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Studies in the early 1990s suggested that a hormone identical to ouabain or an isomer of ouabain is secreted by the adrenal glands into the circulation and plays a role in the regulation of arterial pressure and cardiac and renal function. This hormone, known as endogenous ouabain (EO), was claimed to contribute to the pathophysiology of a number of disorders including heart failure, renal failure, pregnancy-induced, and essential hypertension. However, some research groups have been unable to confirm the presence of EO in the human circulation and the issue remains in dispute. In that the implications are of considerable importance to clinicians who, like the authors, lack biochemical expertise, it would be useful if the dispute could be addressed by disinterested scientists with long-standing and acknowledged expertise in analytical chemistry who could opine as to whether the evidence is, or is not, sufficient to state categorically that EO does (or does not) exist in the circulation in man. This brief review does not present new data but, rather, recommends that adjudication is needed regarding this important issue. © 2018 BioFactors, 44(3):219-221, 2018., (© 2018 International Union of Biochemistry and Molecular Biology.)

Background: Our aim was to examine the effects of adjunctive coenzyme Q(10) therapy on 24-h ambulatory blood pressure (BP) in subjects with the metabolic syndrome and inadequate BP control., Methods: In a randomized, double-blind, placebo-controlled 12-week crossover trial, coenzyme Q(10) (100 mg twice daily) or placebo was administrated to 30 subjects with the metabolic syndrome, and inadequate BP control (an average clinic BP of ≥140 systolic mm Hg or ≥130 mm Hg for patients with type 2 diabetes) while taking an unchanged, conventional antihypertensive regimen. Clinic and 24-h ambulatory BP were assessed pre- and post-treatment phases. The primary outcomes were the changes in 24-h systolic and diastolic BP during adjunctive therapy with coenzyme Q(10) vs. placebo and prespecified secondary outcomes included changes in BP loads., Results: Compared with placebo, treatment with coenzyme Q(10) was not associated with statistically significant reductions in systolic (P = 0.60) or diastolic 24-h ambulatory BP (P = 0.12) or heart rate (P = 0.10), although daytime diastolic BP loads, were significantly lower during coenzyme Q(10) administration with thresholds set at >90 mm Hg (P = 0.007) and ≥85 mm Hg (P = 0.03). Coenzyme Q(10) was well tolerated and was not associated with any clinically relevant changes in safety parameters., Conclusions: Although it is possible that coenzyme Q(10) may improve BP control under some circumstances, any effects are likely to be smaller than reported in previous meta-analyses. Furthermore, our data suggest that coenzyme Q(10) is not currently indicated as adjunctive antihypertensive treatment for patients with the metabolic syndrome whose BP control is inadequate, despite regular antihypertensive therapy.

Aims: Autonomic nervous system dysfunction is observed in Type 2 diabetes. As gestational diabetes is a potent risk factor of later Type 2 diabetes, we set out to determine whether autonomic nervous system imbalance could already be observed in women with this condition. Because activity of the sympathetic nervous system tends to be relatively stable in the nocturnal hours, we performed the study at night., Research Design and Methods: We studied 41 women with gestational diabetes, 22 healthy pregnant controls and 14 non-pregnant controls. We assayed plasma noradrenaline at 24.00, 04.00 and 07.00 h and performed an overnight Holter recording for heart rate variability analysis. In addition, we assayed plasma adrenomedullin, a cardiovascular protective hormone., Results: Compared with non-pregnant controls, plasma noradrenaline levels were increased at 04.00 and 07.00 h in the gestational diabetic (P = 0.003) and pregnant control (P = 0.002) groups, with no difference between them. Heart rate variability, very-low-frequency and low-frequency power were lower in pregnant groups compared to the non-pregnant controls. Heart rate variability remained unchanged between specified sampling times in the gestational diabetic group, in contrast to fluctuation seen in the control groups., Conclusions: Gestational diabetes, compared with normal pregnancy, seems not to be a state of overall sympathetic nervous system activation. At the heart level, however, an inhibitory effect on autonomic nervous system modulation was seen. Plasma noradrenaline and heart rate variability correlated well, supporting the use of this function in future studies of overall sympathetic activity during pregnancy.

