Recently, we showed that compared with 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 left ventricular (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. 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. One hundred twenty-eight mice (66 A/J and 62 B6) were studied. Isoproterenol-treated A/J mice demonstrated greater percent increases in echocardiographic LV mass/body weight (97 Ϯ 11 vs. 20 Ϯ 10%, P ϭ 0.001) and in gravimetric heart mass/body weight versus same-strain controls than B6 mice. Histopathology scores (a composite of myocyte hypertrophy, nuclear changes, fibrosis, and calcification) were greater in isoproterenol-treated A/J vs. B6 mice (2.8 Ϯ 0.2 vs.1.9 Ϯ 0.3, P Ͻ 0.05), as was quantitation of myocyte damage (22.3 Ϯ 11.5 vs. 4.3 Ϯ 3.5%). Interstrain differences in basal -AR density, high-affinity binding, and adenylyl cyclase activity were not significant. However, whereas isoproterenol-treated A/J mice showed nonsignificant increases in all -AR activity measures, isoproterenol-treated B6 mice had lower -AR density (57 Ϯ 6 vs. 83 Ϯ 8 fmol/mg, P Ͻ 0.05), percent high-affinity binding (15 Ϯ 2 vs. 26 Ϯ 3%, P Ͻ 0.005), and GTP ϩ isoproterenol-stimulated adenylyl cyclase activity (10 Ϯ 1.1 vs. 5.8 Ϯ 1.5 pmol cAMP ⅐ mg Ϫ1 ⅐ min Ϫ1 ) compared with controls. 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 mice, do not experience -AR downregulation or uncoupling in response to isoproterenol. Abnormalities in -adrenergic regulation may contribute to strain-related differences in the vulnerability to isoproterenolinduced cardiac changes. echocardiography; myocyte injury LEFT VENTRICULAR (LV) hypertrophy (LVH) results from the chronic pressure or volume overload of the heart that frequently accompanies conditions such as hypertension, myocardial infarction, and valvular heart disease. LVH is a potent and independent risk factor for cardiovascular morbidity, all-cause mortality, and stroke both in patients with cardiovascular disease and in the population at large (9, 13). However, the propensity for reactive hypertrophy does not appear to be uniformly distributed within the human population. For example, hypertensive African-Americans are almost twice as likely to develop LVH than are Caucasians (2), and one populationbased study (1) of hypertensive siblings suggests that LV mass is more tightly correlated between African-American siblings than their Caucasian counterparts. These observations suggest t...