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Abstract: Background. Neurohormonal activation is generally recognised to play an important role in the pathophysiology, prognosis and treatment of chronic heart failure (HF). While the number of patients with diabetes increases, little if anything is known about neurohormonal activation in HF patients with diabetes. Methods. The study population consisted of 371 patients with advanced HF who were enrolled in a multicentre survival trial. Ten different plasma neurohormones were measured (noradrenaline, adrenaline, dopamine, aldosterone, renin, endothelin, atrial natriuretic peptide [ANP], N-terminal (pro)ANP, brain natriuretic peptide [BNP] and N-terminal (pro)BNP. Comparisons were made between patients with diabetes (n=81) and those without (n=290). Results. At baseline, the two groups were comparable regarding age (mean 68 years), left ventricular ejection fraction (23%), severity and aetiology of HF, while body weight was higher in those with diabetes (77.4 vs. 74.2 kg, p=0.04). Most plasma neurohormones were similar between groups, but patients with diabetes had higher values of BNP (94 vs. 47 pmol/l, p=0.03), while a similar trend was observed for N-terminal (pro)BNP (750 vs. 554 pmol/l, p=0.10). During almost five years of follow-up, 51/81 patients with diabetes died (63%), as compared with 144 of 290 non-diabetic patients (50%) who died (p=0.046). Natriuretic peptides and noradrenaline were the most powerful predictors of mortality in both diabetic and non-diabetic HF patients. Conclusion. HF patients with diabetes have higher (N-terminal (pro)) BNP levels than non-diabetic patients, while other neurohormones are generally similar. Natriuretic peptides are also good prognostic markers in diabetic HF patients. (Neth Heart J 2010;18:190-6.)

Background: Controversy exists about the indication of thrombolytic therapy in the subgroup of hemodynamically stable patients with acute pulmonary embolism (PE) and right ventricular dysfunction. Brain natriuretic peptide (BNP) is excreted from the cardiac ventricles in response to cardiomyocyte stretch and can be measured with an easy‐to‐perform blood test. Objective: The objective of this study was to determine the predictive value of elevated BNP levels for early recurrent venous thromboembolism with or without fatal outcome in hemodynamically stable patients with acute PE. In addition, we assessed the potential clinical consequences of initiating thrombolytic therapy based on the BNP levels alone. Methods: A nested case–control study was performed within the framework of a large randomized‐controlled trial totalling 2213 hemodynamically stable patients with confirmed acute, symptomatic PE. Ninety patients experienced a fatal or non‐fatal recurrent venous thromboembolism during the first 3 months of follow‐up (cases); Two hundred and ninety‐seven patients with uneventful follow‐up served as controls. Blood for BNP levels was obtained at referral and assayed in a central laboratory. Results: Cases had significantly higher mean baseline BNP levels (P = 0.0002). The odds ratio (OR) for every logarithmic (log) unit increase in BNP concentration was 2.4 (95% CI: 1.5–3.7). A BNP cut‐off level of 1.25 pmol L−1[the optimal point on the receiver‐operating characteristic (ROC) curve] was associated with a sensitivity and specificity of 60% and 62%, respectively. In theory, for every patient correctly receiving thrombolytic therapy at this cut‐off, 16 patients will receive this therapy unnecessarily. Conclusions: Brain natriuretic peptide level at presentation is significantly associated with early (fatal) recurrent venous thromboembolism in hemodynamically stable patients with acute PE. However, this relationship appears clinically insufficient to guide the initiation of thrombolytic therapy.

OBJECTIVE: Phaeochromocytomas (PCCs) are widely known for their clinical unpredictability. This study intends to define predictive plasma markers for their variable postoperative behaviour. Furthermore, the diagnostic accuracy of these plasma tests was determined. DESIGN AND METHODS: A retrospective correlative study was performed in a series of 83 operated and four autopsied patients in order to correlate preoperative catecholamine (CAT) levels of 103 PCCs with their clinical behaviour. In a subset of cases, chromogranin-A (Chr-A) and enzymes/precursors of the CAT biosynthesis were studied for their predictive value. RESULTS: Basal CAT levels were elevated in 81/87 instances (sensitivity: 93%). Four of six cases with normal measurements showed only medullary hyperplasia. Larger PCCs, particularly those showing necrosis, capsular and vascular invasion, secreted higher CAT levels. Bilateral, hereditary tumours were less productive than their unilateral counterparts. Extra-adrenal PCCs secreted significantly lower levels of epinephrine (EPI) than intra-adrenal tumours. Fourteen patients developed metastases. According to Kaplan-Meier estimations, patients with higher levels of dopamine, norepinephrine (NE) and aromatic l-amino acid decarboxylase as well as lower ratios of EPI/EPI+NE, had significantly shorter metastases-free intervals. Existence of preoperative hypertension, left ventricular hypertrophy and measured blood pressures showed significant positive relationships with CAT levels, but not with Chr-A. CONCLUSIONS: These data showed that plasma CAT measurement is a sensitive method in the diagnostic work-up of PCCs. Those tumours producing normal levels are commonly small and asymptomatic. Furthermore, certain secretion patterns are indicative of the presence of metastases as well as the size and site of sporadic and syndrome-related PCCs.

