with winter seasonal affective disorder. The signs of such physiological effects of light as advance of circadian phase, increase in energy expenditure and activation of sympatho-adrenal system were examined in 61 female patients with winter depression and 36 age-matched controls before and after 1-week treatment (2,500 lux of white light for 2 h daily). Moreover, the indicators of the fourth physiological effect, intensification of non-rapid eye movement sleep, were studied in a subsample of 21 patients and 10 controls. Although the results provide little evidence for a strong association between different physiological responses to light, any of four responses appears to be positively associated with a remission of the depressive syndrome. The findings indicate that neither of physiological responses could play a dominant role, but several additive effects (e.g. responses of sleep-regulating, circadian, energy-regulating and sympatho-adrenal systems) could be necessary for the favorable therapeutic response to bright light. This result raises the possibility that physiology really participates in regulating the mood of winter depressives. However, any simple pathophysiological model of SAD seems not to be adequate.

LONG TERM ANGIOTENSIN CONVERTING ENZYME INHIBITOR TREATMENT INCREASES VASOCONSTRICTOR REQUIREMENT DURING NORMOTHERMIC CARDIOPULMONARY BYPASS

S74 Introduction: Cardiopulmonary bypass (CPB) results in sympathoadrenal and renin angiotensin system activation due to stress of haemodilution and nonpulsatile perfusion. Systemic vascular resistance (SVR) is lower during normothermic than in hypothermic CPB [1]. Long term use of angiotensin converting enzyme (ACE) inhibitors attenuates effects of catecholamines and thus should lower the SVR further during normothermic CPB, in the absence of hypothermic effects. Methods: After ethical committee approval and informed consent, 37 adult patients for elective cardiac surgery were studied prospectively. The study group of 14 patients were on chronic ACE inhibitor therapy and took the drug on the morning of surgery. The control group of 23 patients were not on any preoperative vasoactive drug therapy. All patients were premedicated with Morphine and Phenargan. GA was induced with Morphine/Diazepam/Thiopentone and maintained with Morphine/Vecuronium/Pancuronium/N (2) O/O2. Bubble oxygenator was used on CPB and perfusate was not cooled but temperature was allowed to drift. Haemodynamics and blood gas parameters were recorded at regular interval. MAP was maintained >50 mmHg with 1 mg increments of phenylepherine, if required, and its use recorded. Haemodynamic values at 10 min. after cross clamp were evaluated with pump flow of 3 L m-2 min-1. Results: The two groups had similar demography, preoperative haemodynamics, CPB haematocrit, oxygen delivery and consumption. Study group showed a significant decrease in MAP and SVR Index on CPB and a significant number required vasconstrictor use to maintain MAP > 50 mm Hg. (Table 1)Table 1Discussion: Long term ACE inhibitor therapy significantly altered haemodynamics during normothermic CPB with a significant number of patients requiring vasoconstrictor use to maintain acceptable perfusion pressures on CPB. In another study, haemodynamic control was not altered during hypothermic CPB despite attenuation of adrenergic response in this group of patients [2]. Extra care should be taken in cardiosurgical patients on ACE inhibitors and the safety of hypothermic CPB extended to this group of patients.

Stress-Induced Norepinephrine Release in the Hypothalamic Paraventricular Nucleus and Pituitary-Adrenocortical and Sympathoadrenal Activity: In Vivo Microdialysis Studies

The hypothalamic-pituitary-adrenocortical (HPA) axis and the autonomic nervous system are major effector systems that serve to maintain homeostasis during exposure to stressors. In the past decade, interest in neurochemical regulation and in pathways controlling activation of the HPA axis has focused on catecholamines, which are present in high concentrations in specific brain areas—specially in the hypothalamus. The work described in this review has concentrated on the application of in vivo microdialysis in rat brain regions such as the paraventricular nucleus (PVN) of the hypothalamus, the central nucleus of the amygdala (ACE) the bed nucleus of the stria terminalis (BNST), and the posterolateral hypothalamus in order to examine aspects of catecholaminergic function and relationships between altered catecholaminergic function and the HPA axis and sympathoadrenal system activation in stress. Exposure of animals to immobilization (IMMO) markedly and rapidly increases rates of synthesis, release, and metabolism of norepinephrine (NE) in all the brain areas mentioned above and supports previous suggestions that in the PVN NE stimulates release of corticotropin-releasing hormone (CRH). The role of NE in the ACE and the BNST and most other areas possessing noradrenergic innervation remains unclear. Studies involving lower brainstem hemisections show that noradrenergic terminals in the PVN are derived mainly from medullary catecholaminergic groups rather than from the locus ceruleus, which is the main source of NE in the brain. Moreover, the medullary catecholaminergic groups contribute substantially to IMMO-induced noradrenergic activation in the PVN. Data obtained from adrenalectomized rats, with or without glucocorticoid replacement, and from hypercortisolemic rats suggest that glucocorticoids feedback to inhibit CRH release in the PVN, via attenuation of noradrenergic activation. Results from rats exposed to different stressors have indicated substantial differences among stressors in eliciting PVN noradrenergic responses as well as of responses of the HPA, sympathoneural, and adrenomedullary systems. Finally, involvement of other areas that participate in the regulation of the HPA axis such as the ACE, the BNST, and the hippocampus and the importance of stress-induced changes in expression of immediate early genes such as c- fos are discussed.

