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Objectives: Previous studies have demonstrated that high-dose allopurinol is able to regress left ventricular (LV) mass in cohorts with established cardiovascular disease. The aim of this study was to assess whether treatment with high-dose allopurinol would regress LV mass in a cohort with essential hypertension, LV hypertrophy and well-controlled blood pressure but without established cardiovascular disease. Methods: We conducted a mechanistic proof-of-concept randomized, placebo-controlled, double-blind trial of allopurinol (600 mg/day) versus placebo on LV mass regression. Duration of treatment was 12 months. LV mass regression was assessed by Cardiac Magnetic Resonance. Secondary outcomes were changes in endothelial function (flow-mediated dilatation), arterial stiffness (pulse wave velocity) and biomarkers of oxidative stress. Results: Seventy-two patients were randomized into the trial. Mean baseline urate was 362.2 ± 96.7 μmol/l. Despite good blood pressure control, LV mass regression was significantly reduced in the allopurinol cohort compared with placebo (LV mass −0.37 ± 6.08 versus −3.75 ± 3.89 g; P = 0.012). Oxidative stress markers (thiobarbituric acid reactive substances) were significantly higher in the allopurinol group versus placebo (0.26 ± 0.85 versus −0.34 ± 0.83 μmol/l; P = 0.007). Other markers of vascular function were not significantly different between the two groups. Conclusion: Treatment with high-dose allopurinol in normouricemic controlled hypertensive patients and LV hypertrophy is detrimental. It results in reduced LV mass regression and increased oxidative stress over a 12-month period. This may be because of an adverse impact on redox balance. Cohort selection for future cardiovascular trials with allopurinol is crucial.

Objective:Urate is the most abundant aqueous antioxidant in humans but is pro-oxidant under certain conditions. Allopurinol has been shown to regress left ventricular hypertrophy (LVH) in cohorts with established cardiovascular and cardio-renal disease. This study investigated the impact of lowering

Neuroendocrine activation may be an important adjunctive mechanism for left ventricular hypertrophy (LVH) development. Controversy exists to as to whether LVH regression occurs due to blood pressure (BP) reduction alone or if adjunctive mechanisms play a role. We planned to test the hypothesis that for a similar BP reduction, LVH regression would be greater using a drug combination selected specifically to reduce neuroendocrine activity compared with one that did not.Forty-two patients with hypertension and cardiovascular magnetic resonance (CMR) proven LVH were allocated to one of two equipotent antihypertensive regimens for 6 months. Treatments were chosen on the basis of opposing mechanistic actions on the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS); one arm inhibitory (valsartan and moxonidine), the other neutral (bendroflumethiazide and amlodipine). The primary end point was absolute reduction in CMR-determined left ventricular mass (LVM).All BP indices were highly comparable at the start and end of the trial (P 0.6 between groups). BP was reduced (always P 0.0001) by 37/17 mmHg in the valsartan and moxonidine group and 38/19 mmHg in the bendroflumethiazide and amlodipine group. CMR quantified LVM was comparable between the two groups at baseline and decreased significantly in both treatment groups (P 0.0001). Reduction in LVM was significantly greater in valsartan and moxonidine [-25.9 g; 95% confidence interval (CI) -31.6 to -20.2] compared with bendroflumethiazide and amlodipine (-18.3 g; -23.3 to -13.4) (P 0.05).The magnitude of LVH regression achieved by inhibiting the RAAS and SNS neuroendocrine pathways is greater than that produced by comparable BP reduction alone. This supports the hypothesis that neuroendocrine mechanisms are important in the regression of LVH.

