Fibroblast growth factor receptor 1 is a key regulator of early adipogenic events in human preadipocytes.

Cell number is an important determinant of adipose tissue mass, and the coordinated proliferation and differentiation of preadipocytes into mature lipid-laden adipocytes underpins the increased adipose tissue mass associated with obesity. Despite this, the molecular cues governing such adipose tissue expansion are poorly understood. We previously reported that fibroblast growth factor-1 (FGF-1) promotes both proliferation and differentiation of human preadipocytes and that the major adipogenic effect of FGF-1 occurs during proliferation, priming the cells for adipose conversion. In the current study, we examined whether this effect was linked to the mitogenic action of FGF-1 by investigating the mitogenic and adipogenic potential of other growth factors, platelet-derived growth factor (PDGF; AA and BB) and vascular endothelial growth factor. Although PDGF-AA and PDGF-BB showed comparable mitogenic potential to FGF-1, only FGF-1 treatment resulted in priming and subsequent differentiation. Pharmacological inhibition of FGF receptor (FGFR) tyrosine kinase activity, using the FGFR-specific inhibitors PD-173074 and SU-5402, revealed an obligate requirement for FGFR activity in these processes. A combination of biochemical and genetic approaches revealed an important role for FGFR1. Knock down of FGFR1 expression by small-interfering RNA reduced FGF-1-stimulated signaling events, proliferation, and priming. Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity.

Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism.

Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months' duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G-->T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls (chi2 = 5.31, P = 0.07). Immunoreactive-CBG (IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1+/-1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4+/-1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8+/-1.7 microg/mL (n = 21). Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3+/-1.4 (n = 34) vs. Ser/Ala: 14.0+/-0.7 (n = 66) vs. Ala/Ala: 15.4+/-1.0 (n = 23). Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.

Greater replication and differentiation of preadipocytes in inherited corticosteroid-binding globulin deficiency.

Glucocorticoids are pivotal for adipose tissue development. Rodent studies suggest that corticosteroid-binding globulin (CBG) modulates glucocorticoid action in adipose tissue. In humans, both genetic CBG deficiency and suppressed CBG concentrations in hyperinsulinemic states are associated with obesity. We hypothesized that CBG deficiency in humans modulates the response of human preadipocytes to glucocorticoids, predisposing them to obesity. We compared normal preadipocytes with subcultured preadipocytes from an individual with the first ever described complete deficiency of CBG due to a homozygous null mutation. CBG-negative preadipocytes proliferated more rapidly and showed greater peroxisome proliferator-activated receptor-gamma-mediated differentiation than normal preadipocytes. CBG was not expressed in normal human preadipocytes. Glucocorticoid receptor number and binding characteristics and 11beta-hydroxysteroid dehydrogenase activity were similar for CBG-negative and normal preadipocytes. We propose that the increased proliferation and enhanced differentiation of CBG-negative preadipocytes may promote adipose tissue deposition and explain the obesity seen in individuals with genetic CBG deficiency. Furthermore, these observations may be relevant to obesity occurring with suppressed CBG concentrations associated with hyperinsulinemia.

Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension.

Corticosteroid-binding globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the corticosteroid-binding globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue -12 of the procorticosteroid-binding globulin molecule (c.121G-->A). Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without corticosteroid-binding globulin mutations. Plasma immunoreactive corticosteroid-binding globulin was undetectable in null homozygotes, and mean corticosteroid-binding globulin levels were reduced by approximately 50% at 18.7 +/- 1.3 microg/ml (reference range, 30-52 microg/ml) in null heterozygotes. Morning total plasma cortisol levels were less than 1.8 microg/dl in homozygotes and were positively correlated to the plasma corticosteroid-binding globulin level in heterozygotes. Homozygotes and heterozygote null mutation subjects had a high prevalence of hypotension and fatigue. Among 19 adults with the null mutation, the systolic blood pressure z-score was 12.1 +/- 3.5; 11 of 19 subjects (54%) had a systolic blood pressure below the third percentile. The mean diastolic blood pressure z-score was 18.1 +/- 3.4; 8 of 19 subjects (42%) had a diastolic blood pressure z-score below 10. Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects (86%) and in 2 of 3 null homozygotes. Five cases met the Centers for Disease Control criteria for chronic fatigue syndrome. Fatigue questionnaires revealed scores of 25.1 +/- 2.5 in 18 adults with the mutation vs. 4.2 +/- 1.5 in 23 healthy controls (P < 0.0001). Compound heterozygosity for both mutations resulted in plasma cortisol levels comparable to those in null homozygotes. Abnormal corticosteroid-binding globulin concentrations or binding affinity may lead to the misdiagnosis of isolated ACTH deficiency. The mechanism of the association between fatigue and relative hypotension is not established by these studies. As idiopathic fatigue disorders are associated with relatively low plasma cortisol, abnormalities of corticosteroid-binding globulin may be pathogenic.

