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Cardiovascular Research 1997 33(1):201-208; doi:10.1016/S0008-6363(96)00180-0
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale

David G Kiely*, Robert I Cargill, Nigel M Wheeldon, Wendy J Coutie and Brian J Lipworth

Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK

Received 20 May 1996; accepted 20 July 1996


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: Angiotensin II (ANG II) is known to be a potent vasoconstrictor agent in the pulmonary circulation. Furthermore, type 1 ANG II receptor blockade with losartan attenuates acute hypoxic pulmonary vasoconstriction in normal subjects. The aim of this study was therefore to evaluate the haemodynamic and endocrine sequelae of type 1 ANG II receptor blockade in patients with hypoxaemic cor pulmonale. Methods: Nine patients with chronic obstructive pulmonary disease (COPD) age 67 ± 3 years with pulmonary hypertension and normal left ventricular systolic function were studied on two separate occasions in a double-blind, placebo-controlled, crossover study. They were randomised to receive either 50 mg of oral losartan or matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Haemodynamic measurements and venous blood samples were taken at baseline and after 2 and 4 h. Results: Maximal effects were observed at 4 h where losartan compared to placebo resulted in a significant reduction in both MPAP (28.6 ± 2.0 vs 32.4 ± 1.5 mmHg) and TPR (428 ± 40 vs 510 ± 40 dyn·s·cm–5), respectively. Similarly losartan compared to placebo resulted in a significant reduction in MAP (87 ± 4.5 vs 93 ± 3.2 mmHg) and SVR (1293 ± 94 vs 1462 ± 112 dyn·s·cm–5), and significantly increased CO (5.58 ± 0.43 vs 5.31 ± 0.42 l/min). In addition, plasma aldosterone was significantly lower after treatment with losartan compared to placebo: 76 ± 23 vs 164 ± 43 pg/ml respectively. Conclusions: Thus, selective type 1 ANG II receptor blockade appears to have beneficial pulmonary and endocrine effects, suggesting a possible therapeutic role in the management of hypoxaemic cor pulmonale.

KEYWORDS Angiotensin II; Losartan; Angiotensin receptor; Pulmonary hypertension; Human


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Acute hypoxic pulmonary vasoconstriction (HPV) is an important phenomenon present in a wide variety of different animal species allowing blood to be diverted from areas of alveolar hypoxia, so maintaining ventilation perfusion matching. Although this undoubtedly has beneficial effects, it can also have deleterious effects. In particular, in chronic hypoxic lung disease, hypoxaemia provides a sustained stimulus to pulmonary vasoconstriction, resulting in an elevation of mean pulmonary artery pressure [1], vascular remodelling [2] and over time the development of cor pulmonale and consequently a poor prognosis [3, 4].

The benefits of treating pulmonary hypertension in the context of chronic hypoxic lung disease are unknown. Oxygen therapy has been shown to reduce mean pulmonary artery pressure acutely [5], and reduce mortality in patients with hypoxaemic cor pulmonale [3, 4]. Whether this is primarily due to improved systemic oxygenation or a reduction in right ventricular afterload is not known. Nevertheless, therapy that could either prevent or treat pulmonary hypertension in these patients could conceivably reduce both mortality and morbidity and have additional benefits to oxygen therapy.

