INTRODUCTION/HYPOTHESIS: Cardiac hypertrophy is an independent risk factor predictive of cardiovascular disease and is significantly associated with morbidity and mortality. The mechanism by which angiotensin II (Ang II) and dietary sodium exert additive effects on the development of cardiac hypertrophy is unclear. The goal of this study was to evaluate the hypothesis that, where there is a genetic predisposition to Ang II-dependent hypertrophy, there is also an increased susceptibility to sodium-induced hypertrophy mediated by AT1-receptor expression. METHODS: Diets of low sodium (LS, 0.3% w:w) and high sodium (HS, 4.0% w:w) content were fed to adult (age 25 weeks) control wild-type mice (WT) and to transgenic mice exhibiting cardiac-specific overexpression of angiotensinogen (TG). At the conclusion of a 40-day treatment period, cardiac tissue weights were compared and the relative expression levels of Ang II receptor subtypes (AT(1A) and AT(2)) were evaluated using RT-PCR. RESULTS: WT and TG mice fed HS and LS diets maintained comparable weight gains during the treatment period. The normalised heart weights of TG mice were elevated compared to WT, and the extent of the increase was greater for mice maintained on the HS diet treatments (WT 12% vs TG 41% increase in cardiac weight index). While a similar pattern of growth was observed for ventricular tissues, the atrial weight parameters demonstrated an additional significant effect of dietary sodium on tissue weight, independent of animal generic type. No differences in the relative (GAPDH normalised) expression levels of AT(1A)- and AT(2)-receptor mRNA were observed between diet or animal generic groups. CONCLUSION: This study demonstrates that, where there is a pre-existing genetic condition of Ang II-dependent cardiac hypertrophy, the pro-growth effect of elevated dietary sodium is selectively augmented. In TG and WT mice, this effect was evident with a relatively short dietary treatment intervention (40 days). Evaluation of the levels of Ang II receptor mRNA further demonstrated that this differential growth response was not associated with an altered relative expression of either AT(1A)- or AT(2)-receptor subtypes. The cellular mechanistic bases for this specific ANG II-dietary sodium interaction remain to be elucidated.