In neonatal myocytes grown in culture, reductions in extracellular potassium concentration produced a hypertrophic response as assessed by induction of early response genes, atrial natriuretic peptide and skeletal actin, and repression of the alpha3 isoform of the sodium pump in a dose dependent manner. The degree of alpha3 repression appeared to be dose dependent with decreases in media (K). Similarly, decreases in media potassium concentrations caused increases in cytosolic calcium concentration in a dose dependent manner; moreover these increases in cytosolic calcium concentration correlated quite well with repression of alpha3 expression. In contrast, although moderate reductions of potassium concentration induced upregulation of skACT and ANP, severely reduced potassium concentrations caused repression of skACT and ANP expression. In parallel studies performed in vivo, 3-5 weeks dietary K restriction induced molecular phenotypical changes similar to that seen in the neonatal myocyte model without demonstrable growth as assessed by the heart weight/body weight ratio. However, when rates subjected to dietary K restriction were subsequently subjected to acute aortic constriction, cardiac growth was greater than in rats fed a control diet. These data suggest that hypokalemia may produce molecular phenotypic alterations consistent with cardiac hypertrophy as well as contribute to hypertrophy in an in vivo model.