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Cardiovascular Research 1997 36(2):268-275; doi:10.1016/S0008-6363(97)00171-5
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Copyright © 1997, European Society of Cardiology

Endogenous angiotensin II contributes to basal peripheral vascular tone in sodium deplete but not sodium replete man

David E Newbya,*, Satoko Masumorib, Neil R Johnstona, Nicholas A Boona and David J Webba

aClinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK
bYokohama City University, School of Medicine, Department of Internal Medicine, 3-9 Fukuura Kanazawa-Ku, Yokohama 236, Japan

* Corresponding author. Tel.: +44 131 3321205; Fax: +44 131 3436017; E-mail: d.e.newby@ed.ac.uk

Received 17 February 1997; accepted 5 June 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Both endothelin-1 and nitric oxide make important contributions to the maintenance of basal peripheral arteriolar tone. However, the role of angiotensin II, a key hormone regulating cardiovascular and renal function, in the regulation of peripheral vascular tone has not been fully characterised. Methods: Using local intra-arterial administration of losartan, a selective angiotensin II type 1 (AT1) receptor antagonist, we examined the contribution of endogenous angiotensin II to the maintenance of basal and sympathetically stimulated vascular tone in the forearm of healthy man under conditions of sodium repletion and depletion. The effects of losartan on responses to exogenous angiotensin I, angiotensin II, bradykinin and noradrenaline were also determined. Results: Losartan, in keeping with its actions as a selective AT1 receptor antagonist, inhibited responses to angiotensin I and II, but had no effect on responses to bradykinin or noradrenaline. The dose of angiotensin II required to cause a 20% vasoconstriction was 40- and 250-fold greater with 30 and 300 µg/min of losartan, respectively. However, in sodium replete subjects, losartan alone caused no significant changes in basal forearm blood flow (95% confidence interval of –7.2 to +8.0%), forearm vascular resistance or sympathetically stimulated forearm vasoconstriction. Sodium depletion elevated plasma renin activity and angiotensin II concentrations (p≤0.002) after which acute local administration of losartan increased forearm blood flow in a dose dependent manner (maximum of 69±17%; p<0.001). Conclusions: Endogenous angiotensin II does not contribute to the acute local maintenance of basal peripheral vascular tone in healthy man except under conditions of renin-angiotensin system activation such as sodium depletion.

KEYWORDS Angiotensin II; Losartan; Sodium depletion; Arteries; Blood flow; Human


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Angiotensin II is formed through activation of the renin-angiotensin cascade and plays a fundamental role in the regulation of blood pressure and body sodium and water under circumstances of sodium and volume depletion [1]. Its principal effects appear to be mediated through the angiotensin II type 1 (AT1) receptor, and include arteriolar vasoconstriction, renal sodium reabsorption and stimulation of adrenal aldosterone production [1]. Within minutes of acute hypovolaemia, renin secretion causes rapid generation of angiotensin II leading to compensatory vasoconstriction and fluid retention that serves to sustain blood pressure and prevent circulatory collapse [2]. Intravenous administration of exogenous angiotensin II causes vasoconstriction and elevation of arterial blood pressure [3]. Even at doses insufficient to cause vasoconstrictor or pressor responses, angiotensin II augments sympathetically mediated vasoconstriction [4]via a prejunctional adrenoreceptor mediated mechanism [5]. Thus, angiotensin II has the potential to be a major contributor to the regulation of vascular tone and blood pressure in man.

Systemic AT1 receptor antagonism in healthy man causes a modest reduction in blood pressure of ~10 mm Hg [1, 6, 7]that is enhanced by sodium depletion [8]. Although, changes in peripheral vascular resistance were not assessed in these studies [6–8], when examining in vivo vascular responses in man, systemic drug administration causes concomitant effects on organs, such as the brain, kidney and heart, and influences neurohumoral reflexes through changes in systemic haemodynamics. Because of these confounding influences, vascular responses cannot be wholly attributed to a direct effect of the drug [9]. In contrast, the use of bilateral forearm blood flow measurements, with unilateral brachial artery infusion of vasoactive drugs at subsystemic, locally active doses, provides a powerful and reproducible method of directly assessing vascular responses in vivo [9, 10]. This technique has been utilised very successfully to demonstrate the major contribution of nitric oxide and endothelin-1 to the maintenance of basal peripheral vascular tone in healthy man [11, 12]and to predict that systemic inhibition of these systems would increase [13]and decrease [14]blood pressure, respectively.