The time course of cardiac sympathetic nerve activity (CSNA) following acute myocardial infarction (MI) is unknown. We therefore undertook serial direct recordings of CSNA, arterial blood pressure (MAP) and heart rate (HR) in 11 conscious sheep before and after MI, and compared them with 10 controls. Conscious CSNA recordings were taken daily from electrodes glued into the thoracic cardiac nerves. Infarction was induced under pethidine and diazepam analgesia by applying tension to a coronary suture. MI size was assessed by left ventricular planimetry (%) at postmortem, peak troponin T and brain natriuretic peptide levels (BNP). Baroreflex slopes were assessed daily using phenylephrine-nitroprusside ramps. The mean infarcted area was 14.4 +/- 2.9%, troponin T 1.88 +/- 0.39 microg l(-1) and BNP 8.4 +/- 1.3 pmol l(-1). There were no differences in haemodynamic parameters or CSNA between groups at baseline. MAP and HR remained constant following MI. CSNA burst frequency increased from baseline levels of 55.8 +/- 7.1 bursts min(-1) to levels of 77.5 +/- 8.7 bursts min(-1) at 2 h post-MI, and remained elevated for 2 days (P < 0.001). CSNA burst area also increased and was sustained for 7 days following MI (P= 0.016). Baroreflex slopes for pulse interval and CSNA did not change. CSNA increases within 1 h of the onset of MI and is sustained for at least 7 days. The duration of this response may be longer because the recording fields decrease with time. This result is consistent with a sustained cardiac excitatory sympathetic reflex.

We conducted a randomized crossover trial to establish, within patients, whether long-slow hemodialysis (HD) was associated with better blood pressure (BP) control than standard HD. Nine home HD patients, not on antihypertensive drugs, were dialyzed to the same eKt/V(urea) and target weights for 6-8 h (LD) at home and for 3.5-4.5 h (SD) in the dialysis center 3 times weekly in randomized sequence, with each phase lasting 8 weeks. Ambulatory BP, bioimpedance, neurohormones and autonomic function were measured in each phase. Pre- and postdialysis systolic, ambulatory systolic and diastolic BP were all higher with SD than with LD and intradialysis hypotension was more common. Weight, ECF volume and neurohormones did not differ between treatments. Muscle sympathetic activity was increased in both phases and cardiac sympathetic activity tended higher during SD. These findings suggest that additional factors to ECF volume may contribute to the superior BP control produced by long-slow HD., (Copyright 2001 S. Karger AG, Basel.)

Biologic actions attributed to adrenomedullin include reduction of arterial pressure and suppression of aldosterone secretion. To assess possible in vivo antiangiotensin II actions of adrenomedullin, we examined hemodynamic and adrenal responses to stepped angiotensin II infusions with or without co-infusions of adrenomedullin (33 ng/kg/min) in conscious sheep under controlled conditions of a low sodium intake. Plasma adrenomedullin levels rose during peptide infusions (p < 0.001) to plateau at approximately 15-18 pM. The dose-dependent pressor response (15-20 mm Hg) of angiotensin II was both delayed and markedly attenuated (p = 0.017) by adrenomedullin, which also stimulated heart rate (p < 0.001) and cardiac output (p < 0.001). Adrenomedullin prevented the angiotensin II-induced increase in peripheral resistance (p < 0.001). Plasma aldosterone responses to angiotensin II were variable and were not significantly altered by concomitant adrenomedullin infusion. In conclusion, low-dose infusion of adrenomedullin administered to conscious sheep on a low-salt diet clearly antagonized the vasopressor actions of administered angiotensin II while stimulating cardiac output and heart rate. The data suggest a possible role for adrenomedullin in cardiovascular homeostasis in part through antagonism of the vasopressor action of angiotensin II.

Ouabain is claimed to be a hormone of adrenal origin, capable of raising arterial pressure in rats. We infused ouabain in conscious sheep under carefully controlled circumstances to determine its effects on blood pressure, urine electrolytes, and vasoactive hormones. Eight healthy ewes were studied while taking a constant intake of dietary sodium and potassium. Ouabain infusion at 0.25 mg daily over 22 days reduced heart rate and arterial pressure and had no effect on pressor responsiveness to incremental intravenous infusions of angiotensin II. Ouabain induced minor, but statistically significant, decrements in urine volume, urinary sodium excretion, plasma renin and angiotensin II concentrations, and a rise in plasma aldosterone and cortisol. Plasma ouabain levels averaged 1.37 +/- 0.28 nmol/l during ouabain infusion. In conclusion, high-dose chronic ouabain infusion in sheep did not elevate arterial pressure or alter pressor responsiveness to angiotensin II, was antidiuretic and antinatriuretic, and induced minor perturbations in circulating renin, angiotensin II, aldosterone, and cortisol.