OBJECTIVES We hypothesized that the aldosterone: renin ratio (ARR) predicts the antihypertensive response to mineralocorticoid receptor antagonist, spironolactone (SPIRO), when compared with bendroflumethiazide (BFZ). METHODS We conducted a randomized, crossover, trial on hypertensive patients with either high ARR (HARR defined as >750 and plasma aldosterone >250 pmol/l) or low ARR (LARR defined as

The Losartan Intervention For Endpoint Reduction (LIFE) study demonstrated a clear mortality benefit in treating hypertensive patients with electrocardiogram (ECG) evidence of left ventricular hypertrophy (LVH) with losartan rather than atenolol. Previous studies have also shown that identifying and treating echo LVH is associated with prognostic benefits in hypertensive subjects, and is independent of the presence of ECG LVH. We sought to determine how many cases of echo LVH would be missed by applying the ECG criteria for LVH used in the LIFE study.A prospective study of 219 patients with type 2 diabetes recruited from the hospital diabetic clinic.Fifteen ECG criteria were assessed on each subject and compared with the presence or absence of LVH on echocardiography.All the proposed ECG criteria are poor at identifying echo LVH in people with diabetes.Using ECG LVH to select patients for angiotensin receptor blockade would lead to many diabetics with echo LVH missing out on the benefits of treatment. This assumes that the benefits seen in the LIFE study would also occur if the LIFE strategy were extended to echo LVH patients as well as to ECG LVH patients.

The study of the pulse using the technique of applanation tonometry is undergoing a resurgence with the development of new computerized equipment. We aim here to present a critical review of the uses, potential uses, strengths and weaknesses of the technique of applanation tonometry for the assessment of augmentation index and pulse wave velocity. We will review the technique of applanation tonometry, the physiological factors affecting pulse wave velocity and pulse wave analysis, the changes in pulse wave velocity and pulse wave analysis with pharmacological interventions, and the use of the technique of applanation tonometry as a prognostic tool. We conclude that, although the technique of applanation tonometry initially seems promising, several pertinent issues need to be addressed before it can be used reliably as a clinical or research tool. Importantly, use of the technique of applanation tonometry to derive the central waveform from non-invasively acquired peripheral data needs to be validated prospectively.

The Sphygmocor system purports to be able to assess ascending aortic blood pressure using a transfer function. It has been shown to be accurate when data obtained invasively are used, but has not been tested prospectively using data obtained non-invasively.To investigate the accuracy of this equipment when measurements are obtained non-invasively, as would normally be the case in the clinic setting.The study was observational. Ascending aortic pressure measurements were taken simultaneously with radial artery pressure wave recordings for estimation of ascending aortic blood pressure, in 28 patients undergoing diagnostic cardiac catheterization.The transfer function in the Sphygmocor system significantly underestimated invasively measured systolic blood pressure [mean -7.23 +/- 10.07 mmHg; 95% confidence interval (CI) -3.3 to -11.14 mmHg, P = 0.001] and significantly overestimated invasively measured diastolic blood pressure (mean 12.20 +/- 7.14 mmHg; 95% CI 9.43 to 14.97 mmHg, P0.001). Oscillometrically measured brachial systolic blood pressure was not significantly different from that measured invasively in the ascending aorta (mean 3.36 +/- 10.47 mmHg; 95% CI -0.69 to 7.43 mmHg, P = 0.1), but oscillometric measurement of brachial diastolic blood pressure gave a significant overestimation of that measured invasively (mean 11.70 +/- 7.18 mmHg; 95% CI 8.91 to 14.49 mmHg, P0.001). CONCLUSIONS The transfer function in the Sphygmocor system is no better at estimating ascending aortic blood pressure than are standard peripheral blood pressure measurements. It may be necessary to derive a new transfer system that is based on data that are acquired entirely non-invasively.

Use of the aldosterone-to-renin ratio has controversially suggested that approximately 10% of hypertensives have primary aldosteronism, and most of these individuals are thought to have idiopathic hyperaldosteronism. The usual renin-angiotensin system control is intact in these individuals and is similar to that in low renin and essential hypertensives, differing only in the degree of sensitivity. There is recent evidence suggesting that hyperaldosteronism relates to aldosterone synthase genetic polymorphism, and also that increased angiotensin II stimulation of the adrenal glands appears to paradoxically upregulate the receptors increasing angiotensin II sensitivity. Taken together, the possibility arises that, in susceptible hypertensives, hyperaldosteronism could be acquired. Indeed, it is well known that renin-driven renovascular hypertension is associated with the development of hyperaldosteronism. Hypothetically, within the wider hypertensive population, these findings set the scene that angiotensin II adrenal sensitivity increases over time until the secretion of aldosterone becomes "autonomous" and hence "tertiary" aldosteronism in a significant proportion of hypertensives.