In the context of pulmonary hypertension, the role of vasoactive peptides has been extensively investigated [6]. It is known that angiotensin II (ANG II) is a potent pulmonary vasoconstriction in man [7, 8] and that patients with hypoxaemic cor pulmonale have activation of the renin-angiotensin-aldosterone system (RAAS) [9, 10]. Indeed, ANG II has been shown to promote a growth response in vascular smooth muscle cells [11], suggesting the possibility that, in addition to acting as pressor agent, ANG II could also contribute directly to vascular remodelling. Interestingly angiotensin II converting enzyme inhibitors (ACE inhibitors) have been shown to attenuate the development of pulmonary hypertension in chronically hypoxic rats [12], although there is conflicting evidence from in vitro studies as to whether ANG II plays a facilitatory role in modulating HPV [13, 14]. In normal humans, however, ACE inhibition with lisinopril [15] and type 1 ANG II receptor blockade with losartan [16] have been shown to attenuate acute HPV. Subsequent studies in patients with hypoxaemic cor pulmonale using ACE inhibitors have shown variable pulmonary and systemic haemodynamic benefit [17–21]. Whether the beneficial haemodynamic effects are a consequence of reducing ANG II levels is unknown since ACE inhibitors also increase levels of bradykinin, a vasodilator.

We have therefore evaluated for the first time the effects of selective type 1 ANG II receptor blockade with losartan, in patients with hypoxaemic cor pulmonale.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Subjects
Nine patients (6 male, 3 female), with clinically stable cor pulmonale secondary to hypoxaemic cor pulmonale (mean age ± s.e.m. 67 ± 3 years), were included in the study after attending a screening visit to assess inclusion criteria and characterise the study population. All had spirometric evidence of obstructive airways disease (FEV1/FVC < 70%) and arterial hypoxaemia whilst breathing air (PaO2 < 8.5 kPa) and had or gave a history of having peripheral oedema. On echocardiography subjects were required to be in sinus rhythm, have normal left ventricular function, no evidence of valvular heart disease and a resting mean pulmonary artery pressure, whilst breathing room air, of at least 25 mmHg. In addition, all subjects had evidence of reversible, dynamic pulmonary vasoconstriction as assessed by ≥ 10% fall in MPAP on breathing 60% oxygen for 30 min. All subjects were taking inhaled bronchodilators (beta-agonist n = 9; anticholinergic n = 6) and inhaled steroids, five patients were taking oral loop diuretics and 6 patients used domiciliary oxygen for at least 15 h per day. Medications were unchanged throughout the study period. The summary demographic data for this patient group are given in Table 1.


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  		Table 1 Patient characteristics

 
2.2. Study protocol
All subjects gave informed written consent to the study protocol previously approved by the Tayside Committee for Medical Research Ethics and conforming with the principles outlined in the Declaration of Helsinki. Subjects were studied at the same time of the day on 2 separate occasions at least 1 week apart in a randomised, double-blind placebo-controlled, cross-over design. Patients taking regular diuretics were asked to omit their morning dose of diuretic on each visit. On each study day, an intravenous cannula was sited in the right forearm for venous blood sampling. Subjects then remained semi-recumbent throughout and were studied whilst breathing room air. Patients then received either 50 mg of oral losartan potassium (Merck Sharp and Dohme Ltd, Hertfordshire, UK) or placebo. Haemodynamic parameters were measured and blood samples were taken at baseline after subjects had rested for at least 30 min to obtain stable resting hamodynamics (T0), 2 h (T1) and 4 h (T2) after administration of either losartan or placebo.

2.3. Measurements
2.3.1. Oxygenation
Arterial blood oxygen saturation was continuously monitored by transcutaneous oximetry (CSI 503, Criticare Systems Inc, Waukesha, WI, USA).

2.3.2. Systemic haemodynamics
Mean arterial blood pressure (MAP) and heart rate (HR) were measured by semi-automatic sphygmomanometer (Vital Signs Monitor, Critikon, Tampa, FL, USA) as the mean of 3 consistent readings. Aortic cross-sectional area (CSA) was measured by M-mode echocardiography (Vingmed SD50). The aortic systolic velocity integral (SVI) was measured by on-line computer-assisted determination using pulsed-wave Doppler echocardiography of ascending aortic blood flow from the suprasternal notch. On-line calculations of stroke volume (SV = SVI x CSA) and cardiac output (CO) as the product of SV and HR were made. Total systemic vascular resistance (SVR) was calculated as: SVR = MAP/CO x 80 dyn·s·cm–5. Reproducibility of our haemodynamic measurements including Doppler methodology was assessed in patients with cor pulmonale by 3 repeat measurements over a 4 h period at 2 h intervals. This short-term co-efficient of variability for MAP was 8.2%, CO was 9.6% and SVR was 5.3%.