Previous local forearm studies assessing the role of the renin-angiotensin system in the maintenance of basal peripheral vascular resistance [15, 16]have been confounded by the use of antagonists, such as saralasin, with partial agonist activity. However, losartan, a selective AT1 receptor antagonist devoid of agonist activity has recently become available for clinical use. The aims of the present study were to define a locally active, subsystemic dose of losartan that would effectively inhibit AT1 receptor mediated responses and then to examine its actions in the forearms of healthy men. In subsequent studies, the contribution of endogenous angiotensin II to the maintenance of basal and sympathetically stimulated peripheral vascular tone was studied under conditions of sodium repletion and depletion.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Subjects
Sixteen healthy male non-smokers, aged between 21 and 34 years, participated in a series of ten studies which were undertaken with the approval of the local research ethics committee and the written informed consent of each subject. The investigation conforms with the principles outlined in the Declaration of Helsinki. None of the subjects received vasoactive or non-steroidal anti-inflammatory drugs in the week before each phase of the study, and all abstained from alcohol for 24 h and from food and caffeine-containing drinks for at least 4 h before each study. All studies were performed in a quiet, temperature controlled room maintained at 23.5–24.5°C.

2.2 Measurements and drug administration
Blood flow was measured in both forearms by venous occlusion plethysmography using mercury-in-silastic strain gauges applied to the widest part of the forearm as described previously [9]. Blood pressure was monitored in the non-infused arm at intervals throughout each study using a semi-automated non-invasive oscillometric sphygmomanometer [17](Takeda UA 751, Takeda Medical, Tokyo, Japan). The brachial artery of the non-dominant arm was cannulated with a 27-standard wire gauge steel needle (Cooper's Needle Works, Birmingham, UK) under 1% lignocaine (Xylocaine; Astra Pharmaceuticals Ltd., Kings Langley, UK) local anaesthesia. The total rate of intra-arterial infusions was maintained constant throughout all studies at 1 ml/min. Losartan (Dupont-Merck Inc, Wilmington, USA), noradrenaline (Levophed; Sanofi Winthrop, Guildford, UK), angiotensin I (Clinalfa, Läufelfingen, Switzerland), angiotensin II (Clinalfa) and bradykinin (Clinalfa) were dissolved in physiological saline (0.9%; Baxter Healthcare Ltd., Thetford, UK) and administered intra-arterially. To prevent its oxidation, noradrenaline was dissolved in saline containing 0.1% ascorbic acid (Evans Medical, Langhurst, UK). Doses of losartan (30–300 µg/min) were chosen on the basis of early pilot studies to achieve an effective subsystemic and locally active concentration and to be 10 to 100-fold less than the normal systemic dose of 50–100 mg of losartan.

When required, venous cannulae (17G) were inserted into large subcutaneous veins of the antecubital fossa in both arms using previously described methodology [19]. Five minutes after the commencement of each infusion, 20 ml of blood was withdrawn simultaneously from each arm and 10 ml admixed with 1 ml of 1% disodium EDTA and 10 ml with 0.5 ml of 0.45% O-phenanthroline/4.65% disodium EDTA. The samples were placed on ice before being centrifuged at 2,000 g for 30 min. Plasma was frozen and stored at –80°C prior to assay for plasma renin activity and angiotensin II concentrations. Plasma angiotensin II concentrations (Peninsula Laboratories Europe, St Helens, UK) were determined by radioimmunoassay [20]following extraction using Bond Elut® columns (Varian, Harbor City, CA, USA) [21]. Plasma renin activity was measured under standard conditions through the generation of angiotensin I as determined by radioimmunoassay [22]. Urinary sodium concentration was determined using standard flame photometry.

2.3 Lower body negative pressure and sodium depletion
Subjects were rested supine in a plastic covered steel cage enclosing the lower body from the waist. A constant negative pressure of 15 mm Hg was attained using an industrial strength vacuum cleaner regulated by a servo control unit (Medical Physics Department, Edinburgh, UK), as described previously [4].

Each subject attended at 9.00 a.m. and rested supine for 20 min before venous blood was withdrawn for plasma angiotensin II estimation and a single oral dose of 40 mg of frusemide was administered. For the following 72 h, subjects were given an outpatient diet containing >2000 kcal of energy, >60 g of protein, <12 mmol of sodium and <70 mmol of potassium per day [18]. During the final 24 h, urine was collected to determine urinary sodium excretion.