Objective: To examine the factors that determine the blood pressure response to enalapril and nifedipine monotherapy in the treatment of hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM)., Research Design and Methods: After a 6-week placebo baseline period, 102 hypertensive NIDDM patients were randomly assigned, double-blindly, to treatment with nifedipine retard (slow release) (n = 52) or enalapril (n = 50). The daily dosage of enalapril was increased, if required, from 10 to 20 to 40 mg and that of nifedipine from 40 to 60 to 80 mg at 4-week intervals during the 12-week titration period. Blood pressure, 24-h urinary albumin excretion (UAE), biochemical data, and serum angiotensin-converting enzyme (ACE) activity were measured at weeks -6, -4, 0, 4, 8, and 12. At week 0, venous blood was also sampled for baseline plasma atrial natriuretic peptide, renin, aldosterone, and serum insulin concentrations., Results: At week 12, the mean daily dose of enalapril was 35 +/- 11.4 mg, and 27 (57%) patients were receiving the maximum daily dose of 40 mg. In the nifedipine group, the mean daily drug dose was 50 +/- 12.9 mg, and 4 (8%) were receiving the maximum daily dose of 80 mg. Despite a dose-dependent fall in the serum ACE activity in the enalapril group, the mean arterial pressure (MAP) was reduced by only 8 mmHg throughout the 12-week titration period compared to a decline of 15, 18, and 19 mmHg at weeks 0, 4, and 12, respectively, in the nifedipine group (P = 0.01 between groups). In the enalapril group, changes in MAP between weeks 0 and 12 correlated significantly with baseline plasma glucose (r = 0.45, P = 0.001) and aldosterone concentrations (r = -0.32, P = 0.02) and UAE (r = 0.3, P = 0.04). There was no statistically significant correlation between the changes in MAP and baseline plasma renin concentration. On multivariate analysis, the baseline renal function, glycemic control, and plasma aldosterone and serum insulin concentrations were all independently related to the changes in blood pressure in the enalapril-treated patients. No such statistical associations were observed in the nifedipine group., Conclusions: In hypertensive NIDDM patients, the activity of the renin-angiotensin-aldosterone system, the level of serum insulin, glycemic control, renal function, and proteinuria may be important determinants of the blood pressure response to ACE inhibition. Good glycemic control may optimize the antihypertensive efficacy of concomitant ACE inhibitor therapy.

To assess the effects of ouabain on pressor and vasoactive hormone responsiveness, 10 healthy volunteers were pretreated with ouabain (0.5 mg i.v. 42 and 18 h before study) or placebo before pressor challenge with angiotensin II (ANG II; 2, 4, and 8 ng.kg-1.min-1 for 30 min/dose) and norepinephrine (NE; 5, 15, and 45 ng.kg-1.min-1 for 15 min/dose). There were no differences at baseline between the two study days regarding mean arterial pressure (MAP) or heart rate. Baseline pulse pressure, however, was significantly greater after ouabain (47 +/- 3 vs. 41 +/- 1 mmHg; P < 0.05). The mean maximum increments in MAP during ANG II and NE infusions were 17.5 +/- 1.1 and 10.5 +/- 1.3 (SE) mmHg, respectively, after ouabain and 19.2 +/- 1.3 and 10.4 +/- 1.5 mmHg after placebo (not significant). The mean heart rate was lower during both infusion periods on the ouabain study day compared with control (P < 0.05). Baseline plasma levels of ANG II, aldosterone, plasma renin activity, atrial and brain natriuretic peptide, guanosine 3',5'-cyclic monophosphate, NE, and epinephrine and achieved levels during the two infusions were similar on the two study days. We conclude that short-term ouabain administration does not alter pressor responsiveness or plasma levels of vasoactive hormones in healthy volunteers.

The response of arterial BP and intracranial pressure to an intravenous injection of the serotonin antagonist, ketanserin, was recorded in ten patients with hypertension following intracerebral haemorrhage. Five minutes after ketanserin administration, arterial pressure had fallen by 40/21 mmHg from a baseline level of 213/113 mmHg, and remained below pre-treatment levels for two hours. Intracranial pressure was steady throughout the two hour observation period. Although calculated cerebral perfusion pressures declined and whereas it is not known if cerebral perfusion might have been compromised in zones of borderline ischaemia, the present data suggest that ketanserin might be preferred to drugs known to raise intracranial pressure or agents requiring infusion and intensive haemodynamic monitoring for patients with severe hypertension complicating intracerebral haemorrhage.

