Cor pulmonale

For more than 50 years, since von Euler and Liljestrand[1] first demonstrated that hypoxia is a vasoconstrictor stimulus in the pulmonary circulation, efforts have been directed at elucidating the mechanism for this phenomenon. While a variety of factors are responsible for the development of pulmonary hypertension in the setting of parenchymal lung disease (cor pulmonale), including loss of vascular surface area, mechanical compression of the vascular bed due to loss of elastic forces, hyperviscosity due to polycythemia, and concomitant left heart dysfunction, hypoxic pulmonary vasoconstriction (HPV) and vascular remodeling are the most significant dynamic factors.[2] Considerable progress has been made in our understanding of the responses of vascular smooth muscle cells to hypoxia; nevertheless, treatment for cor pulmonale remains largely supportive, directed at improving the hypoxemia with supplemental oxygen and optimizing gas exchange.[3] Pharmacologic attempts directed at pulmonary hypertension have not, to date, shown an impact on long-term function or survival in cor pulmonale.

Recent studies have demonstrated that hypoxic constriction of pulmonary arteries is a unique property of pulmonary artery smooth muscle cells, which appears to be due to hypoxia-induced inhibition of a membrane-bound K+ channel, leading to increased intracellular K+, membrane depolarization, opening of voltage-gated calcium channels with resultant influx of extracellular Ca++, and vasoconstriction.[4] While the renin-angiotensin system (RAS) is not responsible for this process, which can be induced in isolated vascular rings or single smooth muscle cells, it is certainly possible that RAS activation could promote further vasoconstriction, at least acutely.[5]

In this issue of CHEST, Kiely and colleagues report on the effects of the administration of saralasin acetate, a competitive inhibitor of angiotensin II, on acute HPV in normal volunteers. In these subjects, who received diuretics prior to study to activate the RAS, saralasin acetate attenuated the rise in pulmonary artery pressure and vascular resistance produced by breathing hypoxic gas mixtures. Their results suggest that RAS could contribute to the development or maintenance of acute hypoxic pulmonary vasoconstriction. The authors suggest that the newly developed angiotensin II inhibitor drugs, such as losartan potassium, could, therefore, be of therapeutic value in cor pulmonale.

The angiotensin II blocking agents are a new addition to the antihypertensive armamentarium. These drugs work by selectively antagonizing the binding of angiotensin II to the AT1 receptor, thus inhibiting the vasoconstrictive effects of angiotensin II.[6] Since the angiotensin converting enzyme is not affected, there is no potentiation of bradykinin, as can be seen with the angiotensin converting enzyme inhibitors. In addition to its use in hypertension, preliminary experience suggests that losartan may be useful in treating congestive heart failure,[7] although long-term studies have not been completed.

It is premature, however, to jump on the bandwagon of the treatment of chronic cor pulmonale with yet a new vasodilator agent. First, Kiely and coworkers only studied the effects of saralasin acetate during acute hypoxic ventilation; second, the population selected for study was composed of normal volunteers, not subjects with chronic lung diseases, in whom other factors also contribute to the pulmonary hypertensive state; third, pulmonary hemodynamics were assessed noninvasively, and a number of assumptions were made, including an unchanged downstream (left atrial) pressure after drug administration. The acute and chronic effects of angiotensin inhibition on comprehensively assessed cardiopulmonary hemodynamics, gas exchange, and exercise tolerance in subjects with cor pulmonale should be addressed prior to making any recommendation regarding the potential utility of this approach. Nevertheless, the demonstration by Kiely and colleagues that an angiotensin II blockade may affect HPV in humans opens the door for the exploration of a new and potentially fruitful approach to the prevention and treatment of vasoconstrictive pulmonary vascular disease.

REFERENCES

[1] von Euler US, Liljestrand G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand 1946; 12:301-19

[2] MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease: state of the art. Am J Respir Crit Care Med 1994; 150:833-52(pt 1), 1158-68(pt 2)

[3] Salvaterra CG, Rubin LJ. Investigation and management of pulmonary hypertension in chronic obstructive pulmonary disease. Am Rev Respir Dis 1993; 148:1414-17

[4] Yuan XJ, Goldman WF, Tod ML, et al. Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. Am J Physiol 1993; 264(Lung Cell Mol Physiol):L116-L23

[5] Berkov S. Hypoxic pulmonary vasoconstriction in the rat: the necessary role of angiotensin II. Circ Res 1974; 35:256-60

[6] Siegl PK. Discovery of Iosartan, the first specific non-peptide angiotensin II receptor antagonist. J Hypertens 1993; 11(suppl):S19-S22

[7] Dickstein D, Chang P, Willenheimer R, et al. Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure. J Am Coll Cardiol 1995; 26:438-45

Head, Division of Pulmonary and Critical Care Medicine, Professor of Medicine and Physiology, University of Maryland School of Medicine.

COPYRIGHT 1996 American College of Chest Physicians
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