Treatment of familial hyperaldosteronism type I: only partial suppression of adrenocorticotropin required to correct hypertension.

In familial hyperaldosteronism type I, inheritance of a hybrid 11beta-hydroxylase/aldosterone synthase gene leads to ACTH-regulated overproduction of aldosterone (causing hypertension) and of "hybrid" steroids, 18-hydroxy- and 18-oxo-cortisol. To determine whether complete suppression of the hybrid gene is necessary to normalize blood pressure, we sought evidence of persisting expression in eight patients who were rendered normotensive for 1.3-4.5 yr by glucocorticoid treatment. At the time of the study, six patients were receiving dexamethasone (0.125-0.25 mg/day) and two patients were taking prednisolone (2.5 or 5 mg/day). Urinary 18-oxo-cortisol levels during treatment demonstrated close correlation with mean "day curve" (blood collected every 2 h for 24 h) cortisol (r = 0.74), consistent with regulation by ACTH. Although urinary 18-oxo-cortisol levels were lower during than before treatment (mean 12.6 +/- 2.4 SEM vs. 35.0 +/- 5.6 nmol/mmol creatinine; P < 0.01), they remained above normal (0.8-5.2 nmol/mmol creatinine) in all eight patients. Although mean upright plasma potassium levels during treatment were higher, aldosterone levels lower, PRA levels higher, and aldosterone to PRA ratios lower than before treatment, PRA levels were uncorrected (< 13 pmol/L x min) and aldosterone to PRA ratios were uncorrected (>65) during treatment in four patients. For each of the eight patients, day curve aldosterone levels during treatment correlated more tightly with cortisol (mean r for the eight patients, 0.87 +/- 0.05 SEM) than with PRA (mean r = 0.36 +/- 0.10 SEM). Hence, control of hypertension by glucocorticoid treatment was associated, in all patients, with only partial suppression of ACTH-regulated hybrid steroid and aldosterone production. Normalization of urinary hybrid steroid levels and abolition of ACTH-regulated aldosterone production is not a requisite for hypertension control and, if used as a treatment goal, may unnecessarily increase the risk of Cushingoid side effects.

Severity of hypertension in familial hyperaldosteronism type I: relationship to gender and degree of biochemical disturbance.

