In cardiac muscle, acidic and basic fibroblast growth factors (aFGF and bFGF) regulate at least five genes in common (including alpha and beta myosin heavy chains, atrial natriuretic factor, and the sarcoplasmic reticulum calcium ATPase), provoking a generalized "fetal" phenotype similar to events in pressure-overload hypertrophy; however, aFGF and bFGF differentially control the striated alpha-actins. bFGF stimulates and aFGF inhibits skeletal alpha-actin transcripts associated with the embryonic heart, whereas cardiac alpha-actin mRNA is inhibited by aFGF but not bFGF. To elucidate mechanisms for these selective and discordant actions of aFGF and bFGF on cardiac muscle, chicken skeletal and cardiac alpha-actin promoter-driven reporter genes were introduced into neonatal rat cardiac myocytes by electroporation. Skeletal alpha-actin transcription was selectively stimulated by bFGF, whereas the cardiac alpha-actin promoter was unaffected. In contrast, aFGF suppressed both transfected alpha-actin genes. The differential regulation of skeletal alpha-actin transcription was equivalent with either purified or recombinant FGFs and was observed with 5' flanking sequences from either nucleotide -202 or -2000 to nucleotide -11. Positive and negative modulation of alpha-actin transcription by growth factors corresponded accurately to the endogenous genes in all permutations studied. These investigations provide a model for reciprocal control of gene transcription by aFGF vs. bFGF.