Angiotensin 11 Receptor Blockade and Effects on Pulmonary Hemodynamics and Hypoxic Pulmonary Vasoconstriction in Humans

doi:10.1378/chest.110.3.698

Chest

Volume 110, Issue 3, September 1996, Pages 698-703

https://doi.org/10.1378/chest.110.3.698 Get rights and content

Study objective

We examined the hypothesis that angiotensin II (ANG II) is a modulator of pulmonary vascular tone by examining the effects of ANG II blockade on pulmonary hemodynamics during normoxemia and hypoxemia in normal volunteers with an activated renin angiotensin system (RAS).

Participants and interventions

Eight normal volunteers, pretreated with furosemide, were studied on two separate occasions and received either an infusion of saralasin, 5 µg/kg/min, or placebo. After 20 min, they were rendered hypoxemic, by breathing N₂/O₂ mixture for 20 min to achieve arterial oxygen saturation (SaO₂) of 85 to 90% adjusted for a further 20 min to achieve SaO₂ of 75 to 80%. Doppler echocardiography was used to measure mean pulmonary artery pressure (MPAP), cardiac output, and hence total pulmonary vascular resistance (TPR).

Results

Saralasin compared with placebo resulted in a significant (p>0.05) reduction in MPAP during normoxemia, 6.70±1.0 vs 11.7±1.3 mm Hg; at SaO₂ of 85 to 90%, 14.7±1.4 vs 20.5±1.0 mm Hg; and at SaO₂ of 75 to 80%, 18.1±1.9 vs 27.8±1.9 mm Hg, respectively. Likewise saralasin compared with placebo resulted in a significant reduction in TPR during normoxemia, 104±14 vs 180±20 dyne·s·cm⁻⁵; at SaO₂ of 85 to 90%, 222±24 vs 295±21 dyne·s·cm⁻⁵; and at SaO₂ of 75 to 80%, 238±21 vs 362±11 dyne·s·cm⁻⁵, respectively. The δM?α? response to hypoxemia was likewise significantly (p>0.01) attenuated by saralasin infusion compared with placebo: mean difference 5.0 mm Hg, 95% confidence interval (CI) 1.9 to 8.08, and there was a trend toward attenuation of the ATPR response to hypoxemia (0.05>p>0.10): mean difference 47 dyne·s·cm⁻⁵, 95% CI, −10 to 105.

Conclusion

In addition to causing pulmonary vasodilatation in the presence of an activated RAS, our results suggest that ANG II receptor blockade attenuates acute hypoxic pulmonary vasoconstriction and that ANG II may play a role in modulating this response in normal man.

Section snippets

Subjects

Eight healthy male volunteers, age (mean±SEM) 29±3 years, were studied on 2 separate occasions. There was no abnormality present on clinical history, examination, 12−lead ECG, echocardiography, biochemical screening, or hematologic screening. No medications were permitted during and for 1 month prior to the study. Informed written consent to the study protocol, previously approved by the Tayside Committee for Medical Research Ethics, was obtained.

Study Protocol

Subjects attended the laboratory at the same

Pulmonary Hemodynamics

There was no significant difference in PAT, MPAP, or TPR at baseline (To) between study days. Infusion of saralasin compared to the placebo resulted in a significant (p>0.05) reduction in MPAP during normoxemia (T₁), mean difference 4.6 mm Hg (95% CI, 1.25 to 8.0); at an SaO₂ of 85 to 90% (T₂), mean difference 6.1 mm Hg (95% CI, 1.4 to 10.8); and a significant (p>0.0005) difference at an SaO₂ of 75 to 80% (T3), mean difference 9.6 mm Hg (95% CI, 6.0 to 13.2), respectively (Fig 1, top). Likewise

Discussion

Our results demonstrate that the ANG II antagonist saralasin causes pulmonary vasodilatation in the presence of an activated RAS. In this respect, we have shown that absolute MPAP and TPR were significantly lower during hypoxemia after saralasin compared to placebo and similarly that the δM?α? and δTPR responses from baseline to each level of hypoxemia were also significantly attenuated by saralsin. There is also evidence to suggest that ANG II blockade may attenuate acute hypoxic pulmonary