2.4 Study design
Measurements of forearm blood flow were made for the last 3 min of each infusion period unless otherwise stated. Before participating in one of the following protocols, saline was infused for the first 30 min to allow time for equilibration, with forearm blood flow measurements being made every 10 min and basal blood flow being taken as the final measurement.

Prevention of angiotensin II mediated vasoconstriction by losartan was examined in six subjects who attended each of three study days separated by at least one week. In each study, subjects received incremental doses of angiotensin II (0.1, 1, 10 and 100 pmol/min for 6 min at each dose) [23]administered into the brachial artery on two occasions separated by 30 min of saline infusion. During and 10 min before the second infusion of angiotensin II, saline placebo or losartan at either 30 µg/min or 300 µg/min were co-infused on the 3 study days, in random order. An additional dose of angiotensin II (480 pmol/min) was given when vasoconstriction at 100 pmol/min was <50%. In order to examine the reversal of angiotensin II mediated vasoconstriction by losartan, six subjects attended a subsequent study day. Each subject received an 84 min infusion of angiotensin II at 10 pmol/min. After 12 min of angiotensin II infusion, losartan at 300 µg/min was co-infused for 12 min. Forearm blood flow was measured every 6 min throughout the study.

Ten subjects received saline, losartan 30 µg/min, losartan 300 µg/min and saline; each for 16 min and in this order. Forearm blood flow was measured continuously for the last 9 min of each infusion. Lower body negative pressure was applied for the middle 3 min of the forearm blood flow measurement. After 3 days of sodium depletion, six further subjects attended at 9.00 a.m. and each received saline, losartan 30 µg/min, losartan 90 µg/min and saline; each for 13 min and in this order. Forearm blood flow was measured continuously for the last 6 min of each infusion with lower body negative pressure being applied for the last 3 min.

Six subjects received a continuous infusion of either saline placebo or losartan 30 µg/min on two occasions, in random order, separated by at least one week. Bradykinin was co-infused intra-arterially at 10, 30 and 100 pmol/min [23], for 6 min at each dose. Following a 30 min saline washout period, angiotensin I was co-infused at 0.1, 1, 10 and 100 pmol/min [23]for 6 min at each dose, rising to a final dose of 480 pmol/min when vasoconstriction at 100 pmol/min was <50%. Six subjects received a continuous infusion of either saline placebo or losartan 30 µg/min on two occasions, in random order, separated by at least one week. Noradrenaline was then co-infused intra-arterially at doses of 30, 60, 120, 240 and 480 pmol/min, each for 10 min.

2.5 Data analysis and statistics
Recordings from the first 60 s after wrist cuff inflation were not used because this causes reflex vasoconstriction [9]. Usually, the last five flow recordings in each 3 min measurement period were calculated and averaged for each arm. To reduce the variability of blood flow data, the ratio of flows in the two arms was calculated for each time point: in effect using the non-infused arm as a contemporaneous control for the infused arm [9].

Data were examined by two factor analysis of variance (ANOVA) with repeated measures, two tailed paired Student's t-test and regression analysis using Excel v4.0 (Microsoft). All results are expressed as means±standard errors of the mean. Statistical significance was taken at the 5% level. Based on the responses, we calculated dose response shifts for the ED20; the dose producing 20% vasoconstriction from baseline.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
There were no significant differences between the baseline forearm blood flows in the infused and non-infused arms or between protocols. Throughout all studies, there were no significant changes in heart rate or arterial pressure (data on file; Table 1Table 2). Except during the application of lower body negative pressure, there were no significant changes in blood flow in the non-infused arm.


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  		Table 1 Effect of losartan on systemic haemodynamics, blood flows with and without LBNP, and plasma renin activity under conditions of sodium repletion

 

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  		Table 2 Effect of losartan on systemic haemodynamics, blood flows with and without LBNP, and plasma angiotensin II concentrations under conditions of sodium depletion