In familial hyperaldosteronism type I (FH-I), inheritance of a hybrid 11beta-hydroxylase/aldosterone synthase gene causes ACTH-regulated aldosterone overproduction. In an attempt to understand the marked variability in hypertension severity in FH-I, we compared clinical and biochemical characteristics of 9 affected individuals with mild hypertension (normotensive or onset of hypertension after 15 yr, blood pressure never >160/100 mm Hg, < or = 1 medication required to control hypertension, no history of stroke, age >18 yr when studied) with those of 17 subjects with severe hypertension (onset before 15 yr, or systolic blood pressure >180 mm Hg or diastolic blood pressure >120 mm Hg at least once, or > or = 2 medications, or history of stroke). Severe hypertension was more frequent in males (11 of 13 males vs. 6 of 13 females; P < 0.05). All 4 subjects still normotensive after age 18 yr were females. Of 10 other affected, deceased individuals (7 males and 3 females) from a single family, all six who died before 60 yr of age (4 by stroke) were males. Biochemical studies were conducted in 6 mild and 16 severe subjects. The 2 groups were similar in terms of urinary sodium excretion. Mild subjects tended, although not significantly, to have lower urinary 18-oxo-cortisol (mean +/- SD, 27.4 +/- 9.0 vs. 35.2 +/- 12.9 nmol/mmol creatinine x day), higher plasma potassium (4.0 +/- 0.3 vs. 3.6 +/- 0.4 mmol/L), and lower recumbent (0800 h after overnight recumbency) plasma aldosterone levels (498 +/- 279 vs. 744 +/- 290 pmol/L). Upright (midmorning after 2-3 h of upright posture) plasma aldosterone levels were similar (mild, 485 +/- 150; severe, 474 +/- 188 pmol/L). In 1 normotensive female, upright PRA was much higher, and the upright aldosterone/PRA ratio was much lower than that in the other subjects. The remaining mild subjects had similar upright PRA levels (mild, 2.8 +/- 1.4; severe, 3.7 +/- 3.2 pmol/ L x min) and aldosterone/PRA ratios (mild, 199.5 +/- 133.4; severe, 200.6 +/- 150.9) as severe subjects. During angiotensin II (AII) infusion studies (n = 6 mild and 10 severe), performed during recumbency, aldosterone levels were lower in the mild group both basally (404 +/- 144 vs. 843 +/- 498 pmol/L; P < 0.05) and after 60 min AII (2 ng/kg x min; 261 +/- 130 vs. 520 +/- 330 pmol/L; P < 0.05). Aldosterone was unresponsive (rose by <50%) to AII in all subjects. Day curve studies (blood collected every 2 h for 24 h; n = 2 mild and 7 severe) demonstrated abnormal regulation of aldosterone by ACTH rather than by AII in both groups. In conclusion, in this series of patients with FH-I, males had more severe hypertension, and the degree of hybrid gene-induced aldosterone overproduction may have contributed to the severity of hypertension.

Biochemical evidence of aldosterone overproduction and abnormal regulation in normotensive individuals with familial hyperaldosteronism type I.

We examined in detail biochemical characteristics of 10 normotensive individuals (6 females; age range, 11-43 yr) with glucocorticoid-suppressible hyperaldosteronism (familial hyperaldosteronism type I) in an attempt to understand the development of hypertension in this disorder. All were normokalemic (median plasma potassium, 3.7 +/- 0.4 mmol/L SD), and upright plasma aldosterone levels (478 +/- 333 pmol/L) were within the normal range (140-1110 pmol/L) in nine subjects. However, upright PRA levels (3.3 +/- 30.5 pmol/L x min) were suppressed (<13 pmol/L x min), and the aldosterone to PRA ratio (169.0 +/- 308.3) was elevated (>65) in all but one subject. All subjects had elevated 24-h urinary levels of 18-oxo-cortisol (34.3 +/- 11.2 nmol/mmol creatinine; normal range, 0.8-6.5 nmol/mmol creatinine). Plasma aldosterone failed to rise by at least 50% during 2 h of upright posture in five of seven subjects, or during a 1-h infusion of angiotensin II (2 ng/kg x min) in each of six subjects so studied. Serial, second-hourly (day-curve) aldosterone levels correlated tightly with cortisol (r = 0.79-0.97, P < 0.01 to 0.001), but not with PRA (r = 0.13-0.40, not significant) levels in each of six subjects, and plasma aldosterone suppressed to less than 110 pmol/L during 4 days of dexamethasone administration (0.5 mg 6 hourly) in each of two studied, consistent with ACTH-regulated aldosterone production. In conclusion, biochemical evidence of excessive, abnormally regulated aldosterone production is present not only in hypertensive individuals with familial hyperaldosteronism type I, but also in those who are normotensive. The absence of hypertension in such individuals, therefore, cannot be attributed to lack of biochemical expression of the hybrid gene.

Diastolic ventricular interaction in chronic heart failure: relation to heart rate variability and neurohumoral status.

