Purpose Recently we showed that compared to the A/J inbred mouse strain, C57BL/6J (B6) mice have an athlete's cardiac phenotype. We postulated that strain differences would result in greater LV hypertrophy in response to isoproterenol in B6 than A/J mice, and tested the hypothesis that a differential response could be explained partly by differences in -adrenergic receptor (AR) density and/or coupling. Methods A/J and B6 mice were randomized to receive daily isoproterenol (100 mg/kg, sc) or isovolumic vehicle for 5 days. Animals were studied using echocardiography, tail cuff blood pressure, histopathology, AR density and percent high-affinity binding, and basal and stimulated adenylyl cyclase activities. Results One hundred-twenty eight mice (66 A/J, 62 B6) were studied. Isoproterenol-treated A/J mice demonstrated greater percent increases in echocardiographic left ventricular mass/body weight (97±11 vs. 20±10%, p<0.01) and percent increase in gravimetric heart mass/body weight versus same-strain controls than B6. Histopathology scores (a composite of myocyte hypertrophy, nuclear changes, fibrosis, and calcification) were greater in isoproterenol-treated A/J vs. B6 mice (2.8±0.2 vs.1.9±0.3, p<0.05), as was quantitation of myocyte damage (22.3±11.5 vs. 4.3±3.5%). Inter-strain differences in basal AR density, high-affinity binding, and adenylyl cyclase activity were not significant. However, whereas isoproterenol-treated A/J mice showed non-significant increases in all bAR activity measures, isoproterenol-treated B6 mice had lower AR density (57±6 vs. 83±8 fmol/mg, p<0.05), percent high-affinity binding (15±2 vs. 26±3%, p<0.005), and GTP±iso stimulated adenylyl cyclase activity (10±1.1 vs. 5.8±1.5 pmol cAMP/mg/min) compared with controls. Conclusions High dose, short-term isoproterenol produces greater macro- and microscopic cardiac hypertrophy and injury in A/J than B6 mice. A/J mice, unlike B6, do not experience BAR downregulation or uncoupling in response to isoproterenol. Abnormalities in -adrenergic regulation may contribute to strain-related differences in the vulnerability to isoproterenol-induced cardiac changes.