© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Peripheral vascular tone in patients with cirrhosis: role of the renin–angiotensin and sympathetic nervous systems
aClinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK
bDepartment of Cardiology, University of Edinburgh, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW, Scotland, UK
cDepartment of Medicine, University of Edinburgh, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW, Scotland, UK
* Corresponding author. Tel.: +44 (131) 332 1205; Fax: +44 (131) 343 6017; E-mail: d.e.newby@ed.ac.uk
Received 10 October 1997; accepted 18 December 1997
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objective: The aims of the study were to establish the roles of angiotensin II and of the cardiopulmonary baroreceptor reflex in the regulation of peripheral vascular tone in patients with cirrhosis. Methods: Forearm blood flow responses to subsystemic, locally active intrabrachial infusions were measured in patients with Child's Grade C cirrhosis and matched controls using bilateral venous occlusion plethysmography. Responses were determined to the angiotensin II type I receptor antagonist, losartan, noradrenaline, angiotensin II and the nitric oxide synthase inhibitor, L-NG-monomethyl arginine. Results: Losartan at 30 and 90 µg/min caused no significant change in blood flow in controls, but caused 23±6% and 27±5% increases in patients respectively (p<0.001). Lower body negative pressure caused a mean bilateral reduction in forearm blood flow of 20±4% in controls (p<0.001) but only tended to reduce flow (9±5%; p=0.06) in patients (p<0.001; controls vs. patients). Noradrenaline, angiotensin II and L-NG-monomethyl arginine caused significant vasoconstriction (p<0.001) in both patients and controls although angiotensin II caused significantly less vasoconstriction in patients (p=0.01). Conclusions: We conclude that angiotensin II makes an important contribution to basal peripheral vascular tone in patients with cirrhosis in the face of reduced vascular responses to its local administration. In addition, the vasoconstrictor response to cardiopulmonary baroreceptor unloading is attenuated despite normal vascular responses to noradrenaline. These responses are consistent with chronic activation of the renin–angiotensin and sympathetic nervous systems in patients with advanced cirrhosis.
KEYWORDS Angiotensin; Regional blood flow; Renin angiotensin system; Adrenergic agonists; Autonomic nervous system
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Cirrhotic liver disease is characterised by a hyperdynamic circulation and high cardiac output [1]associated with widespread vasodilatation [2]and low peripheral vascular resistance [3]. Compensatory activation of neurohumoral reflexes involving the sympathetic nervous [4–6]and renin–angiotensin systems [7–9], helps to sustain vascular tone and blood pressure. A failure to compensate fully for the peripheral vasodilatation may be a consequence of hyporesponsiveness to, and desensitisation of, these counter-regulatory vasoconstrictor mechanisms.
Reduced pressor responses to systemic administration of 
-adrenoreceptor agonists and angiotensin II occur in patients with severe cirrhotic liver disease [10]. However, when studying in vivo vascular responses in man, systemically administered agents can cause effects on other organ systems, such as the liver, brain, kidney and heart, and influence neurohumoral reflexes through changes in systemic haemodynamics. Because of these confounding influences, local vascular responses cannot be wholly attributed to a direct effect of the agent on the blood vessels. Subsystemic locally active brachial artery infusions combined with bilateral forearm blood flow measurements using venous occlusion plethysmography provide a means of assessing the responses of an isolated vascular bed without invoking counter-regulatory reflexes [11]. This technique has been instrumental in demonstrating the contribution of basal nitric oxide [12]and endothelin-1 production [13]to the maintenance of peripheral resistance vessel tone in man.
The role of the renin–angiotensin system in counteracting the peripheral vasodilatation and hyperdynamic circulation of cirrhotic liver disease has not previously been fully characterised because, until recently, specific and selective pharmacological antagonists were lacking. Losartan, a selective AT1 receptor antagonist that is devoid of agonist activity, is now available for clinical use. Therefore, the aims of the present study in patients with cirrhosis were as follows: first, to establish the role of endogenous angiotensin II in the maintenance of peripheral vascular tone; second, to determine the effect of sympathetically stimulated vasoconstriction in the presence and absence of angiotensin II antagonism; and third, to document the peripheral vascular responses to the vasoconstrictors noradrenaline, angiotensin II and the nitric oxide synthase inhibitor, L-NG-monomethyl arginine (L-NMMA).
