We have previously noted that in neonatal myocytes grown in culture, reductions in extracellular K+ concentration produced a hypertrophic response as assessed by induction of early response genes, atrial natriuretic peptide and skeletal actin and repression of the alpha 3 isoform of the sodium pump in a dose dependent manner. Similarly, decreases in media K+ concentration caused increases in cytosolic calcium concentration in a dose dependent manner, which correlated with repression of alpha 3 expression. In the current study we demonstrate that decreases in media K+ concentration caused increases in cytosolic calcium concentration in isolated adult rat cardiac myocytes. These increases are potentiated by the addition of the cardiotonic steroid, ouabain and blocked by the addition of the Src kinase inhibitor Herbimycin A. In parallel studies performed in vivo, when rats subjected to dietary K+ restriction were subsequently subjected to partial (5/6th) nephrectomy for 4 weeks, cardiac growth was greater than in rats fed a control diet. These data suggest that hypokalemia may produce phenotypic alterations consistent with cardiac hypertrophy as well as potentiate the cardiovascular effects of cardiotonic steroids.