Children aged 0-3 yr were stratified for age and randomized to receive either continuous morphine (CM, 10 microg x kg(-1) x h(-1)) with three-hourly placebo boluses or intermittent morphine (IM, 30 microg x kg(-1) every 3 h) with a placebo infusion for postoperative analgesia. Plasma concentrations of epinephrine, norepinephrine, insulin, glucose and lactate were measured before and at the end of surgery and 6, 12 and 24 h after surgery. Pain was assessed with validated pain scales [the COMFORT scale and a visual analogue scale (VAS)] with the availability of additional morphine doses. Minor differences occurred between the randomized treatment groups, the oldest IM group (aged 1-3 yr) having a higher blood glucose concentration (P=0.003), mean arterial pressure (P=0.02) and COMFORT score (P=0.02) than the CM group. In the neonates, preoperative plasma concentrations of norepinephrine (P=0.01) and lactate (P<0.001) were significantly higher, while the postoperative plasma concentrations of epinephrine were significantly lower (P<0.001) and plasma concentrations of insulin significantly higher (P<0.005) than in the older age groups. Postoperative pain scores (P<0.003) and morphine consumption (P<0.001) were significantly lower in the neonates than in the older age groups. Our results show that continuous infusion of morphine does not provide any major advantages over intermittent morphine boluses for postoperative analgesia in neonates and infants.

Experimental evidence indicates that the renal circulation is more sensitive to the effects of nitric oxide (NO) synthesis inhibition than other vascular beds. To explore whether in men the NO-mediated vasodilator tone is greater in the renal than in the systemic circulation, the effects of three different intravenous infusions ofNG-nitro-l-arginine methyl ester (l-NAME; 1, 5, and 25 μg ⋅ kg−1⋅ min−1for 30 min) or placebo on mean arterial pressure (MAP), systemic vascular resistance (SVR), renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), and fractional sodium and lithium excretion (FENaand FELi) were studied in 12 healthy subjects, each receiving randomly two of the four treatments on two different occasions. MAP was measured continuously by means of the Finapres device, and stroke volume was calculated by a model flow method. GFR and RBF were estimated from the clearances of radiolabeled thalamate and hippuran. Systemic and renal hemodynamics were followed for 2 h after start of infusions. During placebo, renal and systemic hemodynamics and FENaand FELiremained stable. With the low and intermediate l-NAME doses, maximal increments in SVR and RVR were similar: 20.4 ± 19.6 and 23.5 ± 16.0%, respectively, with the low dose and 31.4 ± 26.7 and 31.2 ± 14.4%, respectively, with the intermediate dose (means ± SD). With the high l-NAME dose, the increment in RVR was greater than the increment in SVR. Despite a decrease in RBF, FENaand FELidid not change with the low l-NAME dose, but they decreased by 31.2 ± 11.0 and 20.2 ± 6.3%, respectively, with the intermediate dose and by 70.8 ± 8.1 and 31.5 ± 15.9% with the highl-NAME dose, respectively. It is concluded that in men the renal circulation is not more sensitive to the effects of NO synthesis inhibition than the systemic circulation and that the threshold for NO synthesis inhibition to produce antinatriuresis is higher than the threshold level to cause renal vasoconstriction.