Orthostatic hypotension commonly accompanies supine hypertension, and is associated with low 25-hydroxyvitamin D levels. We tested whether high-dose intermittent oral vitamin D therapy could ameliorate orthostatic hypotension in older patients with isolated systolic hypertension.We conducted a subgroup analysis of data from a parallel-group, double-blind, randomized, placebo-controlled trial. Patients aged over 70 years with supine office SBP above 140 mmHg and DBP below 90 mmHg received 100 000 units oral vitamin D3 or matching placebo every 3 months for 1 year. Office supine and standing blood pressure were measured at baseline, and 3, 6, 9 and 12 months, along with arterial stiffness and flow-mediated dilatation of the brachial artery.Of 159 patients randomized to the main trial, 75 patients with orthostatic hypotension at baseline were included in this analysis. The mean age was 78 (SD 5) years, baseline blood pressure was 162/76 mmHg and the mean baseline orthostatic fall in blood pressure on standing was 32/5 mmHg. After adjustment for baseline age, 25-hydroxyvitamin D, SBP and orthostatic fall, the fall in SBP was less in the vitamin D group at 3 months [treatment effect 6 mmHg, 95% confidence interval (CI) 0 to 12], but repeated-measures analysis showed no significant treatment effect (3 mmHg for systolic fall, 95% CI -1 to 8; 1 mmHg for diastolic fall, 95% CI -1 to 3).Twelve months of intermittent, high-dose oral vitamin D3 did not significantly improve orthostatic hypotension in older patients with isolated systolic hypertension.

Introduction The natriuretic peptides and natriuretic peptide receptors may play a beneficial role in hypertension and heart failure and possibly in opposing associated detrimental cellular changes in the heart, vasculature and kidney. These responses may be, in part, modulated by the natriuretic peptide clearance receptor rather than the natriuretic peptide receptors (NPR-A or NPR-B). Objective To investigate the expression of the natriuretic peptide receptors (NPR-A,-B,-C) and the natriuretic peptides (ANP, BNP, CNP) in primary cultures of human proximal tubular cells and the role played by endogenously released natriuretic peptides in natriuretic peptide receptor expression. Results Northern analysis demonstrated that freshly isolated human proximal tubular cells express the NPR-C only. However, at confluence mRNA transcripts for both the NPR-A and -B were expressed, accompanied by a significant cyclic guanosine monophosphate (cGMP) response to ANP and CNP, indicating the development of functionally active receptors. A significant increase in immunoreactive ANP, BNP and CNP in the cell supernatant accompanied the appearance of these receptors. Incubation of freshly isolated cells with exogenous ANP, BNP, CNP or with the NPR-C specific ligand C (4-23) ANF induced similar changes in receptor expression, suggesting that these changes were mediated via the NPR-C rather than the NPR-A or -B. Conclusions Significant changes in peptide and receptor expression occur during cell culture and may be integrally linked, with functionally active NPR-A and -B occurring in response to an increase in the expression of the natriuretic peptides possibly acting at the NPR-C.

OBJECTIVE Recent evidence suggests the presence of a dual natriuretic peptide system consisting of atrial natriuretic factor (ANF) from the atrium and brain natriuretic peptide (BNP) from the ventricle. Discrete roles have been postulated for these two natriuretic peptides in the control of circulatory homeostasis. We have therefore compared the release of ANF and BNP in response to an acute saline load to explore a differential pattern of release for the two natriuretic peptides in man. DESIGN The effects of an acute saline infusion on plasma ANF and BNP concentrations were studied in 10 normal male volunteers. METHODS Subjects were studied on two study days in the semirecumbent position. An acute intravenous saline infusion (250 ml/min) of 18 ml/kg isotonic sodium chloride-potassium chloride solution was administered on one of the two study days. No infusion was administered on the other day as a control. RESULTS Plasma ANF concentrations increased significantly (P < 0.01) with saline loading without any detectable changes in plasma BNP concentrations up to 60 min following infusion. Heart rate and systolic and diastolic blood pressure were unchanged after saline loading. CONCLUSIONS We have shown that an acute intravenous saline load causes an increase in plasma ANF concentrations with no detectable increase in plasma BNP at least up to 60 min after the acute saline load in man. These results support the view that the release of ANF and BNP may be regulated differently, especially with regard to the time required for the acute release of each peptide.