 
3.1 Effect of losartan on responses to angiotensin II
At doses of 0.1, 1, 10 and 100 pmol/min of angiotensin II, forearm blood flow was reduced by 4%±5, 16%±9, 35%±5 and 61%±9 respectively with the first challenge and 8%±6, 18%±6, 40%±6, and 61%±9, respectively, with the second. Although angiotensin II caused dose-dependent vasoconstriction (p<0.001) which did not undergo attenuation with repeated dosing, the response was inhibited in a dose-dependent manner by losartan at 30 µg/min and 300 µg/min (p<0.001 for both) (Fig. 1). Mean forearm blood flow in the infused arm decreased from 3.8±0.8 to 1.3±0.2 ml/100 ml/min with 100 pmol/min of angiotensin II, but only decreased from 3.5±0.4 to 2.6±0.4 ml/100ml/min and from 4.4±0.7 to 3.7±0.6 ml/100 ml/min in the presence of losartan 30 µg/min and 300 µg/min, respectively (p≤0.002 for both vs angiotensin II alone). There was a 37-fold increase in the ED20 of angiotensin II with losartan 30 µg/min and a 252-fold increase with losartan 300 µg/min.


Figure 1
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  		Fig. 1 Responses in forearm blood flow to incremental doses of angiotensin II (pmol/min) in the presence of saline ({circ}, {square}) and either 30 µg/min of losartan (bullet) or 300 µg/min of losartan ({blacksquare}).

 
Continuous infusion of angiotensin II at 10 pmol/min achieved a 50±3% reduction in forearm blood flow which was apparent by 6 min and sustained for the first 12 min (p<0.001). Losartan rapidly reversed this vasoconstriction (p<0.001) with a return towards baseline which was apparent by 6 min and persisted for the next 72 min and was not significantly different from baseline blood flow (Fig. 2).


Figure 2
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  		Fig. 2 Responses in forearm blood flow to 10 pmol/min of angiotensin II ({square}) in the presence of saline and during and following a 12 min co-infusion of 300 µg/min of losartan ({blacksquare}).

 
3.2 Effects of losartan on basal blood flow and responses to lower body negative pressure
3.2.1 Sodium replete
There were no significant changes in heart rate, blood pressure, forearm blood flow or forearm vascular resistance in either arm during infusions of saline or losartan (Table 1 and Fig. 3). The Student's t-distribution gives 95% confidence intervals of –6.0 to +8.3% and –7.2 to +8.4% for percentage changes in forearm blood flow with 30 µg/min and 300 µg/min of intra-arterial losartan, respectively. There were no significant differences in the vasoconstriction induced by the application of lower body negative pressure between the infused and non-infused arms across the saline and losartan infusion periods (Table 1). Plasma renin activity and angiotensin II concentrations did not change during losartan infusion (Table 1).


Figure 3
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  		Fig. 3 Absolute (infused arm, {blacksquare}; non-infused arm, {square}) and comparative forearm blood flow responses ({circ}), with intermittent application (arrows) of lower body negative pressure (LBNP), to saline, 30 µg/min and 300 µg/min of losartan in salt replete men (left panels) and saline, 30 µg/min and 90 µg/min of losartan in salt deplete men (right panels).

 
3.2.2 Sodium deplete
In comparison to the sodium replete group, during sodium depletion heart rate was higher (p = 0.03) and blood pressure unchanged (p = 0.2). There were no significant between-group differences in the basal blood flows of the infused arm (Tables 1 and 2Go). Urinary sodium excretion for the last 24 h of the sodium depletion protocol was 9.4±3.9 mmol. Following sodium depletion, plasma renin activity and angiotensin II concentrations rose from 1.6±0.4 pmol/ml/h and 3.6±0.5 fmol/ml to 8.0±0.9 pmol/ml/h (p<0.001) and 7.6±0.9 fmol/ml (p = 0.002), respectively.

There were no significant changes in heart rate, blood pressure or blood flow in the non-infused arm during infusions of saline or losartan (Table 2). Losartan caused a dose dependent increase in forearm blood flow in the infused arm (p<0.001; Table 2 and Fig. 3). The increased blood flow persisted into the saline washout phase and was not significantly different from that during the infusion of losartan at 90 µg/min (p = 0.98). There were no significant differences between the vasoconstriction induced by the application of lower body negative pressure in the infused and non-infused arms, but the absolute and percentage vasoconstriction was significantly greater in the sodium deplete group (ANOVA, p = 0.001). Plasma renin activity and angiotensin II concentrations did not significantly change throughout the study (Table 2).

The maximum vasodilatation to losartan in the infused forearm was inversely correlated with urinary sodium excretion (r = –0.84; p = 0.04) and tended to correlate with plasma renin activity (r = 0.70; p = 0.11) and angiotensin II concentrations (r = 0.80; p = 0.06). As expected, plasma renin activity and urinary sodium excretion were negatively correlated (r = –0.90; p = 0.02).