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Patients with stable Child's Grade C cirrhosis and ascites were recruited together with age- and sex-matched healthy volunteers. Studies were undertaken with the approval of the local research ethics committee and in accordance with the Declaration of Helsinki (1989) of the World Medical Association. The written informed consent of each subject was obtained before the study. 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, caffeine-containing drinks and tobacco for at least 4 h before each study. Patients with alcoholic cirrhosis abstained from alcohol for at least 6 months prior to entry into the study. All patients had been maintained on spironolactone (50 mg bd) therapy, without additional diuretic therapy, for at least 1 month prior to entry into the study. In previous studies, complete withdrawal of spironolactone has resulted in unacceptable clinical deterioration in these patients. Therefore, patients remained on spironolactone therapy but, to avoid acute dosing effects, the morning dose of spironolactone was omitted on the day of attendance. The studies were performed in a quiet, temperature controlled room maintained at 23.5–25.0°C. To minimise between-subject variability, pre-menopausal female control subjects were studied between 7 and 12 days of their menstrual cycle [14]. All female patients had amenorrhea.
2.1 Drugs and intra-arterial administration
Losartan (Dupont-Merck, Wilmington, USA), noradrenaline (Levophed; Sanofi Winthrop, Guildford, UK), angiotensin II (Clinalfa, AG Läufelfingen, Switzerland) and L-NMMA (Clinalfa AG) were dissolved in physiologic saline (0.9%; Baxter Healthcare, 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 (30–90 µg/min) were chosen on the basis of previous studies [15]to achieve an effective subsystemic and locally active concentration.
The brachial artery of the non-dominant arm was cannulated with a 27-standard wire gauge steel needle (Cooper's Needle Works, Birmingham, UK) attached to a 16-gauge epidural catheter (Portex, Hythe, UK) under 1% lignocaine (Xylocaine; Astra Pharmaceuticals, Kings Langley, UK) local anaesthesia. Patency was maintained by infusion of saline via an IVAC P1000 syringe pump (IVAC, Basingstoke, UK). The total rate of intra-arterial infusions was maintained constant throughout all studies at 1 ml/min.
2.2 Measurements
Blood flow was measured in both the infused and non-infused forearms by venous occlusion plethysmography using mercury-in-silastic strain gauges applied to the widest part of the forearm [11]. During measurement periods the hands were excluded from the circulation by rapid inflation of the wrist cuffs to a pressure of 220 mmHg using E20 Rapid Cuff Inflators (D.E. Hokanson, Washington, DC, USA). Upper arm cuffs were inflated intermittently to 40 mmHg for 10 s in every 15 s to achieve venous occlusion and obtain plethysmographic recordings. Analogue voltage output from an EC-4 strain gauge Plethysmograph (D.E. Hokanson) was processed by a MacLab analogue-to-digital converter and Chart v3.3.8 software (AD Instruments, Castle Hill, Australia) and recorded onto a MacIntosh Classic II computer (Apple Computers, Cupertino, USA). Calibration was achieved using the internal standard of the plethysmograph.
Blood pressure was monitored in the non-infused arm at intervals throughout each study using a semi-automated non-invasive oscillometric sphygmomanometer [16](Takeda UA 751, Takeda Medical, Tokyo, Japan).
Subjects were rested supine in a plastic covered steel cage enclosing the lower body from the waist, as described previously [17]. Lower body negative pressure (LBNP) was applied using an industrial strength vacuum cleaner regulated by a pressure control unit (Medical Physics Department, Edinburgh, UK) to produce a constant negative pressure of 15 mmHg which does not affect systemic blood pressure or heart rate [17]. Alteration to and from atmospheric pressure was attained within 1–2 s.