2.3.3. Pulmonary haemodynamics
Pulmonary arterial flow was analysed by pulsed-wave Doppler echocardiography (Vingmed SD50) from the subcostal position to measure the pulmonary acceleration time (PAT), being the time in milliseconds from the onset of pulmonary flow to peak velocity. A stable pulsed-wave Doppler signal was recorded with the mean of 3 consistent waveforms at each time point used for the purpose of analysis. Mean pulmonary artery pressure (MPAP) in mmHg was then calculated using the regression equation MPAP = 90 – (0.62 x PAT) as described by Dabestani for pulmonary acceleration times < 110 ms [22].

Fig. GR1 shows the correlation in our own hands between measurements of PAT and MPAP made simultaneously using pulsed-wave Doppler echocardiography in patients undergoing right heart catheterisation after acute admission to a coronary care unit, over a range of pulmonary artery pressures (r = –0.88, y = 164 – 0.88 x, P < 0.0001, n = 17). Using Dabestani's regression equation, MPAP = 73 – (0.42 x PAT) applicable to this range of pulmonary acceleration times, a close correlation between Doppler and catheter MPAP was also obtained (r = 0.88, y = 0.79 + 4.2, P < 0.0001, n = 17). Total pulmonary vascular resistance (TPR) was calculated as TPR = MPAP/CO x 80 dyn·s·cm–5. Reproducibility was assessed as before and the short term co-efficient of variability for PAT was 3.2%, MPAP was 5.8% and TPR was 12.4%.


Figure 1
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  		Fig. GR1 Validation of Doppler-derived measures of mean pulmonary artery pressure. Upper panel: Data comparing pulmonary acceleration time (PAT) and simultaneously measured mean pulmonary artery pressure (MPAP) during right heart catheterisation in patients with suspected pulmonary hypertension. Lower panel: Data comparing catheter- and Doppler-derived measures of mean pulmonary artery pressue (calculated using Dabestani's regression equation MPAP = 73 – [0.42 x PAT]) during right heart catheterisation in patients with suspected pulmonary hypertension.

 
2.3.4. RAAS activity and plasma creatinine
Samples for measurement of plasma renin activity (PRA) were collected into chilled EDTA tubes and samples for plasma aldosterone were collected in chilled lithium-heparin tubes. They were centrifuged at 4°C immediately and separated plasma was stored at –20°C until assayed in one batch in duplicate at the end of the study. PRA and plasma aldosterone were assayed using commercially available RIA kits (Sorin Biomedica, Saluggia, Italy). PRA was assayed by measurement of amount of ANG I generated per hour. The intra-assay coefficient of variation for analysis of PRA was 6.50% and plasma aldosterone was 8.77%.

2.4. Data analysis
Comparison of values between study days was made by multifactorial analysis of variance (MANOVA) [23] and where there was a significant difference the mean difference and 95% confidence intervals for the mean difference are given (95% CI). Comparisons between serial time points on the same study day were made using Duncan's multiple range test. A probability value of P < 0.05 (two-tailed) was considered to be statistically significant. Data are presented as means and s.e.m.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Systemic haemodynamics
There were no significant differences in absolute values of HR, SV, CO, MAP or SVR at baseline between study days. Although there was no significant difference in either MAP or SVR after treatment with losartan or placebo at 2 h, both MAP (P < 0.05, mean difference 5.7 mmHg, 95% CI 0.4–10.9) and SVR (P < 0.01, mean difference 169 dyn·s·cm–5, 95% CI 71–267) were significantly lower 4 h after treatment with losartan compared to placebo (Fig. GR2). Although losartan compared to placebo had no significant effects on SV, CO was significantly (P < 0.05) higher 4 h after losartan compared to placebo: mean difference 0.27 l/min (95% CI 0.04–0.50) (Table 2). Fig. GR3 shows the changes in SVR 4 h after administration of losartan compared to placebo for individual patients. Whilst there was no significant difference in HR between study days at 4 h, HR was significantly higher 4 h after treatment with losartan compared to baseline (Table 2).