3.3 Effects of losartan on responses to bradykinin, noradrenaline and angiotensin I
Bradykinin produced a dose-dependent vasodilatation (p<0.001) that was unaffected by the presence of losartan 30 µg/min (Fig. 4). Mean blood flow in the infused forearm increased from 3.7±0.5 to 14.3±1.6 ml/100 ml/min with 100 pmol/min of bradykinin and from 3.4±0.4 to 15.9±2.7 ml/100 ml/min when co-infused with losartan 30 µg/min.


Figure 4
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  		Fig. 4 Responses in forearm blood flow to incremental doses of (a) bradykinin ({diamond}), (b) angiotensin I ({circ}), and (c) noradrenaline ({square}) in the presence of saline (open symbols) or losartan 30 µg/min (closed symbols).

 
Noradrenaline produced a dose-dependent vasoconstriction (p<0.001) that was unaffected by the presence of losartan 30 µg/min (Fig. 4). Mean blood flow in the infused forearm decreased from 3.0±0.4 to 1.8±0.3 ml/100 ml/min with 480 pmol/min of noradrenaline and from 2.9±0.3 to 1.8±0.2 ml/100 ml/min when co-infused with losartan 30 µg/min.

Angiotensin I produced a dose-dependent vasoconstriction (p<0.001) that was inhibited by losartan 30 µg/min (Fig. 4). Blood flow in the infused forearm decreased from 3.9±0.4 to 1.2±0.2 ml/100 ml/min with 100 pmol/min of angiotensin I, but only from 3.9±0.4 to 2.5±0.2 ml/100 ml/min when co-infused with losartan 30 µg/min (p<0.001). There was a 25-fold increase in the ED20 of angiotensin I with losartan 30 µg/min.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
As in previous studies [23, 24], intra-arterial angiotensin II produced a dose-dependent vasoconstriction that had a rapid onset and offset, and did not undergo attenuation following repeated exposure. In contrast to the pattern seen with ACE inhibitors [23], intra-arterial losartan had no effect on bradykinin induced forearm vasodilatation, but inhibited the vasoconstriction mediated by both angiotensin I and II. Losartan caused dose-dependent and rapid inhibition of the vasoconstriction produced by exogenous angiotensin II: ~40 fold at 30 µg/min and ~250 fold at 300 µg/min. These findings are consistent with the pharmacological actions of losartan as an AT1 receptor antagonist, and with the results of previous studies using systemic [25]and local [26]doses of losartan.

In agreement with a recent study [26], we have shown, using the selective AT1 receptor antagonist losartan, that endogenous angiotensin II is not a major contributor to the maintenance of basal peripheral vascular tone in healthy sodium replete man. The 95% confidence intervals indicate that if angiotensin II provides any acute local contribution to basal tone in peripheral blood vessels then it is small. Previous work [23]using intra-arterial locally active doses of the ACE inhibitor, enalaprilat, has shown that local ACE activity, under basal conditions, does not determine resistance vessel tone in the forearm of healthy man. This lack of effect could be a consequence of a major role for circulating, rather than locally generated, angiotensin II in regulating vascular tone or a failure to influence local angiotensin II generation mediated through an ACE independent mechanism. However, our study has shown more definitively that, unlike endothelin-1 [12]and nitric oxide [11], angiotensin II does not contribute to the acute local maintenance of basal peripheral resistance vessel tone in healthy sodium replete man.

In contrast, under conditions of sodium depletion sufficient to produce >100% increase in circulating plasma angiotensin II concentrations, losartan produced an acute local increase in forearm blood flow of ~70%. Moreover, the maximum increase in blood flow in the infused arm was inversely correlated with 24 h urinary sodium excretion, with a trend to a positive correlation with plasma angiotensin II concentrations. Thus, we have shown for the first time that endogenous angiotensin II does contribute to the acute local maintenance of basal vascular tone under circumstances of renin-angiotensin system activation. It would appear, at least in Western societies maintained on a relatively high sodium diet [27], that angiotensin II is implicated only in tonic adaptive responses rather than in the maintenance of basal resistance vessel tone.