Ten minutes before giving losartan by infusion and 10 min after its completion, 30 ml of blood was withdrawn from the non-infused arm and 10 ml admixed with each of 1 ml of 1% disodium EDTA, 0.5 ml of 0.45% O-phenanthroline/4.65% disodium EDTA and 1 ml of 1% disodium EDTA/2% sodium metabisulphite. The samples were placed on ice and immediately centrifuged at 2000 g for 15 min. Plasma was frozen and stored at –80°C prior to assay for plasma angiotensin II, endothelin-1, big endothelin-1, adrenaline and noradrenaline concentrations. Following extraction using Bond Elut® columns (Varian, Harbor City, CA, USA) [18], plasma angiotensin II (Peninsula Laboratories Europe, St Helens, UK), endothelin-1 (Peninsula Laboratories Europe) and big endothelin-1 (Peninsula Laboratories Europe) concentrations were determined by radioimmunoassay as previously described [19, 20]. The intra-assay coefficients of variability were 5.2%, 7.0% and 7.2% respectively and the inter-assay coefficients of variability were 8.6%, 9.0% and 9.3% respectively. The cross reactivities of the endothelin-1 assay were endothelin-1 (100%), endothelin-2 (7%), endothelin-3 (7%), big endothelin-1 (10%), C-terminal fragment (0%), angiotensin I (0%) and angiotensin II (0%). The cross reactivities of the big endothelin-1 assay were endothelin-1 (0%), endothelin-2 (0%), endothelin-3 (0%), big endothelin-1 (100%) and C-terminal fragment (100%). Plasma adrenaline and noradrenaline concentrations were determined by an electrochemical method after separation by reverse phase high performance liquid chromatography [21].
2.3 Study design
Subjects rested recumbent throughout each study. Strain gauges and cuffs were applied and the brachial artery of the non-dominant arm cannulated. 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 baseline blood flow being taken as the final measurement.
In protocol 1, eight patients and eight matched control subjects received, in order, saline, losartan 30 µg/min, losartan 90 µg/min [15]and saline, each for 13 min. Forearm blood flow was measured continuously for the last 6 min of each infusion. Lower body negative pressure was applied for the last 3 min of the forearm blood flow measurement. Following 15 min of further saline infusion, noradrenaline was infused intra-arterially at doses of 20, 60, 180 and 540 pmol/min [8, 15], each for 6 min.
In protocol 2, eight patients and eight matched control subjects received incremental doses of angiotensin II (0.1, 1, 10 and 100 pmol/min) [8, 15], each dose administered into the brachial artery for 6 min, followed by 30 min of saline infusion. Thereafter, L-NMMA at 4 µmol/min [8, 22]was administered for 15 min.
Protocols 1 and 2 were conducted at least one week apart and in random order with five patients and seven control subjects common to both protocols.
2.4 Data analysis and statistics
Plethysmographic data were extracted from the Chart data files and forearm blood flows were calculated for individual venous occlusion cuff inflations by use of a template spreadsheet (Excel v5.0; Microsoft). Recordings from the first 60 s after wrist cuff inflation were not used because of the initial reflex vasoconstriction this procedure causes [23]. 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 [11, 24]. Percentage changes in the infused forearm blood flow were calculated [11, 24] as follows:
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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 v5.0 (Microsoft). All results are expressed as means±standard errors of the mean. Statistical significance was taken at the 5% level. Based on the responses, the dose response shifts were calculated for the ED50; the dose producing 50% vasoconstriction from baseline.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Baseline patient characteristics and concomitant therapy is detailed in Table 1. Three patients with cirrhosis underwent liver transplantation before completing their second study phase and were replaced. Patients had a significantly lower systolic and diastolic blood pressure, and higher plasma angiotensin II, endothelin-1 and big endothelin-1 concentrations than controls. However, there were no significant differences in resting heart rate, baseline forearm blood flows or plasma adrenaline and noradrenaline concentrations in the infused and non-infused arms between protocols or between patients and controls. Blood pressure, heart rate and non-infused forearm blood flow did not change significantly during infusions of losartan, noradrenaline, L-NMMA or angiotensin II (data on file; Fig. 1).
