Introduction

Over the last decade, considerable progress has been made in unravelling the mechanisms that underlie the phenomenon of hypoxic pulmonary vasoconstriction (HPV), and it is becoming evident that HPV is a multifactorial process. There is strong evidence that the vascular smooth muscle (VSM) itself contains both the hypoxic sensor and the necessary effector pathways that lead to an increase in intracellular [Ca2+] ([Ca2+]j), though there is still controversy regarding the nature of the sensor and its downstream signal, and the mechanism(s) responsible for the rise in Many of these issues are discussed elsewhere in this volume.

It has often been shown that hypoxia elicits a rise in and an associated constriction in both isolated pulmonary VSM cells and arteries where the endothelium has been removed (11, 24, 43). However, the vasoconstriction in such cases is often either transient, or the hypoxic challenge relatively short (<15min) (reviewed in Ref. 39). Where the challenge is longer (> ~20 min), and particularly in small pulmonary arteries, there is strong evidence from numerous sources that removal of the endothelium substantially depresses or abolishes sustained HPV (7, 12, 17, 20-22). This endothelium-dependent HPV clearly involves additional mechanisms to those resident in the underlying VSM, and presumably requires the production of an endothelium-derived mediator.

The endothelium produces a wide range of vasoactive substances; there are therefore many potential pathways by which it could modulate HPV, including both vasoconstrictor and vasodilator mechanisms. However, it is generally accepted that hypoxia induces a rise in VSM [Ca2+], whether or not the endothelium is present. The question is therefore whether some product of the endothelium (or its lack) either potentiates this rise in [Ca2+]j or, alternatively, modulates the relationship between [Ca2+]| and force development. In addition, it needs to be determined whether this effect ofthe endothelium is specific to the pulmonary circulation, or whether it is a more generalized mechanism that only results in sustained vasoconstriction during hypoxia when combined with pulmonary-specific mechanisms in the underlying VSM.

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