To examine whether endogenous aldosterone can cause either arrhythmias (and some of their underlying mechanisms) or endothelial dysfunction in patients with coronary artery disease (CAD) but without heart failure.Aldosterone blockade has been shown to reduce the incidence of sudden death in patients with heart failure. This could be caused by a reduction in arrhythmias or in coronary events. Whether either effect also occurs in other cardiac patients without heart failure is currently unknown.We performed a randomized, placebo-controlled, double-blind crossover study on 98 patients with CAD but without heart failure on standard therapy, comparing 12.5-50 mg/day spironolactone (3 months) with placebo. Endothelial function was assessed by bilateral forearm venous occlusion plethysmography. Ventricular extrasystoles, procollagen III N-terminal peptide (PIIINP) and QT interval length were used to represent arrhythmias and their determinants.Spironolactone produced a highly significant 75% reduction in ventricular extrasystoles (median 192, range 48-744) on placebo compared with spironolactone (median 48, range 19.2-288, P0.003). Spironolactone also decreased the QT interval from a mean of 440 +/- 28 to a mean of 425 +/- 25 (P0.001) and a collagen marker (PIIINP) from a mean of 3.6 +/- 0.9 to a mean of 3.0 +/- 0.8 (P0.001), but did not significantly change endothelial dysfunction or heart rate variability.These results suggest that despite conventional therapy, endogenous aldosterone can be an arrhythmogenic influence in patients with CAD, but without heart failure. The possible mechanisms are that aldosterone promotes myocardial fibrosis and lengthens the QTc interval as well as decreasing potassium in CAD patients without heart failure.

Objective : To investigate the role of the renin-angiotensin-aldosterone system as a homoeostatic mechanism by examining whether mild activation of the renin-angiotensin-aldosterone system could enhance cyclosporin-induced renal vasoconstriction and hypertension. Methods : We artificially activated the renin-angiotensin-aldosterone system by two means : by pretreatment with frusemide (40 mg/day orally for 2 days) and by administering exogenous angiotensin II (1 ng/kg per min intravenously). In both cases the levels of renin-angiotensin-aldosterone system activation achieved did not by themselves alter renal blood flow, glomerular filtration rate or blood pressure. We then examined the effect of cyclosporin (10 mg/kg twice a day orally) in the presence of the activated renin-angiotensin-aldosterone system in normal humans. Results : Cyclosporin alone acutely altered neither glomerular filtration rate (760 versus 734 ml, NS ; area under the curve for placebo versus cyclosporin) nor effective renal plasma flow (4163 versus 3915 ml, NS ; area under the curve for placebo versus cyclosporin). Co-administration of exogenous angiotensin II with cyclosporin induced a fall in effective renal plasma flow from baseline but no change in glomerular filtration rate. Frusemide pretreatment together with cyclosporin administration induced a fall in glomerular filtration rate and a fall in effective renal plasma flow. Neither exogenous angiotensin II nor frusemide pretreatment influenced the blood pressure rise induced by cyclosporin. The present findings demonstrate that renin-angiotensin-aldosterone system activation augments cyclosporin-induced renal vasoconstriction but not cyclosporin-induced systemic vasoconstriction. We suggest that the renin-angiotensin-aldosterone system suppression, which normally occurs with cyclosporin, may be a homoeostatic mechanism to help prevent cyclosporin-induced renal vasoconstriction. The renin-angiotensin-aldosterone system appears, however, to play little or no role in mediating or preventing the initial increase in blood pressure caused by cyclosporin. Furthermore, frusemide is commonly prescribed together with cyclosporin even though this combination has the potential to cause a marked increase in renal dysfunction.

