The objective of this proposal is to improve our understanding of the regulatory mechanisms in the pulmonary circulation that are of endothelial origin. A novel family of endogenous peptides, endothelins (ETs), have potent systemic vasoactive properties, but the regulatory potential of ETs in the pulmonary vascular (PV) bed represent a gap in our knowledge. A unique model has been perfected to investigate the role of ET isopeptides in regulating the PV bed of intact animals. This model employs cardiac catheterization techniques to directly observe changes in PV resistance under conditions of constant pulmonary blood flow and left atrial pressure.
Three specific aims are proposed.
The first aim deals with the nature of the pulmonary vasodilator and pulmonary vasoconstrictor responses to ET isopeptides. A new feature of this work is the hypothesis that PV responses to ET isopeptides depend on the level of PV tone and the manner by which PV tone is altered.
The second aim i s to characterize the distinct ET receptor complexes which mediate pulmonary vasodilation and vasoconstriction and to detect distinguishing features of the receptor complexes for ET isopeptides in the pulmonary and systemic circulations. This represents a novel approach to receptor characterization by utilizing tachyphylaxis, cross-tachyphylaxis, and changes in the guanine nucleotide (G)-related proteins as pharmacologic tools to generate a functional correlate in vivo to receptor analysis in vitro. These experiments examine the role of ET isopeptides as endogenous ligands for potassium channel activation, a newly-described vasodilator mechanism, and explore the signal transduction mechanism by which ET isopeptides act as endothelial-derived hyperpolarizing factors to induce vasodilation. Utilization of hybrid ET analogues and fragments will expose differences in the structural requirements of ET receptors in the pulmonary and systemic vessels.
The third aim i s to clone and sequence cat ET and investigate in vitro and in vivo conditions which alter expression and release of ET isopeptides in the lung. Although enhanced expression and intravascular release of ET-like substances occur in myocardial infarction, pulmonary hypertension, congestive heart failure, cardiothoracic surgery, and septic shock, the proposed studies will improve our understanding of ET in the development of acute lung injury. Understanding ET receptor complexes and its signal transduction will aid in the development of ET agonists to activate potassium channels and selectively dilate the PV bed.
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