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However, an excessive reduction in central venous pressure may result in worsening of TR severity (2). The use of angiotensin-converting enzyme inhibitors is supported by evidence that chronic RV pressure overload activates the renin-angiotensin-aldosterone system, which may contribute to fluid retention and ventricular remodeling (33); B-type natriuretic peptide is usually increased in cases of RV pressure or volume overload (34). Although a causal relationship between TR severity and more severe renal failure has not been demonstrated, an association between TR grade and lower estimated glomerular filtration rate, higher blood urea nitrogen, and higher blood urea nitrogen/creatinine ratio has been described (35).
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Many drugs used for idiopathic pulmonary arterial hypertension are being considered as treatment options for heart failure–related pulmonary hypertension. This is of particular significance in the heart transplant population. Randomized clinical trials with interventions targeting heart failure patients with elevated pulmonary artery pressure would be justified.
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High-altitude pulmonary oedema (HAPE) is a potentially fatal condition affecting fit and previously well individuals at altitudes in excess of 3000 m. This article discusses the mechanisms of HAPE, considers the contribution of hypoxic pulmonary vasoconstriction and alterations in sodium transport to the pathological process. It discusses the various biochemical mediators such as nitric oxide (NO), endothelin-1 (ET-1), and the renin-angiotensin-aldosterone system (RAS) that may be involved and considers possible oxygen-sensing mechanisms involved in hypoxic adaptation such as hypoxia-inducible factor-1 (HIF-1). Those who have had HAPE once run an unpredictable but significant risk of recurrence; therefore, there may be a constitutional or genetic component in its aetiology. This paper considers the possible involvement of genes that may be involved in physiological adaptation to hypoxia (e.g., angiotensin-1 [AT₁]-converting enzyme [ACE], tyrosine hydroxylase, serotonin transporter [5-HTT], and endothelial NO synthase [eNOS] genes). As yet, no formal association has been identified between an identified genetic polymorphism and HAPE, but genetic variation provides a possible mechanism to explain interindividual variation in response to hypoxia and enhanced or reduced performance at altitude.
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PURPOSE: An association between activation of the renin-angiotensin system and enhanced erythropoiesis has been observed in patients with several diseases, including congestive heart failure and hypertension. Our goal was to examine whether the renin-angiotensin system is associated with secondary erythrocytosis in patients with chronic obstructive pulmonary disease (COPD).
SUBJECTS AND METHODS: Plasma renin activity, plasma aldosterone concentration, serum erythropoietin level, and serum angiotensin converting enzyme (ACE) activity were measured in 12 patients with COPD and secondary erythrocytosis [mean (±SD) hematocrit of 53% ± 3%] and in 12 matched controls with COPD who did not have erythrocytosis (hematocrit 45% ± 5%). All patients had chronic hypoxemia (PaO₂ <60 mm Hg).
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CONCLUSION: Activation of the renin-angiotensin system is associated with the development of secondary erythrocytosis in chronically hypoxemic patients with COPD. The exact mechanism is not yet fully understood, but angiotensin II may be responsible for inappropriately sustained erythropoietin secretion or direct stimulation of erythroid progenitors.

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Chest

clinical investigationsAngiotensin 11 Receptor Blockade and Effects on Pulmonary Hemodynamics and Hypoxic Pulmonary Vasoconstriction in Humans

Study objective

Participants and interventions

Results

Conclusion

Section snippets

Subjects

Study Protocol

Pulmonary Hemodynamics

Discussion

Chest

Pulm Pharmacol

Chest

Am J Cardiol

Am J Med

Am J Med

J Biol Chem

Am Heart J

J Am Soc Echocardiogr

Observations on the pulmonary arterial blood pressure in the cat

Acta Physiol Scand

Hypoxia on the pulmonary circulation: how and where it acts

Circ Res

Elevated levels of brain natriuretic peptide in acute hypoxaemic chronic obstructive pulmonary disease

Clin Sci

Studies on plasma vasopressin and the renin−angiotensin aldosterone system in chronic obstructive lung disease

J Lab Clin Med

Abnormalities of sodium and water handling in chronic obstructive lung disease

Intern Med

Hypoxic pulmonary vasoconstriction in the rat: the necessary role of angiotensin II

Circ Res

Effect of angiotensin on hypoxic pulmonary vasoconstriction in isolated dog lung

J Appl Physiol

clinical investigations
Angiotensin 11 Receptor Blockade and Effects on Pulmonary Hemodynamics and Hypoxic Pulmonary Vasoconstriction in Humans