Objective : To elucidate the sequential mechanisms underlying cyclosporin-induced hypertension and nephrotoxicity. Design : A study of healthy males over the first 9 days of drug ingestion to permit the detection of serial changes in renal function and blood pressure in a situation free from the confounding variables of concomitant disease or drugs. Methods : Double-blind, placebo-controlled, randomized crossover study with cyclosporin (5 mg/kg twice a day) or placebo. Blood pressure and urinary sodium excretion were measured each day, and glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured on days 1, 4, 7 and 9. Cholesterol, lipoprotein (a) and endothelin were measured on days 1 and 9. Results : GFR decreased by 9% with cyclosporin and was significantly lower than with placebo on day 4 of therapy. ERPF fell by 24%. The fall in GFR correlated significantly with suppressed plasma renin activity (P

OBJECTIVE The present study examines the effect of angiotensin converting enzyme inhibition on the renal haemodynamic and sodium excretory responses to noradrenaline in man. DESIGN We studied the effects of intravenous noradrenaline (0.075 micrograms/kg per min) and enalapril pretreatment (5 mg/day for 5 days), alone and in combination, on urinary sodium excretion, effective renal plasma flow, glomerular filtration rate and segmental tubular function in nine normal subjects. METHODS The subjects were studied during maximal water diuresis. The clearance of inulin and of para-aminohippurate were used to estimate the glomerular filtration rate and effective renal plasma flow, respectively. Segmental tubule handling of sodium was assessed by the lithium clearance method. RESULTS Noradrenaline alone decreased urinary sodium excretion (P < 0.01) and the effective renal plasma flow (P < 0.01) without altering the glomerular filtration rate. Enalapril pretreatment significantly attenuated this fall in sodium excretion (P < 0.05) and effective renal plasma flow (P < 0.05), and had a similar attenuating effect on the noradrenaline-induced decrease in the fractional excretion of lithium. The pressor response to noradrenaline infusion was not, however, influenced by the enalapril pretreatment. CONCLUSIONS Enalapril blunts the renal vasoconstrictive effect and the antinatriuretic effect of noradrenaline in man. Our results indicate that there is an important interaction between the sympathetic nervous system and the renin-angiotensin system in the kidneys in man.

Objective: The present study examines the role of a-j-adrenoceptors in determining the renal haemodynamic and sodium excretory responses to a physiological dose of angiotensin II in man. Design: The effects of a low-dose infusion of angiotensin II (1 ng/kg per min) and a non-depressor dose of prazosin (0.25 mg), alone and in combination, on urinary sodium excretion (U|s|aV), effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and segmental tubular function were studied in eight normal male subjects. Methods: Subjects were studied undergoing maximal water diuresis. Clearances of inulin and para-aminohippurate were employed to estimate GFR and ERPF, respectively. Segmental tubular handling was assessed by both lithium clearance (CLi) and solute-free water methods. Results: Angiotensin II decreased UN3V without altering ERPF and GFR. Angiotensin II caused a significant fall in fractional Cy, which may indicate a proximal tubular effect of angiotensin II. Angiotensin II alone also increased fractional reabsorption of sodium delivered to the distal nephron, as evaluated by both the Cy method and by estimation of solute-free water clearance. When angiotensin II was given in combination with prazosin, which on its own had no apparent effects on any renal parameters, the antinatriuretic and tubular effects of angiotensin II were significantly blunted. Conclusions: These findings suggest that low doses of circulating angiotensin II are able to modulate UNaV by increasing sodium reabsorption in the proximal and, to some extent, the distal nephron segment in man. The study also showed that a non-depressor dose of prazosin blunted the renal effects of angiotensin II, thereby providing tentative evidence of a renal interaction between a-adrenoceptors and angiotensin II in man

Objective Atrial natriuretic factor (ANF) has several properties which suggest that it may ameliorate cyclosporin A nephrotoxicity. We therefore investigated the response to a pharmacological dose of ANF in renal transplant recipients treated with cyclosporin A. Design A single-blind randomized crossover design comparing the renal and haemodynamic effects of D-glucose (placebo) with ANF. Methods Seven patients with stable renal function following renal transplantation were studied under maximal water diuresis. Glomerular filtration rate and effective renal plasma flow were estimated from clearances of inulin and para-aminohippurate, respectively. Results Plasma ANF levels increased significantly in association with increased diuresis and natriuresis. Glomerular filtration rate was unchanged after placebo but increased significantly after ANF fusion. Likewise, effective renal plasma flow increased significantly with ANF infusion. There was a significant fall in systolic blood pressure, with no apparent change in heart rate and diastolic blood pressure. Conclusions These results suggest that ANF may have beneficial effects in protecting against cyclosporin A-induced nephrotoxicity and hypertension.

