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

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 ␤-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...

Nociceptin/Orphanin FQ (N/OFQ)-Evoked Bradycardia, Hypotension, and Diuresis Are Absent in N/OFQ Peptide (NOP) Receptor Knockout Mice

“…It is possible that underlying genetic differences between the strains of mice tested contribute to the variations in the magnitude and duration of the systemic cardiovascular depressor responses to central N/OFQ. Numerous studies have reported differences in the specific pattern (e.g., magnitude and time course) of changes in a given physiological parameter among different strains of the same species or substrains generated from the same background (e.g., C57BL/6) (Stiedl et al, 1999;Faulx et al, 2005). Although entirely speculative, it is possible that the mouse strains we studied have differences in basal sympathetic neural tone, which governs resting HR and MAP.…”

Qualification of Cardiac Troponin I Concentration in Mouse Serum Using Isoproterenol and Implementation in Pharmacology Studies to Accelerate Drug Development

“…The cause(s) for the strain differences in response to cardiac injury induced by exposure to ISO was not determined. However, possible causes include desensitization of b-adrenergic receptors (Perrino et al 2005), strain-dependent differences in receptor density, cardiac capacity for aerobic metabolism, or adaptive responses (Faulx et al 2005(Faulx et al , 2007. Desensitization may also account for the lack of dose-response in CD-1 mice treated with greater than 10 mg/kg ISO.…”

β-Adrenergic stimulation and myocardial function in the failing heart

“…If it is an adaptation, is it maladaptive or protective? (i) A mouse strain that downregulates its b-AR density in response to chronic infusion of catecholamines was protected against cardiac toxicity compared to another strain that did not [88]; (ii) A genetic gain-of-function variant of GRK5, an enzyme providing uncoupling and thereby desensitization of b-AR, was recently associated with improved survival in African Americans with heart failure [89]; (iii) Numerous transgenic mouse models show that overactivity of the b-AR pathway induces a heart failure phenotype (see ''Lessons from genetically engineered mice''), but we are not aware of any animal model in which a primary subsensitivity of the b-AR signaling pathway is associated with cardiac pathology; (iv) Therapeutic strategies intended to simply overcome b-AR desensitization such as catecholamines and phosphodiesterase inhibitors cause increased mortality [90][91][92], whereas betablockers decrease mortality in patients with chronic heart failure [93][94][95], lead to reverse remodeling of the ventricles [55,96,97], and improve systolic function in the long term [98]. Thus, b-AR desensitization appears as a predominantly protective adaptation [2].…”