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; non-infused forearm, 
) blood flow and percentage change (infused/non-infused forearm, 
) in blood flow from time 0, with intermittent application (arrows) of lower body negative pressure (LBNP), to saline, 30 µg/min and 90 µg/min of losartan in patients with cirrhosis (right panels) and healthy age- and sex-matched control subjects (left panels) respectively. NS – not significant; *p<0.001, ANOVA.3.1 Effects of losartan on basal blood flow and responses to lower body negative pressure
Plasma angiotensin II concentrations did not change significantly during the study (Table 1).
In the healthy control subjects, there were no significant changes in blood flow of the infused forearm during infusions of saline or losartan (Fig. 1). The Student's t distribution gives 95% confidence intervals of –3.3 to +7.8% and –2.6 to +9.0% for percentage changes in forearm blood flow with 30 µg/min and 90 µg/min of intra-arterial losartan respectively. During saline infusion, LBNP caused a 23.1±3.7% and 21.8±2.8% reduction in the infused and non-infused forearm blood flow respectively (p<0.001). The vasoconstriction induced by the application of LBNP was not different between the infused and non-infused arms either during saline or losartan infusion periods (Figs. 1 and 2
).
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In patients with cirrhosis, blood flow in the infused forearm increased by 26.3% (95% Cl: +12.7 to +39.9%) and 29.5% (+18.6 to +40.4%) with 30 µg/min and 90 µg/min of intra-arterial losartan respectively (p<0.001; Fig. 1). The increase in blood flow at 90 µg/min of losartan correlated inversely with the baseline plasma angiotensin II concentration (r=–0.93; p=0.007). LBNP did not significantly reduce the blood flow in either arm (p=0.06), and was significantly less than that achieved in the control subjects (p<0.001; Fig. 2). The response to LBNP in the infused forearm was also unaffected by losartan (Figs. 1 and 2
).
3.2 Effect of angiotensin II, noradrenaline and L-NMMA infusions
Angiotensin II and noradrenaline caused dose-dependent vasoconstriction in both patients and controls (p<0.001 for all). There was no significant difference in the magnitude of the vasoconstriction response to noradrenaline between patients and controls. However, angiotensin II caused significantly less vasoconstriction in patients with cirrhosis (p=0.01 vs. controls) with a 
2.5-fold right shift in the ED50 from 13 to 30 pmol/min (Fig. 3).
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) and noradrenaline (At the end of the period of L-NMMA infusion, blood flow in the infused forearm was reduced by 33.0±2.9% and 29.9±4.2% in patients and controls respectively (p<0.001 for both). The difference between responses in patients and controls was not significant.
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4 Discussion |
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We have previously shown in healthy volunteers [15]that intra-arterial losartan infusion, at doses of 30–300 µg/min, is locally active only and is able to reverse completely the vasoconstriction caused by angiotensin II infusion at 1 pmol/min. This dose of angiotensin II is sufficient to cause a comparable increase in plasma angiotensin II to that seen in patients with cirrhosis. In the present study, we have shown for the first time that brachial artery infusion of losartan significantly increases forearm blood flow by
30% in patients with cirrhosis. We have also shown, in agreement with previous work [15, 25], that intra-arterial losartan has no effect on basal forearm blood flow or vascular resistance in healthy control subjects. These findings indicate that angiotensin II contributes to the maintenance of basal peripheral vascular tone in patients with liver cirrhosis but not healthy control subjects.
We have previously shown [15]that acute sodium depletion in healthy man causes a 2–3-fold increase in plasma angiotensin II concentrations and is associated with an increase in forearm blood flow of 70% with losartan infusion. Therefore, given that in the patients with cirrhosis the plasma angiotensin II concentrations were 7-fold greater than controls, the magnitude of the vasodilatation to losartan is perhaps smaller than might be anticipated, consistent with a reduced responsiveness to angiotensin II. This is also supported by two other findings in our studies; a reduced vasoconstriction to angiotensin II infusion, and a negative correlation of plasma angiotensin II concentrations with the vasodilatation in response to losartan. This is in keeping with the action of angiotensin II as a compensatory humoral mediator, the vasoconstriction to which is diminished with chronic activation.