The effect of subcutaneous and intraperitoneal administration of recombinant human erythropoietin (rHuEPO) on blood pressure was evaluated in 20 patients with renal failure on continuous ambulatory peritoneal dialysis. The two groups of patients were commenced on a 16-week course of twice weekly rHuEPO by either the subcutaneous (10 patients) or the intraperitoneal route (10 patients). One patient in the latter group was subsequently excluded because of operation and transfusion. The hemoglobulin increased significantly from 6.9 +/- 0.3 g/dl to 9.8 +/- 0.6 g/dl after subcutaneous rHuEPO treatment (p less than 0.01) at an average dose of 84 +/- 9 U/kg body weight/week. For the intraperitoneal group, despite a higher average rHuEPO dosage (133 +/- 7 U/kg body weight/week), the hemoglobin level was not significantly altered (7.0 +/- 0.4 g/dl to 8.0 +/- 0.4 g/dl, p less than 0.05). During the 16-week period of rHuEPO therapy, an increase in antihypertensive therapy was required more frequently in patients in the intraperitoneal group but the difference between groups failed to reach statistical significance. There was no conclusive evidence that the rise in hematocrit was an independent precipitant of hypertension. Patients who were hypertensive prior to rHuEPO therapy appeared most susceptible to the pressor effects in that 8 of 11 treated hypertensive patients required more intensive antihypertensive treatment during EPO administration whereas none of the untreated patients developed hypertension during the study (Fisher's exact test, p = 0.007). Plasma levels of the vasoactive hormones, atrial natriuretic peptide (ANP), plasma renin activity (PRA), and endothelin (ET) remained unchanged during both subcutaneous and intraperitoneal rHuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of an abrupt reduction in atrial pressures on atrial natriuretic peptide (ANP) secretion was studied in four patients with complete atrioventricular block with a dual-chamber pacemaker when the pacing mode was changed from the VVI to the DVI mode at an equal rate of 70/min. Simultaneous continuous hemodynamic monitoring was performed using a balloon-tipped thermodilution catheter. With DVI pacing, there was an immediate decrease of right atrial pressure from 4.5 +/- 0.9 to 1.8 +/- 1.1 mm Hg, and a reduction of pulmonary arterial wedge pressure from 7 +/- 0.8 to 4.5 +/- 0.9 mm Hg, together with a rise in cardiac output from 3.1 +/- 0.2 to 3.7 +/- 0.2 L/min. However, despite a constant hemodynamic status after dual-chamber pacing, the arterial ANP level steadily decreased from 151 +/- 26 pg/ml to a steady low level of 78 +/- 15 pg/ml after 20 minutes of dual-chamber pacing (percentage reduction- 48 +/- 8%, p less than 0.05). This persisted until the end of the study at 60 minutes. The time-dependent decay in ANP secretion after an abrupt and constant change in hemodynamic status should be considered when interpreting ANP levels.

Felodipine, 10 mg twice daily, and placebo were administered for 5 weeks to ten untreated essential hypertensives in a double-blind, random-order, crossover study. At the end of each phase patients were assessed by 36 hours of continuous intraarterial blood pressure recordings, both during normal activities and specified activities. Patients were also assessed by 36-hour Holter analysis, maximal exercise testing, radionuclide cardiac scan, and measurement of endogenous creatinine clearance and 2-hourly vasoactive hormones. Arterial pressure was significantly reduced by felodipine, with mean falls in blood pressure of 25.1 mmHg and 12.5 mmHg (systolic and diastolic, respectively) over 24 hours. Blood pressure was reduced by felodipine during moderate and maximal exercise and mental stress. There were no significant changes in heart rate, exercise capacity, ventricular ectopy, endogenous creatinine clearance, or vasoactive hormones.

The variability of pulmonary arterial pressure, the relation of pulmonary pressure to systemic pressure, pulmonary pressure responses to stimuli (exercise, hypoxia, smoking, free ambulation), and plasma catecholamine responses were assessed in five patients with primary pulmonary hypertension. Ambulatory monitoring techniques provided data for the computerised analysis of continuous, beat-to-beat, direct recordings of both pulmonary and systemic arterial pressures for 8 to 10 hours. The absolute variability of pulmonary arterial pressure and the magnitude of absolute changes in this variable in response to stimuli were increased in primary pulmonary hypertension. The variability of systemic pressure was similar to that in healthy volunteers. Basal and stimulated plasma catecholamine values were normal, suggesting preservation of normal sympathetic nervous system activity in primary pulmonary hypertension.