Plasma semicarbazide-sensitive amine oxidase is raised in patients with Type I (insulin-dependent) diabetes mellitus. It has been suggested that this enzyme is involved in the development of microvascular damage through its ability to convert amines (e. g. methylamine and aminoacetone) into aldehydes, hydrogen peroxide and ammonia. Plasma semicarbazide-sensitive amine oxidase was found to be equally raised both in patients with Type I diabetes (n= 73) and Type II (non-insulin-dependent) diabetes mellitus (n= 88) compared with control subjects (621 ± 209 and 619 ± 202 vs 352 ± 102 mU/l, p< 0.0001) and to correlate in multiple regression analysis with HbA1 c. Since the enzyme could protect the islets from the inhibitory effects of methylamine on insulin secretion, we also tested sera of 100 children, collected consecutively at first diagnosis of Type I diabetes, for semicarbazide-sensitive amine oxidase. The activity was greatly increased compared with serum values of 76 control (siblings) children (757 ± 300 vs 455 ± 138 mU/l, p< 0.0001), but not associated with HbA1 c. Our study confirms the increase of plasma semicarbazide-sensitive amine oxidase in Type I diabetes and extends this finding to Type II diabetes as well as to childhood Type I at first clinical diagnosis. In the last case increased enzyme activities could serve to protect the islets from inhibitory effects of methylamine but cause damage by generation of hydrogen peroxide, aldehydes and ammonia. In the long run the increased enzyme activities could also contribute to vascular damage by direct cytotoxic action on endothelial cells, including increased oxidative stress and glycosylation of proteins. [Diabetologia (1999) 42: 233–237]Plasma semicarbazide-sensitive amine oxidase is raised in patients with Type I (insulin-dependent) diabetes mellitus. It has been suggested that this enzyme is involved in the development of microvascular damage through its ability to convert amines (e. g. methylamine and aminoacetone) into aldehydes, hydrogen peroxide and ammonia. Plasma semicarbazide-sensitive amine oxidase was found to be equally raised both in patients with Type I diabetes (n= 73) and Type II (non-insulin-dependent) diabetes mellitus (n= 88) compared with control subjects (621 ± 209 and 619 ± 202 vs 352 ± 102 mU/l, p< 0.0001) and to correlate in multiple regression analysis with HbA1 c. Since the enzyme could protect the islets from the inhibitory effects of methylamine on insulin secretion, we also tested sera of 100 children, collected consecutively at first diagnosis of Type I diabetes, for semicarbazide-sensitive amine oxidase. The activity was greatly increased compared with serum values of 76 control (siblings) children (757 ± 300 vs 455 ± 138 mU/l, p< 0.0001), but not associated with HbA1 c. Our study confirms the increase of plasma semicarbazide-sensitive amine oxidase in Type I diabetes and extends this finding to Type II diabetes as well as to childhood Type I at first clinical diagnosis. In the last case increased enzyme activities could serve to protect the islets from inhibitory effects of methylamine but cause damage by generation of hydrogen peroxide, aldehydes and ammonia. In the long run the increased enzyme activities could also contribute to vascular damage by direct cytotoxic action on endothelial cells, including increased oxidative stress and glycosylation of proteins. [Diabetologia (1999) 42: 233–237]

In order to understand the complex autonomic adjustments that occur during the psychological challenges of normal daily life, autonomic responses to psychological stress were studied by evaluating the effects of body posture on various indices of sympathetic and parasympathetic regulation during performance of a psychological task. Twelve male subjects were studied in various postures (supine, sitting and standing), and during performance of the Colour Word Test (CWT) when sitting and then when standing. This procedure was subsequently repeated in reverse order (first standing and then sitting) after 15 min of supine rest. Blood samples for assay of plasma catecholamines were obtained before and during each CWT. Spectral analysis of beat-to-beat variations of heart rate (HR) and blood pressure (BP) was applied in order to obtain non-invasive indices of sympathetic and parasympathetic regulation. HR, diastolic BP, mid-frequency band power (0.07-0.14 Hz) of HR and systolic BP, and plasma adrenaline and noradrenaline concentrations showed significant increases when changing from supine to sitting to standing posture, whereas high-frequency band power (0.15-0.50 Hz) of HR decreased in a posture-dependent fashion. In the sitting position, the CWT caused significant increases in HR, BP and plasma adrenaline levels, and decreased HR and BP variability indices. In the standing posture, the CWT responses differed significantly from those during sitting for HR (a mild decrease during standing), high-frequency band power of HR (decreased more while sitting), high-frequency band power of BP (decreased more while standing), and plasma adrenaline responses (larger during sitting). Posture-related differential effects were observed on indices of sympatho-adrenomedullary activation during performance of a psychological challenge, whereas indices of parasympathetic activity indicated primarily less vagolytic effects when the task was performed in the standing posture. Our findings therefore underline the complexity of the adjustments that occur in neurohumoral and haemodynamic parameters during the psychological challenges of daily life.

Cardiovascular and catecholaminergic activity during mental load were studied in patients with Tourette syndrome. Patients and controls performed the Color Word Test, preceded by a baseline period, with continuous measurements of heart rate and blood pressure. Blood samples for assay of plasma catecholamine concentrations were obtained before and during the test. The patients showed higher heart rate and blood pressure during baseline than controls, but no differences regarding plasma catecholamines. The tics corresponded with transient increases in heart rate and blood pressure. Spectral analysis of cardiovascular variability during mental load gave only limited evidence of increased sympathetic activity and no alterations in parasympathetic activity in the patients. Therefore, our findings indicate enhanced cardiovascular activity in the patients but not during mental load. The effects of tics on the cardiovascular parameters illustrate the functional complexity of the autonomic nervous system in Tourette syndrome.