Many studies in experimental animal models suggest that there is an interaction between angiotensin II and the sympathetic nervous system. We have now sought evidence for such an interaction using angiotensin II and beta-adrenoceptor stimulation with isoprenaline. Ten normal volunteers were infused with placebo/placebo, placebo/angiotensin II, placebo/isoprenaline and angiotensin II/isoprenaline in a randomized single-blind fashion. Isoprenaline alone caused a non-significant 11-20% rise in stroke volume. Angiotensin II alone caused no significant change in stroke volume. However, the combination of angiotensin II/isoprenaline caused a significant increase in stroke volume of 31-55% (p less than 0.01), and this increase was significantly greater than with isoprenaline alone (P less than 0.02, by repeated-measures analysis of variance). This occurred with no difference in heart rate change. Isoprenaline significantly reduced total peripheral resistance and this reduction was not affected by concomitant infusion of angiotensin II. This study provides evidence that a physiological dose of angiotensin II can synergistically augment the stroke volume effect of beta-agonism in man. There are several possible mechanisms, but a regional redistribution of venous blood which causes increased cardiac filling seems likely.

References 1 Davies JI, Band MM, Pringle S, Ogston S, Struthers AD. Peripheral blood pressure measurement is as good as applanation tonometry at predicting ascending aortic blood pressure. J Hypertens 2003; 21:571–576. 2 Giannattasio C. How to assess central arterial blood pressure? J Hypertens 2003; 21:495–496. 3 Pauca AL, Wallenhaup SL, Kon ND, Tucker WY. Does radial artery pressure accurately reflect aortic pressure? Chest 1992; 102: 1193–1198. 4 White WB, Berson AS, Robbins C, Jamieson MJ, Prisant LM, Roccella E, Sheps SG. National standard for measurement of resting and ambulatory blood pressures with automated sphygmomanometers. Hypertension 1993; 21:504–509. 5 O’Brien E. Blood pressure measuring devices, recommendations for the ESH. BMJ 2001; 322:531–536. 6 Borow KM, Newburger JW. Noninvasive estimation of central aortic pressure using the oscillometric method for analyzing systemic artery pulsatile blood flow: comparing study of indirect systolic, diastolic, a mean brachial artery pressure with simultaneous direct ascending aortic pressure measurements. Am Heart J 1982; 103:879–886. 7 Breit SN, O’Rourke MF. Comparison of direct and indirect arterial pressure measurements in hospitalised patients. Aust NZ J Med 1974; 4:485–491. 8 Cohn JN, Finkelstein S, McVeigh G, Morgan D, Lemay L, Robinson J, et al. Noninvasive pulse wave analysis for the early detection of vascular disease. Hypertension 1995; 26:503–508. 9 Watson S, Wenzel RR, di Matteo C, Meier B, Luscher TF. Accuracy of a new wrist cuff oscillometric blood pressure device: comparisons with intraarterial and mercury manometer measurements. Am J Hypertens 1998; 11:1469–1474. 10 Lane D, Beevers M, Barnes N, Bourne J, John A, Malins S, Beevers DG. Inter-arm differences in blood pressure: when are they clinically significant? J Hypertens 2002; 20:1089–1095. 11 Pauca AL, O’Rourke MF, Kon ND. Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension 2001; 38:932–937. 12 Davies JI, Struthers. AD. Pulse wave analysis and pulse wave velocity: a critical review of their strengths and weaknesses. J Hypertens 2003; 21:463–472. 13 O’Rourke MF. Target organ damage: use of pulse wave analysis as a manifestation of aortic degeneration in assessment of hypertension. Vasc Med 2002; 7:83–86.

