SELECTIVE CHANGES IN NATRIURETIC PEPTIDE AND EARLY RESPONSE GENE-EXPRESSION IN ISOLATED RAT ATRIA FOLLOWING STIMULATION BY STRETCH OR ENDOTHELIN-1

Objective: Important physiological and pathophysiological conditions are associated with changes in secretion and synthesis of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). The aim of this study was to examine the effects of mechanical stretch and endothelin-1 on ANF and BNP secretion and gene expression in isolated adult rat atria, as paradigms for mechanical and endocrine stimulation of atrial tissue. The expression of the early response genes c-fos, c-jun, Egr-1, and c-myc was also studied, since their protein products may be involved in controlling natriuretic peptide gene expression. Methods: Isolated rat atria were stimulated by stretch (5 g) or endothelin-1 (10(-7) M) for 30 min, 2 h, or 4 h. ANF and BNP secretion was measured by radioimmunoassay, and relative mRNA levels were determined by northern blotting. Results: Atrial stretch resulted in an immediate 1.8-fold increase in ANF release, which returned to basal levels after 160 min. Endothelin-1 caused a gradual increase in ANF release, up to 2.3 times basal levels, and thereafter returned towards basal levels. BNP secretion was increased threefold by endothelin-1, and remained significantly raised for 90 min. BNP mRNA levels were transiently increased by 33% after 2 h of endothelin-1 stimulation. Stretch increased c-fos mRNA levels (+55%) and Egr-1 mRNA levels (+70%) after 2 h, and increased c-myc mRNA levels (+69%) after 4 h. Endothelin-1 increased Egr-1 mRNA levels up to +767% after 4 h. Conclusions: Endothelin-1 stimulates BNP secretion from rat atria; this is followed by an increase in BNP mRNA levels. Conversely, acute secretion of ANF by stretch or endothelin-1 is not accompanied by changes in ANF mRNA levels. Atrial stretch results in changes in the expression of the early response genes c-fos, Egr-1, and c-myc, while endothelin-1 stimulates Egr-1 expression. The specific changes in natriuretic peptide and early response gene expression reveal distinct mechanisms of modulation of atrial gene expression by mechanical and endocrine stimuli.