Also, we have shown an impairment of the vasoconstrictor response to LBNP in patients with cirrhosis. This is consistent with previous reports of a reduced vasoconstrictor [26]and pressor [7]response to head-up tilt. It is well known that the sympathetic nervous and renin–angiotensin systems act synergistically to influence vascular tone. Even at doses insufficient to cause vasoconstrictor or pressor responses, angiotensin II augments sympathetically stimulated vasoconstriction [17]via a prejunctional adrenoreceptor mediated mechanism [27]. Therefore, it might be anticipated that during renin–angiotensin system activation in the presence of elevated plasma angiotensin II concentrations the vasoconstrictor response to LBNP would be augmented; an effect which should be blocked by the infusion of losartan. In contrast, we demonstrated a significant impairment of the LBNP response which was unaffected by losartan infusion. The only study to address this issue of sympathetically stimulated forearm vasoconstriction through cardiopulmonary baroreceptor unloading [28], reported normal forearm vasoconstriction to LBNP in patients with cirrhosis. However, these patients had mild alcoholic cirrhosis without ascites or humoral activation and the forearm blood flow measurements appears to have been made for one minute only. Plethysmographic blood flow recordings within the first 60 s after wrist cuff inflation may be unreliable because of the instability and marked variability in blood flow that occurs initially [11, 23, 24]. We have utilised established methodology and have studied patients with advanced cirrhosis who have high plasma angiotensin II concentrations and a trend for higher plasma noradrenaline concentrations. Given our observation of normal peripheral vascular responses to noradrenaline infusion and the known increases in sympathetic nerve activity in cirrhosis [6], the current findings are consistent with an impaired response to baroreceptor unloading which probably reflects desensitisation of the neuronal reflex secondary to chronic stimulation from relative intravascular volume depletion and hypotension.
Our findings of normal noradrenaline responses but impaired angiotensin II induced vasoconstriction contrast with the results of previous studies by Ryan and colleagues [8, 22]which showed abnormal responses to both agents. In these studies, patients had mild alcoholic cirrhosis without significant humoral changes and were assessed using unilateral forearm plethysmography. The infusion periods of these studies were very brief at 2 min and the plethysmographic recordings and analysis were not predetermined or standardised. Moreover, there is inherent variability in forearm blood flow [11, 24]and the effects of unilateral brachial artery infusions are probably better assessed by comparing the infused forearm responses with the contralateral non-infused arm which acts as a contemporaneous control. It is also recognised that ethanol consumption impairs vascular responsiveness to noradrenaline [29], which remains a concern in patients with alcoholic liver cirrhosis. In our study we excluded all patients with alcoholic cirrhosis who had not achieved sustained abstinence for more than 6 months. In addition, we assessed the noradrenaline responses in the presence of ongoing AT1 receptor antagonism since the effect of intra-arterial losartan persists for at least 60 min after cessation of infusion [15]. An interaction with concomitant endogenous angiotensin II mediated vasoconstriction could, therefore, account for the attenuation in the noradrenaline response seen previously. Overall, the differences between the findings of the current study and those of Ryan et al. [8, 22]probably reflect a combination of differing patient characteristics and methodologies.
The humoral characteristics of our patient population are consistent with the previously documented changes in liver cirrhosis [5, 9]with compensatory increases in plasma angiotensin II and endothelin-1 concentrations which counterbalance the pronounced peripheral vasodilatation. Patients with chronic renal failure have isolated increases in plasma endothelin-1 concentrations without a rise in big endothelin-1 because of a reduction in endothelin-1 clearance by the kidney. In contrast, we have found a predominant increase in big endothelin-1 concentrations consistent with an increase in endothelin-1 production [30].
None of the known endogenous mediators are present in sufficient concentrations to account for the pronounced reduction in peripheral vascular resistance found in cirrhosis. In agreement with previous work [22, 31, 32], we have shown that patients with cirrhosis have normal basal forearm nitric oxide production as assessed by the vasoconstrictor response to L-NMMA. It is therefore unlikely that overproduction of nitric oxide mediates the characteristic peripheral vasodilatation of liver cirrhosis [31]. Indeed, it is also apparent from the L-NMMA and noradrenaline responses that the resistance vessel smooth muscle cells have a normal functional ability to contract and regulate peripheral vascular resistance in patients with cirrhosis.