We wished to determine whether ibopamine, a dopaminergic prodrug with weak agonist activity on α-and β-adrenoceptors, improves orthostatic tolerance in autonomie insufficiency. Three subjects with severe orthostatic hypotension resulting from pure autonomie failure (PAF) were studied. Direct arterial blood pressure (ABP) and heart rate (HR) were recorded continuously. Orthostatic tolerance was evaluated by 60° passive head-up tilting. Tilting was performed before and after a single oral 100-mg dose of ibopamine. Blood samples for measurement of plasma catecholamines, free epinine (the active metabolite of ibopamine), and conjugated epinine were taken at regular intervals. In all 3 subjects, orthostatic tolerance was greatly improved by ibopamine. This improvement occurred as soon as 10–30 min after administration of ibopamine and lasted 20–50 min. α-Adrenoceptor blockade with phentolamine abolished the effect of ibopamine. The interindividual pharmacokinetics of ibopamine varied considerably: Peak plasma concentrations of ibopamine in the three subjects were 2.8, 4.5, and 35.4 ng/ml, respectively. The high level of epinine in one patient was associated with severe hypertension and tachycardia. Ibopamine may be a valuable new pharmacologic treatment for orthostatic hypotension in PAF, but in light of the highly variable interindividual pharmacokinetics further studies must be performed before use of the compound can be advocated in this disorder.

1. Plasma noradrenaline, active and inactive plasma renin, cardiac index and total peripheral vascular resistance were studied in 41 subjects, initially aged 10–19 years, who were followed up for at least 2 years after a blood pressure reading of 140 and/or 90 mmHg or more (initial hypertensives) and in 41 normotensive control subjects selected from the same population and matched for age, sex and body-mass index. 2. The initial hypertensive subjects had a lower mean cardiac index (3.63 ± sd 0.83 vs 4.00 ± 0.89 litre min−1 m−2), a higher mean total peripheral resistance (26.8 ± 5.7 vs 22.8 ± 5.5 units) and a higher mean plasma noradrenaline concentration (336 ± 146 vs 281 ± 126 pg/ml) than the control subjects. 3. Mean plasma noradrenaline concentration was higher in initial hypertensive subjects with a high active renin concentration than in those with a normal renin concentration (442 ± 70 vs 324 ± 100 pg/ml). 4. A weight-adjusted standardized regression coefficient of 0.77 between active plasma renin concentration and left ventricular mass was found in normotensive control subjects. 5. These findings are at variance with the existence of a hyperkinetic phase in young hypertensive subjects and suggest that sympathetic overactivity may be related to early essential hypertension through increase of peripheral vascular resistance.

1. The relationship between the antihypertensive action of captopril and its inhibitory effect on angiotensin I(ANG I)-converting enzyme has been investigated. Converting enzyme was measured in plasma by its ability to generate hippuric acid from the synthetic substrate hippuryl-l-histidyl-l-leucine. Inhibition by captopril appeared transient on storage of the plasma samples at −20°C, so that measurements in such samples were not a valid index of the effect in vivo. 2. Rapid reversal of captopril's inhibitory effect on ANG I-converting enzyme in plasma was achieved by the addition of N-ethylmaleimide (0.1 mmol/l). In this way an estimate of converting enzyme ‘concentration’ was obtained both in stored and in freshly prepared plasma samples. Measurements of converting enzyme ‘activity’ in freshly prepared samples, in the absence of N-ethylmaleimide, were used as an index of inhibition in vivo. 3. In eight hypertensive subjects ANG I-converting enzyme ‘concentration’ did not change after a single oral 100 mg dose of captopril. Long-term treatment of 10 hypertensive subjects with captopril was associated with a gradual increase in converting enzyme ‘concentration’ from 29 ± 2 to 47 ± 3 m-units/ml (mean ± sem) over a period of several weeks. In contrast, captopril caused a rapid fall of converting enzyme ‘activity’. 4. Abrupt withdrawal of captopril after long-term treatment caused a gradual decrease in ANG I-converting enzyme ‘concentration’ to the control value. In contrast, converting enzyme ‘activity’ rose rapidly and became equal to enzyme ‘concentration’ 2 days after the drug had been stopped. 5. The concentration of enzymatically active renin in plasma rose from 13 ± 3 to 81 ± 34 μ-units/ml during long-term captopril treatment (mean ± sem). Blood pressure fell from 168 ±4/108 ± 3 to 140 ± 3/90 ± 3 mmHg and had not returned to the control value in the first week after the drug had been stopped, despite the fact that circulating active renin and ANG I-converting enzyme ‘activity’ were elevated. 6. It is concluded that long-term inhibition of ANG I-converting enzyme by captopril is associated with an increased plasma concentration of this enzyme. The results also suggest that the level of converting enzyme ‘activity’ in plasma is not the only factor that determines the long-term effect of captopril on blood pressure.

