This essay looks at the historical significance of an APS classic paper that is freely available online:
Motley HL, Cournand A, Werko L, Himmelstein A, and Dresdale D. The influence of short periods of induced acute anoxia upon pulmonary artery pressures in man. Am J Physiol 150: 315–320, 1947 (http://ajplegacy.physiology.org/cgi/reprint/150/2/315).
for the lungs to operate efficiently in gas exchange, it is essential for the pulmonary blood flow to be directed to well-ventilated areas of the lungs. Teleologically, one mechanism to accomplish this end might be via nerves and pulmonary reflexogenic zones comparable to the sinus and aortic bodies in the systemic circulation. Although the lungs are richly innervated, no evidence indicates that such zones exist or that the nerves to the lungs play such a role. Instead, a mechanism for the control of the distribution of blood within the lungs is hypoxic pulmonary vasoconstriction, which automatically increases pulmonary vascular resistance in poorly aerated regions of the lungs, thereby redirecting pulmonary blood flow to regions richer in oxygen content.
A first step in uncovering the existence of hypoxic pulmonary vasoconstriction was taken by Euler and Liljestrand (6, 10). In closed-chest, spontaneously breathing cats anesthetized with chloralose, they showed that acute hypoxia elicits pulmonary vasoconstriction (Fig. 2). They postulated that hypoxic pulmonary vasoconstriction is a mechanism that sustains oxygen delivery to systemic tissues and organs by diverting pulmonary blood flow to the better aerated parts of the lungs. This demonstration, which they supplemented by observations on the effects of muscular work and vasoactive drugs on pulmonary arterial pressures, led to the conclusion that the distribution of the pulmonary blood flow within the lungs is regulated primarily by a local vasomotor mechanism that automatically directs the blood to better ventilated parts of the lungs.
Motley et al. (13), in the laboratory of André Cournand (Fig. 1) at Bellevue Hospital, aware of the recent observations by Euler and Liljestrand on anesthetized cats, undertook similar observations on five normal human subjects. The subjects were rendered hypoxic by breathing an inspired gas mixture of 10% O2 in N2 for 10 min. In each subject, acute hypoxia elicited pulmonary vasoconstriction, as indicated by an increase in pulmonary arterial pressure. The demonstration of the hypoxic pulmonary pressor response in unanesthetized humans breathing spontaneously represented a landmark in the growth of understanding of the regulation of pulmonary circulation.
Unexpectedly, they found that the pulmonary arterial pressor effect was accompanied by a decrease in cardiac output, which they calculated by the Fick principle. However, this decrease in calculated cardiac output during acute hypoxia proved later to be in error (8), due to failure to allow sufficient time for the subjects to reach the steady state of the respiration and circulation required for a valid application of the Fick principle. Subsequent experiments in which normal human subjects were exposed to inspired gas mixtures low in oxygen showed that when sufficient time is allotted for a new steady state to be reached, the calculated cardiac output does increase (8).
These early observations on unanesthetized normal human subjects have three implications: 1) as in the case of the anesthetized cat, they demonstrate that the normal human pulmonary circulation responds to hypoxia by vasoconstricting; 2) they suggest that instead of simply serving as a passive conduit between the two sides of the heart, an automatic pulmonary intravascular mechanism directs venous blood returning to the heart to better aerated areas of the lungs for optimal gas exchange; and 3) they underscore the need to satisfy steady-state criteria for valid application of the Fick principle (7).
Despite intensive research since the observations of Euler and Liljestrand (6, 10), the mechanism responsible for hypoxic pulmonary vasoconstriction remains enigmatic. All investigators agree that hypoxic pulmonary vasoconstriction reflects an inherent property of the small precapillary muscular pulmonary arteries and that these vessels respond to alveolar oxygen tensions rather than to vascular oxygen tensions. Moreover, there is a consensus that, even though hypoxic pulmonary vasoconstriction may be modulated by various mediators and by the autonomic nervous system, its intrinsic mechanism is independent of these influences. The search for the initiating mechanism for the hypoxic pulmonary vascular response continues to the present, and the approaches vary considerably (1–5, 9, 11, 12, 14). One line of current research focuses on the role of oxygen-sensitive voltage-gated K+ channels as the possible effector mechanism and explains the pulmonary arterial sensor for the hypoxic pressor response in electrical terms (2, 3). Another explores the role played by endothelin as the mediator of hypoxic pulmonary vasoconstriction (1, 14). However, there is still no consensus concerning the mechanism responsible for sensing and initiating the hypoxic pulmonary pressor response.
- Copyright © 2004 the American Physiological Society