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This Article Full Text Full Text (PDF) All Versions of this Article: 289/1/H30    most recent 00636.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Faulx, M. D. Articles by Hoit, B. D. Search for Related Content PubMed PubMed Citation Articles by Faulx, M. D. Articles by Hoit, B. D.

Strain-dependent -adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice

¹Division of Cardiology, Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, ²Department of Nutrition, Case Western Reserve University, Cleveland, Ohio; ³Cardiovascular Research Institute and Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Newark, New Jersey; ⁴Department of Pathology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio; and ⁵Department of Pathology, Emory University, Atlanta, Georgia

Submitted 25 June 2004 ; accepted in final form 24 February 2005

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 ± 11 vs. 20 ± 10%, P = 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 ± 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%). 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 ± 6 vs. 83 ± 8 fmol/mg, P < 0.05), percent high-affinity binding (15 ± 2 vs. 26 ± 3%, P < 0.005), and GTP + isoproterenol-stimulated adenylyl cyclase activity (10 ± 1.1 vs. 5.8 ± 1.5 pmol cAMP·mg^–1·min^–1) 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 isoproterenol-induced cardiac changes.

echocardiography; myocyte injury

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