Sleep patterns of two young female patients with congenital dopamine beta-hydroxylase deficiency are described. In this orthostatic syndrome central and peripheral noradrenergic failure occurs as a result of impaired beta-hydroxylation of dopamine. Consequently, the levels of dopamine and its metabolites are elevated. The relative importance of noradrenaline deficit in the face of dopamine excess for sleep-regulatory mechanisms can be inferred from the sleep pattern of these patients. No subjective sleep complaints were reported. The sleep patterns showed a high percentage of slow-wave sleep in both patients (29% and 34% of sleep period time) and a relatively low to normal percentage of REM sleep (18% and 21%). A normal cyclic REM sleep pattern was observed. Alpha-delta sleep occurred during light sleep (15% and 8%); consequently, the amount of stage 2 sleep was reduced. These results indicate that functional insufficiency of the noradrenergic system in two patients with dopamine beta-hydroxylase deficiency is not associated with profound changes in the (REM) sleep pattern. This supports a modulatory or permissive role for noradrenaline in REM sleep mechanisms.

The effect of levodopa (l-dopa), alone or in combination with a peripheral decarboxylase inhibitor (PDI), on plasma levels of aromatic-l-amino acid decarboxylase (ALAAD, = dopa decarboxylase), l-dopa, 3-O-methyl-dopa (3-OMD), dopamine (DA), noradrenaline, adrenaline and dopamine beta-hydroxylase has been studied. In healthy subjects and in patients with parkinsonism plasma ALAAD level fell after administration of l-dopa + benserazide, but returned to previous levels within 90 min. In a cross-sectional study blood was obtained, 2 h after dosing, from 104 patients with idiopathic parkinsonism, divided into four groups: no l-dopa treatment (group 1), l-dopa alone (group 2), l-dopa + benserazide (Madopar) (group 3) and l-dopa + carbidopa (Sinemet) (group 4). Plasma ALAAD, which was normal in groups 1 and 2, was increased 3-fold in groups 3 and 4, indicating that there was induction of ALAAD by the co-administration of PDI. Despite this induction of ALAAD, in groups 3 and 4, with half the daily l-dopa dose compared with group 2, plasma l-dopa and 3-OMD levels were 5 times higher, while plasma DA levels were not different. The DA/l-dopa ratio was decreased 5-fold in group 2 and 16-fold in groups 3 and 4 as compared with group 1. Neither 3-OMD levels nor 3-OMD/l-dopa ratios correlated with the occurrence of on-off fluctuations. In a longitudinal study of three patients started on Madopar treatment the induction of plasma ALAAD was found to occur gradually over 3–4 weeks. Further detailed pharmacokinetic studies in plasma and cerebrospinal fluid are required in order to elucidate whether the ALAAD induction by PDI may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.

The metabolism of norepinephrine (NE) and epinephrine (EPI) in peripheral tissues limits the use of venous plasma levels of these parameters as an index of overall sympathetic or adreno-medullary activity. Therefore venous (deep antecubital vein) and arterial (brachial artery) concentrations of NE and EPI were compared in 16 hypertensive subjects. NE and EPI were determined after 30 min supine rest, and immediately before and after isometric exerise, cold provocation, head-up tilting (OST) and Stroop's colour word test (CWT). At rest venous NE exceeds arterial NE. Assuming similar fractional extractions (FE) of NE and EPI, 46±14% (mean±SD) of venous NE appeared to be produced locally. Despite this considerable local production venous and arterial levels of NE were closely correlated (r=0.92). At rest venous EPI was 42±13% lower than arterial EPI, but since the interindividual variation of the FE of EPI was relatively small and independent of arterial levels, venous and arterial levels were also closely correlated (r=0.82). All four tests caused an increase in arterial and venous NE, whereas EPI did not change. Responses of arterial and venous NE were only correlated after OST and CWT. It is concluded that at rest, but not invariably so during different forms of sympatho-adrenal activation, arterial plasma concentrations of NE and EPI can be substituted for by their respective venous equivalents.

