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

Michael D. Faulx, Paul Ernsberger, Dorothy Vatner, Robert D. Hoffman, William Lewis, Ryan Strachan, Brian D. Hoit

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Abstract

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 β-adrenergic receptor (β-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 echo-cardiography, tail-cuff blood pressure, histopathology, β-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 β-AR density, high-affinity binding, and adenylyl cyclase activity were not significant. However, whereas isoproterenol-treated A/J mice showed nonsignificant increases in all β-AR activity measures, isoproterenol-treated B6 mice had lower β-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 -1min-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 β-AR downregulation or uncoupling in response to isoproterenol. Abnormalities in β-adrenergic regulation may contribute to strain-related differences in the vulnerability to isoproterenol-induced cardiac changes.

Original languageEnglish (US)
Pages (from-to)H30-H36
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume289
Issue number1 58-1
DOIs
StatePublished - Jul 1 2005
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Keywords

  • Echocardiography
  • Myocyte injury

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