We used continuous intra-arterial pressure monitoring and hourly venous hormone sampling over 24 hours in 5 patients with primary aldosteronism to study blood pressure and hormone regulation. Three patients were restudied under identical conditions of controlled diet electrolyte intake and body posture 3-7 months after removal of the aldosterone-secreting adrenal tumor. Prior to surgery there was no positive relationship of arterial pressure to renin or to aldosterone. Norepinephrine fluctuations showed positive correlations with arterial pressure but these 2 indices were more closely related after surgery. Plasma aldosterone levels paralleled those of cortisol both before and after cure of primary aldosteronism. Aldosterone/cortisol regression lines were steeper before surgery, and norepinephrine/renin regression lines were steepened in the post-operation studies. Our findings indicate that in established primary aldosteronism, fluctuations in arterial pressure are regulated in part by the sympathetic nervous system: the pattern of aldosterone secretion is controlled mainly by ACTH: aldosterone responsiveness to endogenous ACTH is enhanced: and sympathetic modulation of renin release in inhibited.

To investigate the regulation of arterial pressure and vasoactive hormones in phaeochromocytoma, we measured intra-arterial pressure and hourly venous hormones (renin, angiotensin II, aldosterone, catecholamines and cortisol) for 24 h in two patients before and three months after removal of a catecholamine-secreting tumour. Before surgery, plasma catecholamines, renin and angiotensin II levels showed a weak inverse correlation with arterial pressure, whereas after surgery norepinephrine-blood pressure correlations were close and positive. Heart rate and arterial pressure fluctuations were reciprocal during short-term recordings but were parallel after removal of the tumour. Renin, angiotensin II and aldosterone levels, initially elevated, fell into the normal range after surgery. Circulating norepinephrine correlated in a positive fashion with renin before and after operation. Slopes of log renin (or angiotensin II)/aldosterone, and log cortisol/ aldosterone regression lines were steeper in the initial study compared to the second. We conclude that arterial pressure fluctuations measured hourly are not determined by concurrent levels of catecholamines or angiotensin II in phaeochromocytoma, although we surmise that minute-by-minute changes in blood pressure are catecholamine-related. Renin release is, at least in part, controlled by circulating catecholamines. Aldosterone responsiveness to angiotensin II and to ACTH is enhanced in phaeochromocytoma.

To assess the effects of improved glycaemic control on arterial pressure and plasma levels of vasoactive hormones, we studied 5 male insulin dependent (Type 1) diabetic patients before and one month after commencement of rigorous control of blood glucose levels. On each occasion, continuous ambulatory intra arterial pressure monitoring for a 10-hour period, together with hourly venous sampling for plasma glucose and vasoactive hormone determinations, was performed under standardised conditions of diet and posture. Mean (+/- SEM) plasma glucose before and after improved glycaemic control was 9.4 +/- 0.3 and 6.6 +/- 0.4 mmol/l respectively (P less than 0.001). There was a small but significant fall in arterial pressure in each patient as well as for the group overall (mean arterial pressure fall 4.8 +/- 1.2 mmHg, p less than 0.01) after improved glycaemic control. The fall in individual (10 hr mean) diastolic arterial pressure levels correlated with concomitant falls in plasma glucose levels (r = 0.92, p less than 0.05) but not with changes in any of the other variables measured.

Following an intravenous infusion of methylphenidate (0.3 mg/kg) there were significant increases in plasma epinephrine, heart rate, systolic and diastolic pressure, but there was no change in plasma norepinephrine. This pattern of response differs from that seen with D-amphetamine or caffeine.

The effect of an acute and sustained reduction in atrial pressure on atrial natriuretic factor (ANF) and vasoactive hormone secretion was studied in 9 patients with congestive heart failure (CHF). Intravenous nitroglycerin was titrated to reduce the pulmonary artery wedge pressure by 30 to 50% and maintain this reduction for 4 hours. After 60 minutes of nitroglycerin administration, the mean decrement in wedge pressure was 10.0 +/- 1.7 (standard error) mm Hg (35%) and plasma ANF was 65.3 +/- 13.9 pmol/liter (35%). The initial decrease, sustained reduction and later increase in plasma ANF levels closely paralleled the changes in pulmonary arterial wedge (r = 0.94, p less than 0.0001) and right atrial pressures (r = 0.91, p less than 0.0001) during and immediately after the nitroglycerin infusion. Plasma aldosterone and cortisol levels increased during the first 2 hours of the nitroglycerin infusion, but there was little change in plasma norepinephrine or plasma renin activity. Although levels were elevated in CHF, plasma ANF still responded rapidly to changes in atrial pressure. A sustained reduction in pressure produced a sustained reduction in ANF levels. These findings provide further support for a regulatory role of ANF, even in chronic CHF.