Figure 2
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  		Fig. GR2 Systemic haemodynamics. Upper panel: Mean arterial blood pressure (MAP) measured at baseline, after 2 h and after 4 h. Lower panel: Systemic vascular resistance (SVR) measured at baseline, after 2 h and after 4 h. Treatment with losartan is represented by the bold triangles whereas treatment with placebo is represented by the open circles. Values are given as mean±s.e.m. * Represents a significant (P < 0.05) difference between placebo and losartan at that time point whereas a +-sign represents a significant (P < 0.05) difference between that timepoint and baseline.

 

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  		Table 2 Systemic haemodynamics

 

Figure 3
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  		Fig. GR3 Individual patient data on changes in vascular resistance. Upper panel: Total pulmonary vascular resistance (TPR), measured at basline and 4 h after acute administration of losartan 50 mg in 9 patients with hypoxaemic cor pulmonale. Lower panel: Systemic cascular resistance (SVR), measured at basline and 4 h after acute administration of losartan 50 mg in 9 patients wih hypoxaemic cor pulmonale. Values are given as mean±s.e.m. * Significant (P < 0.05) difference 4 h after administration of losartan compared to baseline.

 
3.2. Pulmonary haemodynamics
There was no significant difference in absolute values of MPAP or TPR at baseline (T0) between study days. Losartan compared to placebo resulted in a significant (P < 0.01) reduction in MPAP at 2 h (T1) (mean difference 3.1 mmHg, 95% CI 1.6–4.6) and a significant (P < 0.05) reduction at 4 h (T2) (mean difference 3.8 mmHg, 95% CI 0.3–7.3), respectively. Although there was no significant difference in TPR between treatment with losartan and placebo at 2 h, TPR was significantly (P < 0.05) lower 4 h after treatment with losartan compared to placebo: mean difference 82 dyn·s·cm–5 (95% CI 15–150). In addition, both MPAP and TPR were significantly (P < 0.05) lower 4 h after treatment with losartan compared to baseline (Fig. GR4). Fig. GR3 shows the changes in TPR 4 h after administration of losartan compared to baseline for individual patients.


Figure 4
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  		Fig. GR4 Pulmonary haemodynamics. Upper panel: Doppler mean pulmonary artery pressure (MPAP) measured at baseline, after 2 h and after 4 h. Lower panel: Total pulmonary vascular resistance (TPR) measured at baseline, after 2 h and after 4 h. Treatment with losartan is represented by the bold triangles whereas treatment with placebo is represented by the open circles. Values are given as mean±s.e.m. * Represents a significant (P < 0.05) difference between placebo and losartan at that time point whereas a +– sign represents a significant (P < 0.05) difference between that timepoint and baseline.

 
3.3. RAAS activity and serum creatinine
There were no significant differences in absolute values of PRA, plasma aldosterone or serum creatinine at baseline between study days. Although there were no significant differences between study days for PRA either at baseline or 2 and 4 h after administration of losartan or placebo, PRA was significantly increased 4 h after administration of losartan compared to baseline. There were significant (P < 0.05) falls in plasma aldosterone with time on both study, but in addition losartan compared to placebo resulted in a significant (P < 0.05) reduction in plasma aldosterone at 4 h (T2) (mean difference 89 pg/ml, 95% CI 19–159). There were no significant differences in plasma creatinine at baseline (T0), T1 or T2 between study days or with time on either study day (Table 3).


