Hypoxic pulmonary vasoconstriction: mechanisms and controversies

Abstract

The pulmonary circulation differs from the systemic in several important aspects, the most important being that pulmonary arteries constrict to moderate physiological (20-60 mmHg PO2) hypoxia, whereas systemic arteries vasodilate. This phenomenon is called hypoxic pulmonary vasoconstriction (HPV), and is responsible for maintaining the ventilation-perfusion ratio during localized alveolar hypoxia. In disease, however, global hypoxia results in a detrimental increase in total pulmonary vascular resistance, and increased load on the right heart. Despite many years of study, the precise mechanisms underlying HPV remain unresolved. However, as we argue below, there is now overwhelming evidence that hypoxia can stimulate several pathways leading to a rise in the intracellular Ca2+ concentration ([Ca2+]i) in pulmonary artery smooth muscle cells (PASMC). This rise in [Ca2+]i is consistently found to be relatively small, and HPV seems also to require rho kinase-mediated Ca2+ sensitization. There is good evidence that HPV also has an as yet unexplained endothelium dependency. In this brief review, we highlight selected recent findings and ongoing controversies which continue to animate the study of this remarkable and unique response of the pulmonary vasculature to hypoxia.

Figure 1. Contractions caused by a range of vasoconstrictors in rat intrapulmonary arteries (IPA) are more sensitive to block by La³⁺ (10 μM), but less sensitive to block by diltiazem (10 μM) compared with those evoked in third or fourth order arterial branches of two systemic arteries, the mesenteric (MA) and femoral (FA) arteries

The amplitude of contraction is expressed as a percentage of that caused by depolarization with 80 mm K⁺ solution. Control responses are shown as open bars, and responses in the presence of La³⁺ and diltiazem are shown as grey bars. Asterisks indicate a significant (P < 0.05) effect of La³⁺ or diltiazem. Experiments with diltiazem were carried out using Krebs solution, whereas those with La³⁺ used a Hepes-buffered solution (Snetkov et al. 2003) to avoid La³⁺ precipitation. Note that Hepes itself often suppressed contraction to some extent. Concentrations for 5-HT (3–10 μm), endothelin 1 (0.1 μm) and PGF_2α (30 μm) were chosen to give a response which was 80–90% of the maximum obtained for the agonist in each artery. A maximal angiotensin II concentration (0.3 μm) was used because the response to this agonist tended to be small and transient. Each bar represents 4–6 experiments using arteries from different rats. The resting tension for the each type of artery was set to correspond closely to its internal pressure in vivo, as described in Robertson et al. (2000b).

Figure 2. Hypoxic pulmonary vasoconstriction in rat IPA is influenced by the nature of the pretone agent used to enhance it

When 30 mm K⁺ was used as a pretone-inducing agent, the response was essentially monophasic, whereas when PGF_2α (10 μm) was used for this purpose, the response consisted of an initial transient (phase 1) contraction superimposed on a sustained contraction which continued to increase for many minutes (phase 2). The response to 80 mm K⁺ on the left of each trace represents a maximal contraction, and is included to show the relative magnitude of HPV.