In this study, we have confined ourselves to examining patients who have severe liver cirrhosis and ascites associated with pronounced humoral activation. Therefore, extrapolation of our findings to milder forms of liver cirrhosis can only be made tentatively. Antecedent spironolactone therapy may also have affected our results, although the main effects of aldosterone antagonism are to cause a mild accentuation of the plasma renin activity [33]and angiotensin II concentrations [Allan D. Struthers, personal communication]. Finally, baseline systemic haemodynamics in the patient and control populations were significantly different. Consequently, the geometry and resting tonus of the forearm resistance vessels will be dissimilar and may affect the magnitude of responses to the study agents [24]. However, given the similar basal forearm blood flows and responses to L-NMMA and noradrenaline infusion, we believe that the observed differences in responsiveness to angiotensin II are real. Moreover, the substantial differences in responses to losartan infusion and LBNP cannot be explained by these haemodynamic differences.
In conclusion, we have found that in patients with advanced cirrhotic liver disease angiotensin II makes an important contribution to the maintenance of peripheral vascular tone even though the resistance vessels are less sensitive to its vasoconstrictor actions. In addition, the vasoconstrictor response to cardiopulmonary baroreceptor unloading is attenuated in association with preservation of vascular responsiveness to noradrenaline. It is suggested that these abnormalities may reflect a response to chronic activation of the renin–angiotensin and sympathetic nervous systems in patients with advanced cirrhosis.
Time for primary review 25 days.
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Acknowledgements |
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DEN is the recipient of a British Heart Foundation Junior Research Fellowship (FS/95009). This work was supported by a grant from the Sir Stanley and Lady Davidson fund. We would like to acknowledge the assistance of Neil Johnston (Clinical Pharmacology Unit, Western General Hospital, Edinburgh) and Rhona Stevens (Department of Clinical Biochemistry, Royal Hospital for Sick Children, Edinburgh) in performing the assays.
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Notes |
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1 Present address: Yokohama City University, School of Medicine, Second Department of Internal Medicine, 3-9 Fukuura, Kanazawa-Ku, Yokohama 236, Japan.
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References |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
- Murray JF, Dawson AM, Sherlock S. Circulatory changes in chronic liver disease. Am J Med (1958) 32:358–367.
- Kontos HA, Shapiro W, Mauck HP, Patterson JL. General and regional circulatory alterations in cirrhosis of the liver. Am J Med (1964) 37:526–535.[CrossRef][Web of Science][Medline]
- Kowalski HJ, Abelman WH. Cardiac output at rest in Laennec's cirrhosis. J Clin Invest (1953) 32:1025–1033.[Web of Science][Medline]
- Henriksen JH, Christensen NJ, Ring-Larsen H. Noradrenaline and adrenaline concentrations in various vascular beds in patients with cirrhosis: relation to haemodynamics. Clin Physiol (1981) 1:293–304.[Web of Science][Medline]
- Bichet DG, Van Putten VJ, Schrier RW. Potential role of increased sympathetic activity in impaired sodium and water excretion in cirrhosis. N Engl J Med (1982) 307:1552–1557.[Abstract]
- Floras JS, Legault L, Morali GA, Hara K, Blendis LM. Increased sympathetic outflow in cirrhosis and ascites: direct evidence from intraneural recordings. Ann Intern Med (1991) 114:373–380.[CrossRef][Web of Science][Medline]
- Bernardi M, Trevisani F, Santini C, Ligabue L, Capelli M, Gasbarnini G. Impairment of blood pressure control in patients with liver disease during tilting: study on adrenergic and renin–angiotensin systems. Digestion (1982) 25:124–130.[Web of Science][Medline]
- Ryan J, Sudhir K, Jennings G, Esler M, Dudley F. Impaired reactivity of the peripheral vasculature to pressor agents in alcoholic cirrhosis. Gastroenterology (1993) 105:1167–1172.[Web of Science][Medline]
- Martinet J-P, Legault L, Cernacek P, et al. Changes in plasma endothelin-1 and big endothelin-1 induced by transjugular intrahepatic portosystemic shunts in patients with cirrhosis and refractory ascites. Hepatology (1996) 25:700–706.[CrossRef]
- MacGilchrist AJ, Sumner D, Reid JL. Impaired pressor reactivity in cirrhosis: evidence for a peripheral vascular defect. Hepatology (1991) 13:689–694.[CrossRef][Web of Science][Medline]
- Webb DJ. The pharmacology of human blood vessels in vivo. J Vasc Res (1995) 32:2–15.[Web of Science][Medline]
- Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet (1989) ii:997–1000.
- Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone in man. Lancet (1994) 344:852–854.[CrossRef][Web of Science][Medline]
- Hashimoto M, Akishita M, Eto M, et al. Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation (1995) 92:3431–3435.
[Abstract/Free Full Text] - Newby DE, Masumori S, Johnston NR, Boon NA, Webb DJ. Endogenous angiotensin II contributes to basal peripheral vascular tone in sodium deplete but not sodium replete man. Cardiovasc Res 1997;36:268–275.
- Wiinberg N, Walter-Larson S, Eriksen C, Nielsen PE. An evaluation of semi-automatic blood pressure manometers against intra-arterial blood pressure. J Ambulatory Monitoring (1988) 1:303–309.
- Seidelin PH, Collier JG, Struthers AD, Webb DJ. Angiotensin II augments sympathetically mediated arteriolar constriction in man. Clin Sci (1991) 81:261–266.[Web of Science][Medline]
- Rolinski B, Bogner SJ, Goebel FD. Determination of endothelin-1 immunoreactivity in plasma, cerebrospinal fluid and urine. Res Exp Med (1994) 194:9–24.[Medline]
- Morton JJ, Webb DJ. Measurement of plasma angiotensin II. Clin Sci (1985) 68:483–484.[Web of Science][Medline]
- Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation (1992) 85:504–509.
[Abstract/Free Full Text] - Goldstein DS, Feuerstein G, Izzo JL, Kopin IJ, Keiser HR. Validity and reliability of liquid chromatography with electrochemical detection for measuring plasma levels of norepinephrine and epinephrine in man. Life Sci (1981) 28:467–475.[CrossRef][Web of Science][Medline]
- Ryan J, Jennings G, Dudley F, Chin-Dusting J. Smooth muscle-derived nitric oxide is elevated in isolated forearm veins in human alcoholic cirrhosis. Clin Sci (1996) 91:23–28.[Web of Science][Medline]
- Kerslake DMcK. The effect of the application of an arterial occlusion cuff to the wrist on the blood flow in the human forearm. J Physiol (Lond) (1949) 108:451–457.
[Free Full Text] - Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D. Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension (1995) 25:918–923.
[Abstract/Free Full Text] - Baan J, Chang PC, Vermeij P, Pfaffendorf M, van Zwieten PA. Effects of losartan on vasoconstrictor responses to angiotensin II in the forearm vascular bed. Cardiovasc Res (1996) 32:973–979.
[Abstract/Free Full Text] - Lunzer M, Newman SP, Sherlock S. Skeletal muscle blood flow and neurovascular reactivity in liver disease. Gut (1973) 14:354–359.