Plasminogen can be activated by intrinsic activators that circulate in plasma in a precursor form, by extrinsic activator originating from tissues or the vessel wall and by the exogenous activators, urokinase and streptokinase. Tissue activator and vascular activator are probably identical. Dialysis of plasma against pH 4.0 buffer causes denaturation of the plasmin inhibitors, α2-antiplasmin and C1-inhibitor, while α2-macroglobulin is left intact. Incubation of pH 4.0-pretreated plasma with urokinase or streptokinase at pH 7.5 led to activation of plasminogen and prorenin. Incubation of a plasma fraction, which contained plasminogen and prorenin but no α2-antiplasmin and renin, with highly purified tissue plasminogen activator also led to activation of prorenin. The vasopressin analogue, 1-des-amino-8-D-arginine vasopressin (DDAVP), is a potent stimulant for the release of extrinsic activator into the bloodstream. After infusion of DDAVP, 0.4 μg/kg, into normal subjects, parallel increments in plasma fibrinolytic activity and renin were observed. Infusion of DDAVP into patients with type IV hyperlipoproteinaemia had little effect on plasma fibrinolytic activity and the response of plasma renin was also subnormal. These observations warrant further studies on a possible role for plasminogen activators in prorenin activation in vivo.

In 18 healthy volunteers, in a double-blind placebo-controlled study, we investigated of whether 14 days treatment with a therapeutic dose of ibopamine (3×100 mg/day p.o.), respectively its active metabolite epinine, would desensitize lymphocyte ß2- or platelet a2-adrenoceptors, or a1- and ß-adrenoceptor mediated (phenylephrine-and isoprenaline infusions, respectively), changes in systolic and diastolic blood pressure and heart rate.

Neuron specific enolase (NSE) is widely used as a neuro-endocrine marker. However the presence of NSE in many non-neuroendocrine tissues has raised questions on the specificity of NSE. We have investigated NSE immunoreactivity (NSA-ag), gamma-enolase activity and total enolase activity in small cell lung cancer (SCLC) cell lines. During well-controlled exponential growth comparison of NSE-ag content and gamma-enolase activity with the doubling-time (Td) and NSE-ag content with gamma-enolase and total enolase activity led to a clear distinction of two types of cell line: variant cell lines plus part of the classic cell lines (type I) and the remaining classic cell lines (type II). The distinction was based upon both an abrupt 6-fold increase of gamma-enolase activity and an 18-fold increase of NSE-ag, which for the larger part was enzymatically inactive. Within each group the increase of NSE-ag content was significantly correlated with the increase of gamma-enolase activity and both NSE-ag content and gamma-enolase activity increased linearly with Td. It is concluded that gamma-enolase seems to be associated with the regulation of growth rate and that a compound with the gamma-enolase antigen but without enzyme activity can distinguish two different classes of SCLC cell lines. Furthermore the demonstration that NSE-ag can represent the active enzyme as well as an enzymatically inactive compound may explain why a controversy about neuron- or non-specificity of NSE exists.

1. The new peripherally acting selective 5-hydroxytryptamine receptor blocking agent ketanserin was given (10 mg intravenously) to 17 patients with essential hypertension. 2. Systemic mean systolic arterial pressure fell from 192 ± 6 to 146 ± sem 10 mmHg and mean diastolic arterial pressure fell from 90 ± 4 to 68 ± 5 mmHg. Right atrial pressure, pulmonary arterial pressure and pulmonary capillary ‘wedge’ pressure, measured in 12 patients, were also significantly lowered. Heart rate, cardiac output and plasma noradrenaline rose after ketanserin, probably due to baroreflex-mediated sympathetic stimulation, but the changes were small compared with the fall in systemic arterial pressure. 3. Phenylephrine (50, 100 and 200 µg intravenously) was given to five patients before ketanserin and during continuous infusion of ketanserin (2 mg/h after a loading dose of 10 mg) and dose-response curves for mean systemic arterial pressure were constructed. The pressor response to phenylephrine was not shifted by ketanserin. Thus ketanserin, in a dose capable of lowering systemic arterial pressure, does not act as an a-adrenoceptor antagonist. 4. 5-Hydroxytryptamine receptor blockade appears to cause dilatation of resistance vessels and possibly also of capacitance vessels. The data suggest a hitherto unknown role for 5-hydroxytryptamine in the maintenance of high blood pressure.