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  		Table 3 Renin-angiotensin-aldosterone system activity and serum creatinine

 
3.4. Oxygen saturation
There were no significant differences in oxygen saturation between days on which patients received placebo or losartan at baseline (T0) (91.4 ± 1.2 vs 91.1 ± 1.1%), at T1 (90.7 ± 1.1 vs 90.7 ± 1.1%), or at T2 (90.7 ± 1.2 vs 90.8 ± 1.1%), respectively, or with time on either study day.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
We have demonstrated for the first time that the selective type 1 ANG II receptor blocker, losartan, has beneficial pulmonary haemodynamic effects in hypoxaemic cor pulmonale without altering oxygen saturation. In this respect both MPAP and TPR were significantly lower after treatment with losartan compared to placebo, although this effect was of small magnitude and of uncertain clinical relevance. In addition, type 1 ANG II receptor blockade appears to have beneficial endocrine effects reflected by significantly lower levels of plasma aldosterone after treatment with losartan compared to placebo. We also noted a significant reduction in both MAP and SVR as well as a small but significant increase in cardiac output after treatment with losartan. This suggests that ANG II blockade may have a therapeutic role in the management of hypoxaemic cor pulmonale.

Losartan a potent, orally active type 1 ANG II receptor blocker (AT1) has provided us with a tool for elucidating the role of ANG II in the pulmonary circulation in man. It is a selective orally active selective AT1 receptor antagonist which shows no affinity for other hormonal receptors and at a functional level excepting ANG II it does not alter contractile response to a variety of different stimuli [24] and has been shown to produce concentration-dependent inhibition of ANG-II-induced vasoconstriction in vitro and in vivo [25, 26]. Losartan undergoes an important first-pass effect and is extensively transformed to its active metabolite, EXP 3174, reaching peak concentrations between 2 and 4 h after oral administration of losartan [27]. Early studies in normal volunteers have confirmed antagonism of pressor responses to exogenous administration of ANG I and ANG II with approximately 60–70% inhibition of control responses at maximum effect (3 h) [25, 28]. Although the interaction of losartan with the eicosanoid system has been observed in animals with high concentrations of the drug by some workers [29, 30] it seems unlikely that this accounts for the observed effects to a significant degree. Indeed, conflicting results surround evidence suggesting that losartan stimulates prostacyclin synthesis [29, 31, 32].

We examined the acute haemodynamic effects of a single dose of oral losartan. Our patients had activation of the RAAS system reflected by elevated levels of PRA at baseline compared with our own normal reference range (0.2–2.8 ng/ml/h). We also observed a significant increase in PRA 4 h after administration of losartan compared to baseline, consistent with blockade of the type 1 ANG II receptor in the juxtaglomerular apparatus, resulting in renin secretion due to inhibition of ANG II mediated negative feedback.

In terms of both systemic and pulmonary haemodynamic changes we observed maximal effect at 4 h. Whether the peak effect may have occurred after 4 h or if larger doses of losartan would achieve greater pulmonary haemodynamic benefit or whether this would be limited by systemic haemodynamic effects is not answered by this study. Interestingly, acute dosing studies in patients with congestive cardiac failure have shown no greater systemic haemodynamic effects with doses of losartan of greater than 25 mg of losartan and noted falls in MAP and SVR after 2 h with peak effect observed between 4 and 12 h and an effect still seen at 24 h [33]. This study does however suggest that ANG II contributes to the maintenance of both pulmonary and systemic vascular tone in patients with hypoxaemic cor pulmonale. Although ANG II has been shown to have pressor effects in man [7, 8], studies using ACE inhibitors in patients with hypoxaemic cor pulmonale have not consistently shown a pulmonary haemodynamic benefit, possibly as a consequence of inclusion criteria[17–21]. We have, however, specifically excluded patients who did not have demonstrable pulmonary vascular reactivity as assessed by the absence of a significant fall in mean pulmonary artery pressure in response to acute oxygen administration. In this respect we feel it is important that patients who are included in vasodilator trials have at least some dynamic component to their pulmonary hypertension, a situation analogous to studying bronchodilator therapy, where the degree of airway reversibility is established before evaluating the impact of therapy.