[Abstract/Free Full Text] - Hjemdahl P, Friberg P. Biochemical assessment of sympathetic activity and prejunctional modulation of noradrenaline release in humans. J Hypertens (1996) 14:147–150.[CrossRef][Web of Science][Medline]
- Wong F, Logan A, Blendis L. Systemic hemodynamic, forearm vascular, renal and humoral responses to sustained cardiopulmonary baroreceptor deactivation in well-compensated cirrhosis. Hepatology (1995) 21:717–724.[Web of Science][Medline]
- Howes LG, Reid JL. Decreased vascular responsiveness to noradrenaline following regular ethanol consumption. Br J Clin Pharmacol (1985) 20:669–674.[Web of Science][Medline]
- Plumpton C, Ferro CJ, Haynes WG, Webb DJ, Davenport AP. The increase in human plasma immunoreactive endothelin but not big endothelin-1 or its C-terminal fragment induced by systemic administration of the endothelin antagonist TAK-044. Br J Pharmacol (1996) 119:311–314.[Web of Science][Medline]
- Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role of nitric oxide? Lancet (1991) 337:776–778.[CrossRef][Web of Science][Medline]
- Calver A, Harris A, Maxwell JD, Vallance P. Effect of local inhibition of nitric oxide synthesis on forearm blood flow and dorsal hand vein size in patients with alcoholic cirrhosis. Clin Sci (1994) 86:203–208.[Web of Science][Medline]
- Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic heart failure secondary to coronary artery disease. Am J Cardiol (1995) 76:1259–1265.[CrossRef][Web of Science][Medline]
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 J. Goddard, N. R. Johnston, M. F. Hand, A. D. Cumming, T. J. Rabelink, A. J. Rankin, and D. J. Webb Endothelin-A Receptor Antagonism Reduces Blood Pressure and Increases Renal Blood Flow in Hypertensive Patients With Chronic Renal Failure: A Comparison of Selective and Combined Endothelin Receptor Blockade Circulation, March 9, 2004; 109(9): 1186 - 1193. [Abstract] [Full Text] [PDF]
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R B Vaughan, P W Angus, and J P F Chin-Dusting Evidence for altered vascular responses to exogenous endothelin-1 in patients with advanced cirrhosis with restoration of the normal vasoconstrictor response following successful liver transplantation Gut, October 1, 2003; 52(10): 1505 - 1510. [Abstract] [Full Text] [PDF]
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 S C Apostolopoulou, S Rammos, Z S Kyriakides, D J Webb, N R Johnston, D V Cokkinos, and D T. Kremastinos Acute endothelin A receptor antagonism improves pulmonary and systemic haemodynamics in patients with pulmonary arterial hypertension that is primary or autoimmune and related to congenital heart disease Heart, October 1, 2003; 89(10): 1221 - 1226. [Abstract] [Full Text] [PDF]
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A Helmy, D E Newby, R Jalan, P C Hayes, and D J Webb Enhanced vasodilatation to endothelin antagonism in patients with compensated cirrhosis and the role of nitric oxide Gut, March 1, 2003; 52(3): 410 - 415. [Abstract] [Full Text] [PDF]
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 D.E. Newby and P.C. HAYES Hyperdynamic circulation in liver cirrhosis: not peripheral vasodilatation but 'splanchnic steal' QJM, December 1, 2002; 95(12): 827 - 830. [Full Text] [PDF]
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J H Henriksen, S Moller, S Schifter, J Abrahamsen, and U Becker High arterial compliance in cirrhosis is related to low adrenaline and elevated circulating calcitonin gene related peptide but not to activated vasoconstrictor systems Gut, July 1, 2001; 49(1): 112 - 118. [Abstract] [Full Text] [PDF]
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R JALAN, D E NEWBY;, F WONG, and L BLENDIS Losartan and renal sodium handling Reply Gut, October 1, 2000; 47(4): 596a - 597. [Full Text] [PDF]
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R Jalan and P C Hayes Sodium handling in patients with well compensated cirrhosis is dependent on the severity of liver disease and portal pressure Gut, April 1, 2000; 46(4): 527 - 533. [Abstract] [Full Text] [PDF]
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 T. V. Bilfinger and G. B. Stefano Human aortocoronary grafts and nitric oxide release: relationship to pulsatile pressure Ann. Thorac. Surg., February 1, 2000; 69(2): 480 - 485. [Abstract] [Full Text] [PDF]
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 F. E. Strachan, J. C. Spratt, I. B. Wilkinson, N. R. Johnston, G. A. Gray, and D. J. Webb Systemic Blockade of the Endothelin-B Receptor Increases Peripheral Vascular Resistance in Healthy Men Hypertension, January 1, 1999; 33(1): 581 - 585. [Abstract] [Full Text] [PDF]
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