It is likely that abnormal baroreflex control mechanisms are at least partially responsible for autonomic dysfunction in chronic heart failure. We recently demonstrated that diastolic ventricular interaction is associated with impaired baroreflex control of vascular resistance in heart failure. We reasoned that by constraining left ventricular filling, such interaction would decrease baroreflex activity and, thereby, increase sympathetic and decrease parasympathetic outflow. We hypothesized, therefore, that diastolic ventricular interaction in chronic heart failure patients would be associated with autonomic dysfunction. We used radionuclide ventriculography to measure changes in left and right ventricular end-diastolic volumes during acute volume unloading achieved by -30 mm Hg lower-body negative pressure in 30 patients with chronic heart failure. An increase in left ventricular volume in association with a reduction in right ventricular volume indicates diastolic ventricular interaction (a larger increase indicating a greater degree of interaction). We also measured heart rate variability (n = 23) and resting venous plasma norepinephrine (n = 24), epinephrine (n = 24), and atrial natriuretic peptide (ANP) (n = 14). During lower-body negative pressure, while right ventricular volume decreased in all patients (P < 0.001), left ventricular end-diastolic volume increased (from 152 +/- 25 to 157 +/- 36 ml/m2, P = 0.01). The change in left ventricular volume was positively correlated with resting plasma norepinephrine (P < 0.01) and ANP (P < 0.005), and negatively correlated with the standard deviation of normal to normal R-R intervals (P < 0.005), the root-mean-square of differences between successive normal to normal R-R intervals (P < 0.05), total power (P < 0.01), low-frequency power (P < 0.01), and high-frequency power (P < 0.05). Diastolic ventricular interaction in patients with chronic heart failure is associated with sympathetic nervous system activation evidenced by increased plasma norepinephrine and reduced heart rate variability.

Hormonal, immunological, and hematological responses to intensified training in elite swimmers.

The purpose of this study was to compare the responses of selected hormonal, immunological, and hematological variables in athletes showing symptoms of overreaching with these variables in well-trained athletes during intensified training. Training volume was progressively increased over 4 wk in 24 elite swimmers (8 male, 16 female); symptoms of overreaching were identified in eight swimmers based on decrements in swim performance, persistent high ratings of fatigue, and comments in log books indicating poor adaptation to the increased training. Urinary excretion of norepinephrine was significantly lower (P < 0.05, post hoc analysis) in overreached (OR) compared with well-trained (WT) swimmers throughout the 4 wk. There were no significant differences between OR and WT swimmers for other variables including: concentrations of plasma norepinephrine, cortisol, and testosterone, and the testosterone/cortisol ratio; peripheral blood leukocyte and differential counts, neutrophil/lymphocyte ratio, and CD4/CD8 cell ratio; serum ferritin and blood hemoglobin concentrations, erythrocyte number, hematocrit, and mean red cell volume (MCV). MCV increased significantly over the 4 wk in both groups, suggesting increased red blood cell turnover. These data show that, of the 16 hormonal, immunological, and hematological variables measured, urinary norepinephrine excretion appears to be the only one to distinguish OR from WT swimmers during short-term intensified training. Low urinary norepinephrine excretion was observed 2 to 4 wk before the appearance of symptoms of overreaching, suggesting the possibility that neuroendocrine changes may precede, and possibly contribute to, development of the overreaching/overtraining syndromes.

Production of 18-oxo-cortisol in subtypes of primary aldosteronism.

