ATRIAL-NATRIURETIC-FACTOR (ANF) AND ANF RECEPTOR C-GENE-EXPRESSION AND LOCALIZATION IN THE RESPIRATORY SYSTEM - EFFECTS INDUCED BY HYPOXIA AND HEMODYNAMIC OVERLOAD

Atrial natriuretic factor (ANF) and ANF receptor C (ANF.RC) expression have been investigated in healthy and cardiomyopathic hamsters (CMPH) with widespread necrosis of the diaphragm and myocardium leading to r espiratory and heart failure. ANF- and AN- F.RC-producing cells were l ocalized in different structures of the respiratory system, and the re gulation of their expression by the individual and/or combined action of hypoxia and hemodynamic overload was analyzed. The study was perfor med in 20-, 90-, and 150-day-old animals using immunohistochemistry, i n situ hybridization, Northern blot, and RIA analyses. ANF was shown t o be expressed in the tracheo-bronchial epithelium and muscle and, to a lesser extent, in the alveolar wall and muscular media of the pulmon ary arteries and extraparenchymal pulmonary veins in both healthy hams ters and CMPH. In 150-day-old CMPH, hypoxia (PaO2 <50 mm Hg) induced a 10-fold increase in ANF messenger RNA accumulation and a 6-fold incre ase in the immunoreactive ANF (IR-ANF) concentration in lungs, as quan titated by RIA. As plasma IR-ANF concentrations were elevated in all C MPH age groups, it was most likely produced by the myocardium. ANF.RC messenger RNA was homogeneously distributed throughout the entire resp iratory system and was increased 2-fold in hypoxic 150-day-old CMPH on ly. These results suggest that ANF originating in the respiratory syst em exerts only paracrine effects on different structures of the respir atory system in addition to the action of circulating ANF. Hemodynamic overload (left ventricular end-diastolic pressure, 17.20 +/- 3.80 mm Hg) might contribute to enhanced ANF gene expression only in extrapare nchymal pulmonary vein walls of 150-day-old CMPH. We also propose that ANF.RC overexpression might be a protective mechanism operated via ei ther ANF clearance or inhibition of adenylate cyclase activity to coun teract exaggerated smooth muscle relaxation.