The factors determining the outcome of blood pressure after removal of the aldosterone-secreting adenoma in primary aldosteronism are largely unknown. We have studied the results of surgery in 21 patients with this disorder, all of whom were investigated and treated in a single referral centre, and evaluated the contributions of clinical, biochemical and pathological factors to blood pressure outcome. Blood pressure before surgery was high (mean 210/121 mmHg), but after an average period of 5.4 years 12 patients (60 per cent) were considered by their primary physician not to require antihypertensive medication and a further seven had reduced drug requirements. In only two patients was arterial pressure unimproved by surgery. Blood pressure recordings within six months of surgery were not a good predictor of later levels. Of the clinical, electrolyte, hormone and pathological features assessed, only the systolic pressure before surgery, and abnormalities in the optic fundi, correlated statistically with final blood pressure ranking. There was no relationship between the severity of vascular changes in the adrenal or kidney biopsy tissue and final blood pressure. These results show that while the blood pressure response to the removal of a single adrenal adenoma is usually good, it is not possible to predict accurately the final blood pressure response using these criteria.

To determine whether moderate restriction of dietary sodium content or supplementation of potassium intake reduces blood-pressure in patients with mild essential hypertension, twelve patients were put on three different diets--a control diet (180 mmol sodium/day), a sodium restricted diet (80 mmol/day). Each diet was taken for at least 4 weeks and the sequence of the regimens was randomised. At the completion of each regimen intra-arterial pressure was recorded continuously, and vasoactive hormones were measured hourly, for 24 h, under standardised conditions, in hospital. Compared with the control diet, sodium restriction was associated with lower blood-pressure readings in seven patients, higher levels in five, and an overall reduction in mean pressures of only 4.0/3.0 mm Hg (not significant). Individual differences in blood-pressure between these two diets correlated closely with concomitant differences in plasma renin activity (r = 0.75). Potassium supplementation also resulted in variable changes in arterial pressure, and the mean difference in pressure recordings (0.1/0.8 mm Hg) was insignificant. The results show that moderate restriction of sodium intake or supplementation of dietary potassium has variable effects on arterial pressure in individuals with mild essential hypertension, and that overall the blood-pressure changes induced are very small. Responsiveness of the renin-angiotensin system may limit the fall in blood-pressure induced by sodium restriction.

The role of the brain opioid system in the control of hypothalamic-pituitary-adrenal activity was studied in 10 conscious sheep with an indwelling cannula in a cerebral lateral ventricle. On separate days, sheep received infusions of artificial CSF (control) and the opiate antagonist, naloxone (100 micrograms/hr) before and during acute moderate hemorrhage (15 ml/kg over 10 min). Infusion of naloxone before hemorrhage raised plasma ACTH and resulted in a significant increase in cortisol compared to the control infusion. In contrast, ACTH and cortisol responses to hemorrhage tended to be blunted by central naloxone infusion. The responses of vasopressin, aldosterone and the catecholamines remained unaffected by naloxone. The fall in blood pressure and the rise in heart rate accompanying hemorrhage were likewise unaltered. These results suggest that brain opioid peptides have an inhibitory effect on basal ACTH secretion but do not play a major role in modulating the hemodynamic or pituitary-adrenal responses to acute moderate hemorrhage in conscious sheep.

Six healthy volunteers were studied by use of a continuous ambulatory recording technique to document the normal range and variability of pulmonary artery pressure (PAP) and to examine its relationship to systemic arterial pressure (SAP) both at rest and during standardized interventions. Vasoactive hormone levels were measured at frequent intervals. Over 8-10 h of study the mean PAP was 15.7/6.3 mmHg. Parallel changes in PAP and SAP were observed at rest and during exercise and eating. On the contrary, PAP rose and SAP fell with hypoxia, whereas smoking was associated with a rise in SAP but no change in PAP. Sympathetic nervous system activity, as gauged by plasma norepinephrine levels, may have contributed to pressure and heart rate changes during exercise and smoking, but activity of the renin-angiotensin system was not altered by any of the maneuvers. These results provide base-line information on the level of PAP and its variability in healthy volunteers under standardized conditions. Pressures within the systemic and pulmonary circuits change in parallel under some circumstances but move in opposite directions under other conditions.