1. In familial hyperaldosteronism type I (FH-I), expression of an adrenocorticotropic hormone (ACTH)-dependent hybrid 11 beta-hydroxylase/aldosterone synthase gene causes excessive 'hybrid steroid' (18-hydroxy- and 18-oxo-cortisol) production. In order to study the mechanism of elevated 'hybrid steroid' levels in angiotensin-unresponsive (AII-U) aldosterone-producing adenoma (APA), we compared responses of 24 h urinary 18-oxo-cortisol, aldosterone and cortisol to dexamethasone (0.5 mg q6h for 4 days) in 11 FH-I patients, 11 patients with AII-U APA, 11 patients with AII-responsive (AII-R) APA and 10 patients with bilateral adrenal hyperplasia (BAH). 2. Consistent, marked suppression (by at least 60%) of 18-oxo-cortisol levels by dexamethasone was seen in all groups except AII-U APA. Aldosterone levels were consistently suppressed to undetectable levels only in FH-I. Cortisol levels were suppressed to undetectable levels in all patients except two with AII-U APA. 3. Production of both 18-oxo-cortisol and aldosterone (and occasionally cortisol) in AII-U APA appears relatively ACTH-independent, consistent with a common mechanism involved in the formation of these two steroids from their respective precursors, which differs from that in FH-I. 4. In AII-R APA and BAH, 18-oxo-cortisol production appears markedly ACTH-dependent, but aldosterone production is not.

Clinical, biochemical and genetic approaches to the detection of familial hyperaldosteronism type I.

AIM: Since detection of familial hyperaldosteronism type I (glucocorticoid-suppressible hyperaldosteronism) allows specific treatment of hypertension with dexamethasone, we compared clinical, biochemical and genetic approaches to detection. PATIENTS AND METHODS: We studied 22 affected patients, 21 from a single, large family and an additional adopted male. Plasma aldosterone, plasma renin activity and urinary 18-oxo-cortisol were measured by radioimmunoassay. The hybrid gene was demonstrated using either Southern blotting or a long polymerase chain reaction technique. RESULTS: Thirteen out of 22 (59%) patients with familial hyperaldosteronism type I, but only four out of 12 (33%) under 20 years of age, were hypertensive. Plasma potassium and aldosterone were each normal in 20 out of 22 (91%), and unhelpful in diagnosis. Plasma renin activity, the aldosterone: plasma renin activity ratio and 18-oxo-cortisol were more sensitive, being abnormal in 20 out of 22 (91%), 19 out of 22 (86%) and 20 out of 20 (100%) patients, respectively. Aldosterone was unresponsive (<50% rise) to 2 h of upright posture following overnight recumbency in 15 out of 15 (100%) patients studied, and to angiotensin II infusion (2 ng/kg per min for 1 h) in 14 out of 14 patients (100%). Whereas all the abovementioned abnormalities are also characteristic of angiotensin II-unresponsive aldosterone-producing adenoma, marked aldosterone suppression following 4 days of dexamethasone (0.5 mg every 6 h) was sensitive and specific for familial hyperaldosteronism type I (n = 11). The hybrid gene was detectable in peripheral blood leucocyte DNA in all 22 affected patients by Southern blotting, and by a faster, long polymerase chain reaction method developed in our laboratory, both methods requiring only a single blood collection. CONCLUSIONS: Should studies in other families confirm its universal applicability, long polymerase chain reaction should prove to be the most practical means of detecting familial hyperaldosteronism type I in laboratories equipped with this technique.

Hybrid gene or hybrid steroids in the detection and screening for familial hyperaldosteronism type I.

1. Early diagnosis of Familial Hyperaldosteronism Type I (FH-I, glucocorticoid-suppressible hyperaldosteronism) in asymptomatic, affected individuals is essential if death from stroke is to be prevented. 2. In 21 patients with FH-I (presence of the causative hybrid 11 beta-hydroxylase/aldosterone synthase gene confirmed by Southern blot testing), various biochemical parameters were compared as possible screening tests. Hypokalaemia and elevated plasma aldosterone each detected only two (10%) of the affected individuals. 3. Plasma renin activity 19 (90%) and aldosterone/renin ratio 18 (86%) were more reliable but not free from false negatives. 4. Levels of the urinary 'hybrid' steroid, 18-oxocortisol, were elevated (P < 0.01) in all 15 patients tested (138.2 +/- 17.4 micrograms/g creatinine, range 41.6 +/- 281.0 micrograms/g) with no overlap when compared with 11 normals (9.7 +/- 1.3 micrograms/g, range 2.8-17.4 micrograms/g). 5. We conclude that measurement of urinary 'hybrid' steroids is probably the most rapid and reliable biochemical screening test currently available for FH-I, with confirmation dependent on demonstration of the hybrid gene by genetic techniques.

