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 a re associated with changes in secretion and synthesis of atrial natriu retic factor (ANF) and brain natriuretic peptide (BNP). The aim of thi s study was to examine the effects of mechanical stretch and endotheli n-1 on ANF and BNP secretion and gene expression in isolated adult rat atria, as paradigms for mechanical and endocrine stimulation of atria l 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 in volved in controlling natriuretic peptide gene expression. Methods: Is olated 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 i ncrease 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 secre tion was increased threefold by endothelin-1, and remained significant ly 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 le vels up to +767% after 4 h. Conclusions: Endothelin-1 stimulates BNP s ecretion from rat atria; this is followed by an increase in BNP mRNA l evels. Conversely, acute secretion of ANF by stretch or endothelin-1 i s not accompanied by changes in ANF mRNA levels. Atrial stretch result s 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 spec ific changes in natriuretic peptide and early response gene expression reveal distinct mechanisms of modulation of atrial gene expression by mechanical and endocrine stimuli.