Epinine (N-methyl-dopamine, the active metabolite of ibopamine), is a full agonist at dopamine (DA)-receptors and a- and ß-adrenoceptors. To study whether in vivo DA-receptor mediated effects can be separated from a- and ß-adrenoceptor effects we compared in 10 male volunteers the effects of i.v. epinine (0.5; 1; 2; 4 µg/kg/min for 15 min each) on DA-receptor (changes in serum prolactin)- and a- and ß-adrenoceptor (changes in systolic [P syst] and diastolic blood pressure [P diast] and heart rate)-mediated effects with those of dopamine before and after propranolol (5 mg i.v. 45 min pre-infusion), bisoprolol (15 mg p.o. 2 h pre-infusion) and domperidone (10 mg p.o. 1 h pre-infusion). At the 0.5 and 1 µg doses dopamine and epinine did not affect P syst, P diast and heart rate but significantly decreased prolactin levels. At the higher dose both dopamine and epinine significantly increased P syst and heart rate, while only epinine significantly increased P diast. In addition, both dopamine and epinine significantly increased diuresis and natriuresis; in contrast, only dopamine, but not epinine, dose-dependently increased plasma noradrenaline levels. Domperidone did not affect dopamine- and epinine-evoked blood pressure- and heart rate-changes, but antagonized their prolactin-effects (at least at the lower doses). Bisoprolol and propranolol significantly reduced dopamine-induced P syst- and heart rate-increases to about the same extent. Propranolol enhanced epinine-induced P syst- and P diast-increases while bisoprolol reduced epinine-evoked P syst-increase but not P diast-increase. Epinine-induced heart rate-increase was abolished by biso-prolol and was converted into a heart rate-decrease by propranolol. We conclude that in 0.5 and 1 µg doses (plasma levels of 20–80 nmol/l) epinine acts only at DA-receptors. Thus, ibopamine in therapeutically recommended doses (3×100 mg/day with peak plasma epinine-levels of 50–80 nmol/l) very likely activates only DA-receptors. In higher doses, however, epinine - like dopamine - activates a- and ß-adrenoceptors whereby epinine has a stronger a-adrenoceptor agonistic activity than dopamine. Moreover, part of the dopamine-effects are indirect via release of endogenous noradrenaline whereas epinine-effects do not appear to include an indirect component.

Ketanserin is a serotonin antagonist with high affinity for S2-serotonergic receptors, which mediate the vasoconstrictor effects of serotonin. It does not block the vasodilator effects of this monoamine, and it is devoid of agonist activity and serious central side effects. Ketanserin, however. also hinds to a1-adrenoceptors. The compound (10 mg i.v.) was given to 30 patients with essential hypertension and four normotensive patients with chronic autonomic failure. owing to an efferent sympathetic lesion. Ketanserin lowered systolic and diastolic arterial pressure by about 20. The effects on cardiac output, cardiac filling pressures, forearm blood flow, renal blood flow, and glomerular filtration rate revealed a hemodynamic pattern compatible with dilatation of both resistance and capacitance vessels. These vasodilator effects were accompanied by moderate reflex stimulation of the heart. The drug did not alter the pressor effect of bolus injections of the a1-adrenoceptor agonist phenylephrine, which contrasted with the competitive antagonism exerted by the a1-adrenoceptor antagonist prazosin. Baroreflex-mediated bradycardia after phenvlephrine also was not affected by ketanserin. The drug had a distinct hypotensive effect in patients with autonomic failure, despite the fact that these patients did not respond to the nonselective a1-adrenoceptor antagonist phentolamine, 20 mg i.v. Thus, ketanserin is capable of lowering arterial pressure independently of a1-adrenoceptor blockade. The results are therefore indirect evidence supporting a role of serotonin in hypertension.

Specific binding (up to 50%) of catecholamines to the plasma proteins albumin, transthyretin and alpha-1 acid glycoprotein has been reported repeatedly, but data are conflicting. In binding studies of tritiated norepinephrine (NE) to human serum albumin, we found specific binding to be an artifact, due to the presence of one or more oxidation products of NE which are rapidly formed at pH greater than 6.5. In the presence of large amounts of antioxidants NE is stable, and no specific binding occurs. The decrease in binding of tritiated NE with increasing amounts of nontritiated NE, previously thought to represent displacement, is actually the result of the inherent greater stability of NE at higher concentrations. A similar decrease in binding, this time representing real displacement, was obtained with increasing amounts of oxidation products, obtained by treating NE first with sodium hydroxide. Results with transthyretin, alpha-1 acid glycoprotein and with plasma were in full agreement with these conclusions. These observations emphasize the necessity for careful investigation of the purity and stability of the labeled ligand, not only in binding assays with catecholamines, but in binding assays in general. Our findings may also have bearings on the currently hotly pursued topic of catecholamine release in in vivo and in vitro experiments.