We observed a small but significant increase in cardiac output after treatment with losartan compared to placebo, and although HR was not significantly different between study days, losartan significantly increased HR compared to baseline. Although no significant increase in heart rate has been observed in acute dosing studies with losartan in patients with congestive cardiac failure, it is interesting that an increase in HR was noted in studies performed in normal volunteers pre-treated with oral frusemide [34]. This could possibly represent a reflex vagal withdrawal response to an acute reduction in afterload or a direct effect of losartan on the autonomic nervous system.

In terms of the methodology employed to measure pulmonary haemodynamic changes, we have used the pulmonary acceleration time as a measure of mean pulmonary artery pressure which we have shown to be reproducible in both normal volunteer [35] and patient studies [36] and has been shown to have a good correlation with catheter-derived measures in both our own hands and those of other workers [22, 37], although it is generally accepted that the pulmonary acceleration time cannot be used to precisely measure MPAP in a patient population [22]. We have previously employed these methods to study the pulmonary vascular effects of vasoconstrictors [8] and vasodilators[38], giving results which concur well with invasive studies of the same agents [7, 39] although some sudies have shown a poor correlation between changes in pulmonary acceleration time and catheter-measured MPAP[40, 41]. Doppler echocardiography is also a well-validated and reproducible measure of cardiac output [42]. We do not think that that the observed changes in TPR are likely to be confounded by alterations in wedge pressure since in cor pulmonale the increase in resistance is confined to the precapillary vasculature.

In addition to beneficial pulmonary haemodynamic changes, the inclusion of a placebo limb has allowed us to examine the effects of ANG II receptor blockade on plasma aldosterone levels. Plasma aldosterone is known to increase following the assumption of the upright posture and decrease following resumption of the supine posture[43, 44], an effect thought to be due to changes in both aldosterone secretion and clearance [45]. As expected with supine rest, plasma aldosterone levels fell on both study days with falls on the placebo day similar to those seen in normal volunteers [43]. In addition, however, treatment with losartan appears to have additional beneficial effects with plasma aldosterone significantly lower 4 h after dosing. This reduction in plasma aldosterone is likely to reflect a reduction in ANG-II-mediated aldosterone biosynthesis and secretion, and although ACE inhibitors have been shown to have a similar effect, ANG II blockers may theoretically produce greater aldosterone suppression since bradykinin may indirectly potentiate aldosterone release[46]. By lowering plasma aldosterone, ANG II receptor blockade may act to prevent excessive salt and water retention, which may be an important precipitating factor in acute exacerbations of cor pulmonale [47]. The RAAS also has significant trophic effects on vascular and cardiac muscle [48], whether lowering aldosterone levels and inhibiting the trophic effects of ANG II is sufficient to inhibit these mitogenic effects is unknown but may be important in arresting the cardiopulmonary remodelling characterising this condition.

So to conclude, in addition to previous work demonstrating that ANG II receptor blockade can attenuate the acute hypoxic pulmonary vasoconstrictor response, we have now shown that the acute administration of losartan has beneficial pulmonary haemodynamic and endocrine effects without worsening systemic oxygenation. Whether manipulating the renin-angiotensin-aldosterone system with ACE inhibitors or angiotensin II blockade may be of therapeutic value in hypoxaemic cor pulmonale by inhibiting cardiopulmonary remodelling or reducing right ventricular afterload can only be answered by conducting large, long-term follow-up studies.


   Notes
 
* Corresponding author. West Suffolk Hospital, Hardwick Lane, Bury St Edmunds, Suffolk, IP33 2QZ, UK. Tel. +44 1382 66011; Fax +44 1382 644972. Back


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

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