The effects of moderate restriction of dietary sodium and potassium supplementation on plasma levels of renin, angiotensin II, aldosterone, and cortisol and on arterial pressure were studied in 12 patients with mild essential hypertension. To define hormone-blood pressure relationships, venous hormone levels were measured hourly and intra-arterial pressure continuously for 24 hours after 4 to 6 weeks of sodium restriction, 4 to 6 weeks of potassium supplementation, and a similar period of control diet. Our results show that compared with the control diet, moderate sodium restriction was associated with increased levels of aldosterone but no overall change in renin, angiotensin II, or cortisol levels. Further, slopes of regression lines relating log renin and log angiotensin II to aldosterone were increased, as were log cortisol/aldosterone regression lines. On the contrary, regression lines of log renin and log angiotensin II versus arterial pressure were unaltered by sodium restriction. Hormone and blood pressure relationships were not changed by the potassium supplemented diet. Although confirmatory data are needed, our findings suggest that moderate sodium restriction enhances aldosterone responsiveness to endogenous angiotensin II and adrenocorticotropic hormone without diminishing the pressor activity of endogenous angiotensin II. These results may explain in part the disappointingly small hypotensive effect of modest sodium restriction in mild essential hypertension.

To investigate the regulation of arterial pressure and vasoactive hormones in hypothyroidism associated with hypertension, we measured intra-arterial pressure and hourly venous hormones (renin, angiotensin II, aldosterone, catecholamines and cortisol) for 24 hours in five hypertensive patients with primary hypothyroidism before commencing treatment, and again after three to six months of thyroxine replacement therapy. Arterial pressure fell significantly after thyroxine replacement in four patients. Thyroxine treatment was associated with a fall in plasma norepinephrine levels together with a decline in slopes of norepinephrine/arterial pressure regression lines which suggests that the sympathetic system may contribute to the hypertension in hypothyroidism. Variability of heart rate, blood pressure and plasma norepinephrine fell with thyroxine replacement consistent with impaired damping of swings in sympathetic activity in the untreated state. Reciprocal changes in arterial pressure and renin-angiotensin-aldosterone system activity suggested that this system was not the mediator of hypertension in hypothyroidism.

In order to determine arterial pressure and vasoactive hormone relationships in normotensive man, we measured intra-arterial pressure continuously along with hourly venous hormone levels (renin, angiotensin II, aldosterone and catecholamines) for 24 hours in 5 healthy volunteers under standardized conditions. Mean 24-hour levels of intra-arterial pressure 106/63 +/- 5.4/4.9 mmHg were much lower than in patients with mild essential hypertension studied earlier. A common diurnal pattern was seen for plasma renin, angiotensin II, and catecholamines, with higher levels in the day time and lower levels at night. Aldosterone levels however, paralleled those of cortisol at night. Plasma norepinephrine levels showed close, positive correlations with arterial pressure in all volunteers. We conclude that the level of blood pressure as measured continuously over 24 hours is lower than might be expected from regular clinic recordings; that aldosterone regulation is contributed to by ACTH in the nocturnal hours; and that fluctuations in arterial pressure and sympathetic activity over 24 hours are closely coupled.

Research on the physiological role of atrial peptides in man is limited, and the potential for these peptides, or more stable analogues, in therapeutics is uncertain. It is clear, however, that plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP) are increased in volunteers taking a high sodium diet, and are elevated in patients with heart failure, chronic renal failure, and primary aldosteronism. There is suggestive evidence that IR-ANP levels are increased also in essential hypertension, although overlap with normotensives is considerable. Injection or infusion of atrial peptides into man results in a diuresis, an increased output of urine electrolytes, a fall in blood pressure and a rise in heart rate, suppression of aldosterone and sometimes of renin also, and stimulation of norepinephrine. In essential hypertensives, urinary effects may be greater than in normotensives. Heart failure patients show a rise in cardiac output and falls in both systemic and pulmonary arterial pressure. Over the next few years and especially if specific antagonists can be developed, the physiologic and pathophysiologic roles of atrial peptides in normal man and in clinical disorders should be clarified. It is possible that stable analogues of atrial peptides will find a place in the treatment of cardiac failure, renal failure, and perhaps hypertension.

