Hypoxic pulmonary vasoconstriction: a radical view.

Abstract

In 1894, when Bradford and Dean1 reported that asphyxia caused pulmonary hypertension, no one paid much attention. But ever since 1946, when von Euler and Liljestrand2 reported that acute hypoxia increased pulmonary arterial pressure attributable to pulmonary vasoconstriction, investigators have been hard at work to determine the underlying mechanisms. They have kept at it for more than half a century because of the important roles hypoxic pulmonary vasoconstriction (HPV) plays in health and disease. Early work on HPV was performed almost exclusively in intact animals or isolated lungs. These preparations provided reproducible relevant responses, but their complexity placed limits on mechanistic investigation. The last decade has seen accelerated use of more reduced preparations, such as isolated vessels and vascular cells. These preparations provide more investigative precision, but relevance is sometimes uncertain, and special conditions are often necessary to achieve adequate reproducibility. Because of these problems, the mechanisms of HPV remain unknown, and a rapidly growing mass of inconsistent data has generated confusion and frustration, leading one investigator to title his symposium on HPV, “Can everyone be right?” and another investigator to title his review, “Can anyone be right?” Nevertheless, areas of tentative consensus are emerging.3 The primary mechanisms of HPV are contained entirely within pulmonary vascular tissue. The main locus of the response is small distal pulmonary arteries. The smooth muscle effector pathway depends on an increase in cytoplasmic calcium concentration ([Ca2+]c) caused by influx of calcium from extracellular fluid. Voltage-gated calcium channels provide a major influx pathway; however, release of calcium from sarcoplasmic reticulum (SR) seems to be essential, and influx also occurs through other pathways, such as channels dependent on internal calcium stores.3 One hypothesis resolves this complexity by proposing that hypoxia first causes SR release of calcium, which then leads …