The Influence of the Major Vasoactive Mediators Relevant to the Pathogenesis of Pulmonary Hypertension

Abstract

The pulmonary circulation exhibits unique responses to vasoactive factors compared with the systemic circulation owing to the many differences in the structure and function of the systemic and pulmonary circulations. The pulmonary circulation is normally virtually fully vasodilated, whereas the systemic circulation is tonically vasoconstricted. This in itself imparts a unique responses to vasoactive factors to the pulmonary arterial bed as vascular tone per se alters the responses to many vasoactive factors. In addition, in vivo and in vitro studies suggest that the pulmonary arterial circulation is composed of phenotypically distinct heterogeneous populations of smooth muscle cells with unique developmental lineages. They differ in their vasoactivity and ability to proliferate and therefore there are regional differences in the responses to many vasoactive factors between the smaller, distal pulmonary resistance arteries and the larger, proximal elastic pulmonary arteries. This differential responsiveness might be expected as the proximal and distal pulmonary arteries have differential developmental origins and proximal pulmonary arteries develop via angiogenesis, whereas distal vessels form by vasculogenesis. There are differences between the proximal and distal pulmonary arteries, for example, in the distribution of K+ channels, endothelin receptors, prostacyclin synthase, nitric oxide (NO) production, NO synthase expression, phosphodiesterase activity, and store-operated Ca2 + entry. This chapter describes the normal pharmacology of the major endogenous vasoactive factors involved in the pathogenic mechanisms of pulmonary arterial hypertension, pulmonary artery regional diversity, and how this alters following experimental and clinical pulmonary hypertension.