This study documents the determinants and plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) among hypertensive and normotensive subjects in a multi-ethnic population in the United Arab Emirates (UAE). We obtained demographic, anthropometric and clinical data, together with fasting NT-proBNP and biochemical indices from 128 hypertensive patients and 138 normotensive subjects matched for age, gender and ethnicity. Plasma NT-proBNP levels were significantly (P<0.001), and several-fold higher among hypertensives (median 5.92, inter quartile range (IQR): 1.79–18.48 pmol/l) than normotensives (median 1.78, IQR: 0.59–4.32 pmol/l) in the total study population, and the same was true for the ethnic groups separately. Similarly, plasma levels of glucose, blood urea nitrogen (BUN) and creatinine, but not insulin, were significantly (P<0.05) higher among hypertensives than normotensives. For all subjects combined, log NT-proBNP correlated positively and significantly with age (P<0.01), log glucose (P<0.05), systolic blood pressure (SBP, P<0.001), log BUN (P<0.001) and log creatinine (P<0.001). Multivariate regression analysis showed that NT-proBNP levels were independently and positively correlated with SBP, age, gender, log BUN, Emirati and South East Asian ethnic groups and inversely associated with current exercise. In conclusion, we found circulating levels of NT-proBNP to be significantly increased in hypertensive versus normotensive subjects in the UAE and independently related to SBP, age, gender, indices of renal function and possibly exercise. Our results further suggest a possible modulating effect of ethnicity on NT-proBNP levels.Journal of Human Hypertension (2007) 21, 647–653; doi:10.1038/sj.jhh.1002210; published online 26 April 2007 [ABSTRACT FROM AUTHOR]

Hypertension has been the single most important risk factor for heart failure until the last few decades. Now, it is frequently claimed that atherosclerotic coronary artery disease dominates as the major underlying cause, and hypertension is of lesser importance. We here review evidence regarding the contribution of hypertension to heart failure in the recent decades. It is not possible, in our view, to be confident of the relative importance of hypertension and coronary artery disease since there are significant limitations in the available data. The often-questionable diagnostic criteria used in defining heart failure is one such limitation. The absence or inadequacy of blood pressure recordings over the years prior to a diagnosis of heart failure seriously hinders the reaching of firm conclusions in many reports. Extrapolations from aetiological observations in one racial group to those in other racial groups, and from highly selected study groups in tertiary referral centres to patients with heart failure in primary and secondary care, may not be justified. Finally, the situation of heart failure primarily due to impaired left ventricular diastolic function, where hypertension is a frequent precursor, is often ignored in discussions of aetiology. Our view is that hypertension remains and probably is the single most, important modifiable risk factor for cardiac failure in some races and countries, where the dominant cardiac abnormality is left ventricular diastolic dysfunction. The situation is less clear for patients with heart failure primarily due to left ventricular systolic dysfunction.Journal of Human Hypertension (2005) 19, 267-275. doi:10.1038/sj.jhh.1001820 Published online 20 January 2005 [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the normality or otherwise of neurohormone indices, particularly the sympathetic nervous system, in pre-eclamptic patients and document whether changes in body posture magnify any differences between pre-eclamptic and normal women. We studied 11 women with pre-eclampsia and compared them with 17 matched normotensive pregnant women and eight nonpregnant women. Measurements of arterial pressure, heart rate and neurohormones were carried out with subjects in the left lateral position, then supine, left lateral, with upright posture and finally with assumption of the left lateral position again. Main outcome measures were arterial pressure, heart rate and hormones (plasma norepinephrine, renin activity, natriuretic peptides and endothelin-1). We observed that plasma norepinephrine levels were higher in pre-eclamptic than normotensive pregnant women and this was most obvious in the upright position. Plasma renin activity was likewise higher in pre-eclamptic than normotensive pregnant women, again most obvious with upright posture. Plasma natriuretic peptides and endothelin-1 levels were similar in pre-eclamptics and normotensive pregnant women. These data strengthen the premise that pre-eclampsia is associated with sympathetic overactivity as reflected by plasma norepinephrine levels, most obviously observed in the upright position.Journal of Human Hypertension (2004) 18, 789-794. doi:10.1038/sj.jhh.1001743 Published online 3 June 2004 [ABSTRACT FROM AUTHOR]

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. Background. In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 ± 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. Methods. After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (β-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). Results. In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs.... [ABSTRACT FROM AUTHOR]