New approaches to evaluate sympathoadrenal system activity in experiments on Earth and in space

In previous studies the activity of the sympathoadrenal system (SAS) in cosmonauts during space flights was evaluated by measuring plasma catecholamines (CA) levels and urinary CA and their metabolites concentrations. Plasma CA levels are accepted indicators of SAS activity, however, they are determined by the plasma clearances as well as the rates of CA release (spillover-SO) into the bloodstream. Nowadays methods are available which evaluate not only plasma levels of CA but also their release, spillover, uptake, reuptake, degradation and also CA synthesis in vivo measured by plasma levels of dihydroxyphenylalanine (DOPA). Plasma concentrations of DOPA, the CA noradrenaline (NE), adrenaline (ADR), and dopamine (DA), the deaminated catechol metabolites dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC), and the O-methylated metabolites methoxyhydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were measured during immobilization stress (IMO) in conscious rats. Radiotracer methods were used to measure NE SO. IMO markedly increased arterial NE levels but NE SO was less elevated bacause the NE clearance was slightly reduced in IMO rats. Simultaneous measurements of plasma CA and their metabolites provide another means to obtain information about SAS function. For instance, dissociation between changes of plasma DHPG and NE levels can indicate changes in neuronal reuptake of NE. We found marked parallel increases in plasma NE and DHPG levels during acute IMO; however after repeated IMO, plasma NE levels were increased but DHPG responses were less pronounced suggesting a reduced NE reuptake. DOPA, the CA precursor, circulates in plasma at a concentration higher than NE. During stress, increased sympathoneural outflow stimulates DOPA synthesis and release into the circulation supporting the view that changes in plasma DOPA levels during stress reflect in vivo changes in the rate of CA synthesis. We propose to measure the new plasma indicators of SAS activity in cosmonauts and/or in animals before, during and after space flights.

Sleep disorders and anxiety as symptom profiles of sympathoadrenal system hyperactivity in major depression

Recently, it has been reported that major depression is accompanied by an increased sympathoadrenal system (SAS) activity. In order to study the psychopathological correlates of SAS activity in depression, the authors measured the 24 h urinary excretion of catecholamines (CA), i.e., noradrenaline (NE), adrenaline (E), dopamine (DA) and the NE/E metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in 80 unipolar depressed subjects. The excretion of these indices of SAS activity have been studied in relation to the depressive items of the Structured Clinical Interview for DSM-III (SCID) and the Hamilton Depression Rating Scale (HDRS). There were significant positive correlations between the SCID item sleep disorders and the HDRS item middle insomia, on the one hand, and NE, E and DA excretion, on the other. The MHPG excretion in 24 h urine was significantly and negatively related to somatic anxiety and hypochondriasis. It is suggested that these intertwined relationships between increased CA turnover, sleep discontinuity and anxiety may reflect the occurence of a hyperarousal state in some major depressives that may be regarded as a coping response to various putative noxious stimuli.

Mania: Sympathoadrenal function and clinical state

We investigated sympathoadrenal and sympathetic nervous system activity, catecholamine disposition, and clinical state in 19 hospitalized manic patients. Severity of the core manic syndrome, anxiety, and hostility correlated with 24-hour urinary excretion of epinephrine relative to its metabolites, but only weakly with norepinephrine. Agitation, however, correlated most strongly and significantly with norepinephrine. Eight of the patients had mixed states: concurrent manic and depressive syndromes. There were no differences between mixed and pure manic patients with respect to catecholamine or metabolite excretion or precursor/product ratios, but mixed manic patients tended to have higher excretion of norepinephrine and had increased variance with respect to catecholamine measures. These data suggest that the function of the adrenal medulla, whether directly or indirectly, is important in the symptoms of both mixed and pure mania.

Sympathoadrenal system activity at birth: integration of postnatal adaptation.

In this article we have reviewed available information characterizing an increase in SAS activity at birth, in the so-called "catecholamine surge." Also, we have described the sources of circulating CA in the sheep fetus at birth and reviewed recent data on the significance of the CA surge at birth with regard to vital events of postnatal metabolic and cardiovascular adaptations. The results available to date suggest a unique, early neonatal dependence on circulating catecholamines for maintenance of physiologic homeostasis. The duration of this dependence and the ability of newborn animals or humans to sustain such high circulating catecholamine levels is not known. Further studies will clarify the relative importance of circulating and neuronally released CA in these adaptive events in various organ systems and test the applicability of a wide variety of adrenergic agents for therapeutic intervention.

Captopril: clinical pharmacology and benefit-to-risk ratio in hypertension and congestive heart failure.

Captopril, a competitive antagonist of angiotensin converting enzyme, has been marketed in the United States for the treatment of resistant hypertension. Despite extensive study, its exact mechanism of action remains unclear; decreased renin-angiotensin-aldosterone and sympathoadrenal system activity as well as increased bradykinin and prostaglandin E and F activity have been postulated. The drug decreases peripheral vascular resistance. Controlled trials in resistant hypertension of various etiologies and chronic congestive heart failure have demonstrated sustained effectiveness and therapeutic benefits. Side effects include skin rash, loss of taste, proteinuria, and leukopenia; higher doses and concomitant renal dysfunction appear to be predisposing factors. The benefit-to-risk ratio for captopril clearly justifies its use in resistant cases of hypertension and congestive heart failure, but further experience is needed to evaluate its use in milder forms of these diseases.