Objective: Nocturnal hypertension frequently occurs in autonomic failure (AF). We assessed the prevalence of supine hypertension in patients with different degrees of AF due to familial amyloidotic polyneuropathy (FAP). Subjects and methods: In 230 patients (age 36 yrs, range 26 to 49 yrs) with FAP, a hereditary mixed polyneuropathy with progressive (para)sympathetic AF, and 45 age-matched controls. AF was assessed by heart response to deep breathing, blood pressure (BP) response to 60° head-up tilting and a Valsalva maneuver, and a plasma norepinephrine (NE) concentration. Ambulatory (A) BP was measured with the Spacelabs 90207 BP monitor. Based on a composite grading system to score the degree of AF, four groups of patients were distinguished: Group I (n = 40, no AF) group II (n = 40, mild AF), group III (n = 68, moderate AF) and group IV (n = 82, severe AF). Twenty patients of group IV had a second ABP recording after 3 months treatment with the unnatural NE precursor L-DOPS for treatment of incapacitating orthostatic hypotension. Results: Day-Night BP difference decreased or even reversed with the progression of AFI however nocturnal HT (diastolic BP >90 mmHg) did never develop, even not in L-DOPS users. (See Table) Day BP (9–22 h)Night BP (24–7h)Day-Night BPSBPDBPSBPDBPSBPDBPControl120 ± 975 ± 6103 ± 859 ± 517 ± 5Group I118 ± 1077 ± 6101 ± 861 ± 617 ± 516 ± 5Group II118 ± 1078 ± 7107 ± 1267 ± 811 ± 611 ± 5Group III110 ± 1071 ± 8105 ± 1264 ± 85 ± 77 ± 6Group IV101 ± 968 ± 8108 ± 1469 ± 10-7 ± 7-1 ± 5 Conclusions: Contrary to other forms of AF nocturnal (supine) HT does not occur in FAP. This implies that apart from AF other factors, presumably salt and water retention are a prerequisite for the development of nocturnal hypertension in AF.

The effects of graded infusions of the β-agonists isoproterenol (nonselective), l-prenalterol β1-selective), and salbutamol (β2-selective) on plasma potassium and norepinephrine were compared in subjects with borderline hypertension. Potassium levels fell with all three agonists, and norepinephrine levels rose with isoproterenol and salbutamol. These effects on potassium and norepinephrine were closely correlated and occurred at the same dose ranges as the cardiovascular responses. The fall in plasma potassium was probably caused by activation of β-receptors, mainly on skeletal muscle, with subsequent stimulation of active sodium-potassium transport across the cellular membrane. The rise in plasma norepinephrine may have been due to activation of β-receptors on sympathetic nerve endings. Activation of these presynaptic receptors is known to enhance the release of norepinephrine during nerve stimulation. For a given increase in heart rate and cardiac contractility, as measured by the heart rate-corrected duration of total electromechanical systole, which are mainly β1-responses, the effects on potassium and norepinephrine were in the order: salbutamol > isoproterenol > prenalterol. β-Blockade with propranolol (nonselective), 80 mg four times a day, or atenolol (β1-selective), 100 mg once a day, antagonized the hypokalemic effect of isoproterenol as well as the rise in norepinephrine, but when isoproterenol was infused in doses high enough to overcome the blockade of the heart rate response, the effects on norepinephrine and potassium were abolished by propranolol and not by atenolol. Thus, the receptors in question appear to be of the β2-subtype. Epinephrine, which is known to circulate in high concentrations under stressful conditions, is generally considered to be the endogenous activator of these receptors. β-Blockers may prevent hypokalemia and may suppress sympathetic activity, which could contribute to their so-called cardioprotective action. The evidence presented here and in other studies that β2-type receptors are involved in stress-induced hypokalemia and in presynaptic facilitation of norepinephrine release warrants further consideration of the clinical significance of β-blocker selectivity.

Plasma dopamine, noradrenaline, adrenaline and renin-activity were measured In 39 subjects with stable mild hypertension (mean age 23.9 years, 34 males), and In 39 age-matched normotensive controls from the same open population. Mean sitting blood pressure In hypertensives was 142/82 mmHg. In normotensives average blood pressure was 125/74 mmHg. Plasma catecholamlnes were measured with a COMT radioenzymatic assay.Plasma dopamine was significantly higher in hypertensives (72 ± SE 7 pg/ml) than in normotensives (46 ± SE 4 pg/ml; p<0.001). The same was true for noradrenaline (302 ± SE 23 pg/ml in hypertensives, and 157 ± SE 9 pg/ml In normotensives; p<0.001), and for adrenaline (91 ± SE 13 pg/ml in hypertensives and 38 ± SE 4 pg/ml in normotensives; p<0.001). There were no significant differences in pulse rate between hypertensives (71 beats/min) and normotensives (72 beats/min). Also, 24 hr urinary sodium and potassium excretion was not different between the groups.In normotensives a positive relation between plasma noradrenaline and systolic blood pressure, and a negative one between plasma dopamine and systolic blood pressure was observed. In hypertensives no significant association between noradrenaline, dopamine and systolic blood pressure was found.These findings provide evidence for the hypothesis that excessive sympathetic outflow plays a role in the early pathogenesis of hypertension. They also Indicate that dopaminergic activity may be Implicated in early hypertension.