Atrial natriuretic peptide (
ANP) is a natriuretic,
diuretic and vasodilatory
peptide normally synthesized and secreted by the atria of the adult mammalian heart. Synthesis of
ANP in the ventricle has also been demonstrated in the fetus and neonate. In the adult, ventricular
ANP is expressed under pathological conditions such as
hypertension and
congestive heart failure. The purpose of the present study was to analyse the spatial and temporal development of
ANP expression in the right ventricle of the rat heart during the onset, establishment, and recovery from
hypoxia-induced
pulmonary hypertension and
right ventricular hypertrophy (RVH). Significant RVH and immunoreactive
ANP (ir-
ANP) were detected in the right ventricles of hypoxic rats after only 3 days of exposure and continued to increase with the duration of
hypoxia through 21 days. The presence of ir-
ANP became apparent in the left ventricle as well as the right after 14 days of hypoxic exposure. Twenty-one days of normoxia following 21 days of
hypoxia reduced RVH and ir-
ANP to the levels seen at 3 days. Light microscopic immunohistochemistry demonstrated initial focal concentrations of ir-
ANP in cardiomyocytes near the junction of the right ventricular free wall and the septum, as well as surrounding isolated blood vessels in the right ventricular wall, after 3 days of exposure. With increasing duration of hypoxic exposure, these immunoreactive areas enlarged to encompass the entire right ventricular wall and right half of the septum by 14 days. While many right ventricular cardiomyocytes were intensely stained at the light level, electron microscopic immunocytochemistry revealed only a sparse number of
ANP-positive secretory granules. In immunohistochemical studies with an anti-
clathrin antibody, there was a homogeneous staining pattern for
clathrin in cardiomyocytes from the hypertrophied right ventricles. This pattern was not typical of the staining observed in other secretory cells which typically exhibit a perinuclear localization of
clathrin. The alterations in ultrastructural immunocytochemistry for
ANP suggest that ventricular
ANP synthesis differs from atrial synthesis of this
peptide. The differences in
clathrin staining indicate that its expression may also be related to the hypertrophic adaptation of ventricular cardiomyocytes. Our results suggest that ventricular
ANP expression in the adult rat is a dynamic event which is regulated by stress in the ventricular wall. The initial sites of ventricular
ANP expression may represent zones of maximum tension in the ventricular wall following increased workload. To our knowledge this is the first study to demonstrate topographical changes in ventricular
ANP expression in response to the development and reversal of
cardiac hypertrophy.(ABSTRACT TRUNCATED AT 400 WORDS)