Markers for monitoring overtraining and recovery.

Physiological and mood state parameters were monitored during a 6-month swimming season in an attempt to determine markers of overtraining and recovery. Fourteen elite male and female swimmers were tested early-, mid-, and late-season and shortly before and after major competition. Training details and subjective ratings of well-being were compiled by the athletes in daily logs. Three swimmers were classified as stale based upon performance deterioration and prolonged, high fatigue levels. Staleness scores were calculated for each athlete using performance change from early- to late-season and daily fatigue ratings for the season. Regression analysis revealed a battery of well-being ratings which predicted staleness scores, accounting for 76% of the variance. The late-season stress ratings and plasma catecholamine levels at rest predicted staleness scores, accounting for 85% of the variance. During tapering, well-being ratings predicted improvement in competitive performance, accounting for 72% of the variance of the improvement in race times from previous best times. It was concluded that self-reported ratings of well-being may provide an efficient means of monitoring both overtraining and recovery; plasma catecholamine levels at rest may provide an additional objective tool for diagnosis.

An association of primary aldosteronism and adrenaline-secreting phaeochromocytoma.

1. Two patients with adrenaline-only secreting phaeochromocytomas and primary aldosteronism were studied. 2. Urinary adrenaline levels were raised and plasma adrenaline was not suppressed normally following administration of clonidine. Plasma aldosterone to plasma renin activity ratios were repeatedly elevated. 3. Both had large intra-adrenal phaeochromocytomas visible on computerized tomography (CT) scanning. Surrounding adrenal cortical tissue contained an adenoma in one and nodular hyperplasia in the other. 4. Following removal of the adrenal gland containing the phaeochromocytoma, plasma and urinary adrenaline levels, and plasma aldosterone to plasma renin activity ratios returned to normal. 5. Adrenaline-only secreting phaeochromocytomas and primary aldosteronism have been rarely diagnosed even as separate entities, but reliable screening tests are now available. 6. Simultaneous presence of these two conditions of hormone excess is probably a chance occurrence. Alternatively, there may be a genetic predisposition to endocrine dysplasia, or an interaction between the contiguous medullary and cortical tissues, particularly after the normal architecture has been disturbed by an enlarging phaeochromocytoma.

Hormonal responses of elite swimmers to overtraining.

Fourteen elite swimmers had measurements of stress hormones taken at five points during a 6-month season: early-, mid- and late-season, during tapering for National Trials, and 1-3 d after the Trials. Training details and subjective ratings of fatigue were recorded daily in log books. Plasma norepinephrine and epinephrine concentrations were significantly correlated with swim training volume (r = 0.37 and 0.33, respectively, P < 0.05 for each). No significant differences were seen in norepinephrine or cortisol concentrations at the five sampling times. Epinephrine levels were significantly lower (P < 0.05) after competition compared with values early in the season and shortly before competition. Symptoms of the overtraining syndrome were identified in three of the swimmers, based on performance decrements and high, prolonged levels of fatigue. In these three swimmers, norepinephrine levels tended to be higher than those of the other swimmers from mid-season onward and were significantly higher (P < 0.01) during tapering. If these findings can be confirmed in larger numbers and different types of athletes, norepinephrine level may provide a useful marker of the overtraining syndrome.

Effect of positive family history of hypertension on the blood pressure and catecholamine responses to a 6 hour adrenaline infusion.

1. The effects of 6 h infusion of adrenaline (INF-A) or dextrose (INF-D) and of post-infusion cold pressor test (CPT) were compared in normal subjects, with (FH+) and without (FH-) a family history of hypertension. 2. Increased urinary excretion rates suggested facilitated noradrenaline (NA) release during and after INF-A in both FH+ and FH-. 3. Urinary adrenaline (UADR) excretion increased during INF-A, as expected, and was also slightly higher after INF-A than INF-D. 4. The effect of INF-A on systolic blood pressure (SBP) was greater in FH- than in FH+ but diastolic blood pressure (DBP) did not fall as quickly with nocturnal recumbency after INF-A in FH+. 5. A significantly greater response in plasma NA to CPT was seen in FH+ than in FH- after INF-A. A similar trend was also seen after INF-D. 6. Increases in DBP due to CPT were higher in FH+ than in FH- after both infusions. 7. This study provides evidence of increased noradrenergic activity during and after INF-A, and also of a difference in response to sympathetic stimulation between FH+ and FH-.