Objective To test the hypothesis that an imbalance in intrarenal prostaglandins plays a role in cyclosporin-induced nephrotoxicity. Methods and results Indomethacin was given in combination with cyclosporin to healthy volunteers. Cyclosporin alone (10 mg/kg twice a day) for 4 days had no effect on effective renal plasma flow (ERPF) and glomerular filtration rate but 4 days of therapy with cyclosporin (10 mg/kg twice a day) and indomethacin (50 mg twice a day) in combination resulted in a 37% fall in glomerular filtration rate and a 32% fall in ERPF. This suggests that autoregulatory mechanisms, possibly involving renal prostaglandins, may participate in counteracting the tendency for cyclosporin-induced renal vasoconstriction in humans. Cyclosporin increased systemic blood pressure acutely, and this was not influenced by indomethacin even though indomethacin on its own caused sodium retention. This suggests that, in contrast to the renal vasculature, the systemic vascular response to cyclosporin is neither augmented nor buffered by prostaglandins. Conclusion The reduction in intrarenal prostaglandins clearly played a key role in the development of cyclosporin-induced renal vasoconstriction, but we could not demonstrate a role for prostaglandins or for sodium retention in the initiation of cyclosporin-induced hypertension.

Objective: To study the acute effects of cyclosporin on blood pressure, renal function and hormones within the first few hours of drug ingestion in healthy man. Design: A therapeutic (12 mg/kg) and a supratherapeutic (30 mg/kg) dose of cyclosporin were administered orally to 10 salt-replete normal healthy volunteers. Their renal haemodynamic parameters were assessed by inulin and para-aminohippurate clearances, and their blood pressure was recorded every 20 min. Results: Cyclosporin had an acute hypertensive effect while having no effect on sodium excretion or renal function. The earliest renal effect of cyclosporin was on water handling, with a marked antidiuretic effect

Much animal evidence exists to suggest that there is an interaction between noradrenaline (NA) and angiotensin II (AII). We have now sought evidence for a postsynaptic AII/NA interaction. Ten normotensive volunteers were infused with dextrose/saline, All/saline, dextrose/NA or AII/NA in a randomized single-blind fashion. The respective increases in systolic blood pressure (SBP) were -4 +/- 6, -2 +/- 9, 4 +/- 6 and 14 +/- 16 mmHg at comparative time intervals while the corresponding increases in diastolic blood pressure (DBP) were 2 +/- 4, 6 +/- 7, 9 +/- 6 and 14 +/- 8 mmHg. ANOVA confirmed that AII and NA had a synergistic interaction (P less than 0.05) in elevating SBP while there was merely an additive effect in elevating DBP. Plasma NA and AII levels were unchanged by the coincidental presence of AII and NA, respectively, which excludes a generalized pharmacokinetic interaction between AII and NA. This study provides evidence for a postsynaptic AII/NA interaction with regard to SBP but not DBP although the precise location of this interaction remains uncertain. Therefore, in considering the pathogenesis of SBP abnormalities, concomitant measurements of both NA and AII may be important.

Low-dose (0.025 micrograms/kg per min) noradrenaline infusion, resulting in a physiological plasma increment (280 pg/ml), was antinatriuretic in normal salt-replete male subjects. The reduction in sodium excretion (-20%, P less than 0.01) occurred without any change in the glomerular filtration rate but was associated with a significant (P less than 0.02) decline in lithium clearance. These results suggest that changes in circulating noradrenaline, within the physiological range, can decrease sodium excretion in man by enhancing proximal tubular sodium reabsorption. These findings extend previous investigations in man which used pharmacological doses of noradrenaline and are in agreement with animal evidence for a renal tubular antinatriuretic effect of the sympathetic nervous system.

In order to determine whether angiotensin II may influence sympathetically mediated arteriolar constriction in man, we have examined the effect of angiotensin II, infused directly into the left brachial artery of normal subjects, on the reduction in forearm blood flow produced by a lower-body negative pressure (LBNP) of 15 mmHg. Angiotensin II (320 fmol/min) caused no reduction in blood flow when given alone but significantly augmented the reduction in blood flow in response to LBNP. The same dose of angiotensin II did not affect a similar reduction in forearm blood flow produced by infused noradrenaline (12.5-50 ng/min). We conclude that angiotensin II augments sympathetically mediated constriction of resistance vessels in man at concentrations with no direct effect on vessel tone. The lack of an effect of angiotensin II on constriction in response to infused noradrenaline suggests the involvement of a presynaptic mechanism.