Lower body negative pressure of 15 mm Hg causes a selective forearm vasoconstriction through sympathetically mediated prejunctional release of noradrenaline [28]; an effect which is augmented by exogenous administration of angiotensin II [4]. However, we have found no effect of losartan on vasoconstriction induced by lower body negative pressure. This absence of effect is not attributable to a balanced effect of losartan causing decreased prejunctional release of noradrenaline and an increased postjunctional {alpha}-adrenoreceptor sensitivity because the response to noradrenaline was unaffected by losartan. Our findings are in agreement with a recent systemic study [31]that also failed to detect an attenuation of sympathetically stimulated vasoconstriction by losartan. Despite the significantly greater sympathetically mediated vasoconstriction produced during sodium depletion, which is presumably in part related to the elevation in circulating angiotensin II concentrations, losartan did not attenuate this response. Although it seems from these observations that basal circulating concentrations of angiotensin II do not influence sympathetic function, it remains a possibility that the induction of prejunctional noradrenaline release by angiotensin II is mediated by a non-AT1 receptor mechanism. However, there are some inconsistencies in the responses to angiotensin II infusion during lower body negative pressure [4, 29, 30]with some workers finding facilitation of prejunctional noradrenaline release only at high plasma angiotensin II concentrations (25–97 fmol/ml) [29]. The lack of an effect of losartan on the lower body negative pressure response in the present study may, therefore, reflect the modest increase in plasma angiotensin II concentrations obtained with sodium depletion. Thus, an attenuation of the response may only become apparent at higher plasma angiotensin II concentrations such as those seen in chronic heart failure or cirrhotic liver disease with ascites.

The sustained inhibition of angiotensin II mediated vasoconstriction for up to 60 min after cessation of losartan infusion was unexpected but was also seen during the washout phase of the sodium depletion study. Losartan is a competitive AT1 receptor antagonist and we anticipated its effects would be rapidly reversed after local infusion was stopped. Although losartan itself is active as an AT1 receptor antagonist, our observations could be explained by its peripheral conversion to the long acting metabolite, E-3174, which is a potent pseudo-noncompetitive receptor antagonist [7, 32]. Alternatively, given the very high protein binding of losartan (>99%), it may be that losartan is sequestrated and bound to proteins in the extravascular compartment enabling it to have a sustained action on the vascular smooth muscle.

All doses of losartan used intra-arterially were locally active, with no significant effects on blood pressure or heart rate, or contralateral forearm blood flow, plasma renin activity or plasma angiotensin II concentration. In contrast, when losartan is given systemically, it causes substantial increases in plasma renin activity and plasma angiotensin II in healthy volunteers [12]. There was a small non-significant trend for the circulating plasma renin activity and plasma angiotensin II to rise following completion of the infusion of losartan in the sodium replete and deplete studies: total dose 5.3 and 1.6 mg, respectively. This would suggest that we may be approaching a systemic dose.

Endothelin antagonists produce vasodilatation when given into the forearm [12, 14]and lower blood pressure, in association with a marked reduction in systemic vascular resistance, when given systemically [14]. However, the mechanism whereby losartan and its long acting metabolite E3174 reduces blood pressure acutely in healthy sodium replete man is unlikely to be peripheral vasodilatation. This does not preclude the possibility of a hypotensive effect of angiotensin II antagonism being mediated through actions on the kidney [31, 33]or central nervous system [34, 35]. Indeed, Duranteau et al. [31]have shown that in healthy volunteers, 50 mg of oral losartan causes a selective increase in renal blood flow without demonstrable reductions in blood pressure or systemic vascular resistance. In situations where the renin-angiotensin system is stimulated, such as sodium depletion [8]and cardiac failure [36], losartan causes a more pronounced reduction in blood pressure that, in the case of cardiac failure, is at least partly mediated through a decrease in systemic vascular resistance [36]. The present study suggests that sodium depletion should augment the reduction in blood pressure caused by losartan through this mechanism.

In conclusion, using a dose of losartan sufficient to increase the ED20 of exogenous angiotensin II by ~250 fold, we have shown that endogenous angiotensin II does not contribute to the acute local maintenance of basal or sympathetically stimulated peripheral vascular tone in the human forearm. However, under circumstances of sodium depletion, endogenous angiotensin II does augment basal peripheral vascular tone. It would appear, therefore, that in healthy men eating a Western diet, angiotensin II contributes to the maintenance of peripheral vascular tone only under circumstances of activation of the renin-angiotensin system.

Time for primary review 22 days.


   Acknowledgements
 
D.E.N. is the recipient of a British Heart Foundation Junior Research Fellowship (FS/95009).


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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