Elevation of plasma atrial natriuretic peptide occurs during adrenaline infusion in hypertensive but not normotensive subjects.

The levels of plasma atrial natriuretic peptide in response to graded adrenaline infusion were determined in six patients with essential hypertension and six healthy normotensive subjects (controls). Basal plasma adrenaline concentration was similar in both groups and rose progressively and to a similar level during adrenaline infusion. Plasma noradrenaline rose in both groups and to the same extent during the 26 and 39 ng/kg/min adrenaline infusion rates. Basal plasma atrial natriuretic peptide levels were higher in the hypertensives than in the controls. Graded adrenaline infusion had no effect on atrial natriuretic peptide levels in the controls but significantly raised atrial natriuretic peptide levels in the hypertensives. Systolic blood pressure rose progressively during adrenaline infusion at a lower infusion rate in the hypertensives than in the controls. Similarly, while heart rate rose during adrenaline infusion in both groups, there was a greater rise in the hypertensives. The increased cardiovascular responsiveness to adrenaline infusion in patients with essential hypertension may explain why plasma atrial natriuretic peptide levels rose only in this group and not the normotensive subjects.

Effects of repeated doses of pseudoephedrine on blood pressure and plasma catecholamines in normal subjects and in patients with phaeochromocytoma.

1. Increases in blood pressure (BP) and in plasma noradrenaline concentration (NA) were observed after two doses of a non-prescription decongestant containing pseudoephedrine (PE) in two of three patients with phaeochromocytoma, before but not after removal of the tumour. The pressor response was terminated by oral phenoxybenzamine, and modified by prior exposure to this drug. 2. In eight normal subjects administration of the same two doses prevented falls in BP and in NA usually seen with prolonged recumbency, but neither BP nor NA increased. However, a pressor response was observed in a normal subject with a strong family history of hypertension. 3. Exposure to PE in non-prescription decongestants is not without risk in hypertension.

Inappropriately elevated levels of atrial natriuretic peptide may contribute to the pathophysiology of orthostatic hypotension.

1. Overnight recumbent and upright plasma atrial natriuretic peptide (ANP) levels were markedly elevated (P less than 0.001) in patients with orthostatic hypotension (OH). 2. Overnight urinary clearance of ANP was significantly lower (P less than 0.01) in patients with OH, and was inversely correlated with plasma ANP levels (r = -0.94, P less than 0.01). The same negative correlation (r = -0.87, P less than 0.01) was seen in normal subjects. 3. Reduced urinary clearance of ANP may be associated with reduced filtered load and increased binding of ANP to the neutral endopeptidase 24.11 receptor binding sites in the proximal renal tubule. 4. ANP may be involved in the pathophysiology of orthostatic hypotension.

Evidence for presynaptic beta-adrenoceptor stimulation 24 hours after a 6 hour adrenaline infusion.

1. The effects of 6 h infusions of adrenaline (INF-A) and dextrose (INF-D) were compared in nine normal subjects. 2. A significant increase in systolic blood pressure was observed during INF-A compared with INF-D and, 24 h after infusion, diastolic blood pressure was higher after INF-A than after INF-D. 3. Heart rate (HR) was significantly higher during INF-A than during INF-D. 4. As expected, plasma ADR increased significantly during INF-A but, unexpectedly, remained elevated 60 min post infusion compared with INF-D. Levels during activity the next morning were somewhat higher after INF-A, but not significantly different from INF-D. 5. Plasma NA increased transiently during INF-A and decreased during INF-D. Urinary NA was significantly higher during INF-A than during INF-D, and insignificantly higher during overnight recumbency, consistent with enhanced noradrenergic transmission.