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

2005 ◽  
Vol 289 (1) ◽  
pp. H30-H36 ◽  
Author(s):  
Michael D. Faulx ◽  
Paul Ernsberger ◽  
Dorothy Vatner ◽  
Robert D. Hoffman ◽  
William Lewis ◽  
...  
Keyword(s):  
Body Weight ◽  
Adenylyl Cyclase ◽  
Adrenergic Receptor ◽  
Left Ventricular ◽  
Cyclase Activity ◽  
Affinity Binding ◽  
Adenylyl Cyclase Activity ◽  
High Affinity Binding ◽  
High Affinity ◽  
Cardiac Phenotype

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 echocardiography, 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−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 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.

Esmolol Improves Left Ventricular Function via  Enhanced β-Adrenergic Receptor Signaling in a Canine Model of Coronary Revascularization

2002 ◽  
Vol 97 (1) ◽  
pp. 162-169 ◽  
Author(s):  
John V. Booth ◽  
Donat R. Spahn ◽  
Robert L. McRae ◽  
Lynn C. Chesnut ◽  
Habib El-Moalem ◽  
...  
Keyword(s):  
Left Ventricular Function ◽  
Adenylyl Cyclase ◽  
Ventricular Function ◽  
Adrenergic Receptor ◽  
Canine Model ◽  
Left Ventricular ◽  
Cyclase Activity ◽  
Control Group ◽  
Adenylyl Cyclase Activity ◽  
Plasma Catecholamine Concentrations

Background Recent American Heart Association guidelines highlight the paucity of data on effectiveness and/or mechanisms underlying use of beta-adrenergic receptor (beta AR) antagonists after acute coronary syndromes in patients subsequently undergoing revascularization. It is important to assess whether beta AR antagonists might protect the heart and improve ventricular function in this scenario. The authors therefore used esmolol (an ultra-short-acting beta AR antagonist) to determine whether beta AR antagonist treatment improves left ventricular function in a canine model of acute reversible coronary ischemia followed by coronary reperfusion during cardiopulmonary bypass (CPB). The authors also tested whether the mechanism includes preserved beta AR signaling. Methods Dogs were randomized to either esmolol or saline infusions administered during CPB (n = 29). Pre-CPB and end-CPB transmyocardial left ventricular biopsies were obtained; plasma catecholamine concentrations, myocardial beta AR density, and adenylyl cyclase activity were measured. In addition, left ventricular systolic shortening and postsystolic shortening were determined immediately prior to each biopsy. Results While beta AR density remained unchanged in each group, isoproterenol-stimulated adenylyl cyclase activity decreased 26 +/- 6% in the control group but increased 38 +/- 10% in the esmolol group (pre-CPB to end-CPB, mean +/- SD, P = 0.0001). Left ventricular systolic shortening improved in both groups after release of coronary (LAD) ligature; however, the esmolol group increased to 72 +/- 23% of pre-CPB values compared to 48 +/- 12% for the control group (P = 0.0008). Conclusions These data provide prospective evidence that esmolol administration results in improved myocardial function. Furthermore, the mechanism appears to involve enhanced myocardial beta AR signaling.

Effects of coronary arterial reperfusion on beta-adrenergic receptor-adenylyl cyclase coupling

1993 ◽  
Vol 264 (1) ◽  
pp. H196-H204 ◽  
Author(s):  
D. E. Vatner ◽  
K. Kiuchi ◽  
W. T. Manders ◽  
S. F. Vatner
Keyword(s):  
Adenylyl Cyclase ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Cyclase Activity ◽  
Receptor Density ◽  
Beta Adrenergic Receptors ◽  
Adenylyl Cyclase Activity ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic ◽  
High Affinity

The effects of 1 h of coronary arterial occlusion (CAO) followed by 15 min reperfusion (CAR) were examined in nine conscious dogs. Ischemia was verified by decreased regional blood flow (radioactive microspheres) and loss of systolic regional wall motion in the ischemic zone. beta-Adrenergic receptor density assessed by 125I-labeled cyanopindolol binding in a crude membrane fraction tended to decrease but was not significantly different. However, adenylyl cyclase activity and the guanine nucleotide stimulatory protein (Gs) were reduced in ischemic subendocardium compared with nonischemic subendocardium. The fraction of beta-adrenergic receptors binding agonist with high affinity increased in ischemic subendocardial and subepicardial layers. Compared with prior data in experiments with 1 h CAO without CAR, the increase in beta-adrenergic receptor density that occurs with myocardial ischemia is rapidly reversed with CAR of 15 min duration, while the decreased fraction of receptors binding agonist with high affinity was reversed to an increase in high-affinity receptors. The global decreases in adenylyl cyclase and Gs, which have been observed with simple CAO, persist but are observed selectively in the previously ischemic subendocardium after CAR. Thus both CAO and CAR affect beta-adrenergic receptors and adenylyl cyclase differently. During CAR, increased numbers of beta-adrenergic receptors binding agonist with high affinity occur potentially as a compensatory mechanism in the face of persistent reductions in adenylyl cyclase activity and Gs.

Desensitization of β3-adrenergic receptor- stimulated adenylyl cyclase activity and lipolysis in rats

Life Sciences ◽  
1998 ◽  
Vol 62 (7) ◽  
pp. 627-638 ◽  
Author(s):  
Pasquale P. Vicario ◽  
Mari R. Candelore ◽  
Marie-Therese Schaeffer ◽  
Linda Kelly ◽  
G.Marie Thompson ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Adrenergic Receptor ◽  
Cyclase Activity ◽  
Adenylyl Cyclase Activity

1-acetyl-7-deacetylforskolin: A potential non-specific inactive analog of forskolin for estimation of its specific high-affinity binding and adenylyl cyclase stimulation in vitro

Life Sciences ◽  
1995 ◽  
Vol 57 (14) ◽  
pp. 1367-1373 ◽  
Author(s):  
Tom Sasaki ◽  
Kohsuke Furukata ◽  
Takamasa limori ◽  
Shiro Ikegami ◽  
Shoichiro Ide ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Affinity Binding ◽  
High Affinity Binding ◽  
High Affinity ◽  
Inactive Analog

TNF-alpha inhibits isoproterenol-stimulated adenylyl cyclase activity in cultured airway smooth muscle cells

1997 ◽  
Vol 272 (4) ◽  
pp. L644-L650 ◽  
Author(s):  
C. W. Emala ◽  
J. Kuhl ◽  
C. L. Hungerford ◽  
C. A. Hirshman
Keyword(s):  
Signal Transduction ◽  
Smooth Muscle ◽  
Adenylyl Cyclase ◽  
Airway Smooth Muscle ◽  
Adrenergic Receptor ◽  
Cyclase Activity ◽  
Tnf Alpha ◽  
Adenylyl Cyclase Activity ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic

Inflammation, increased cytokine production, and decreased responsiveness of airway smooth muscle (ASM) to beta-adrenergic agonists are characteristics of asthma. We questioned whether the cytokine tumor necrosis factor-alpha (TNF-alpha) directly impaired beta-adrenergic signal transduction in cultured canine ASM cells. Confluent ASM cells exposed to TNF-alpha (0.1-10 ng/ml) for 72 h showed lower maximal levels of adenylyl cyclase activity in response to isoproterenol (10 ng/ml; 14 +/- 4.3 vs. 7.5 +/- 1.3 pmol adenosine 3',5'-cyclic monophosphate x well(-1) x 20 min(-1), control vs. treated, respectively), despite no changes in beta-adrenergic receptor numbers (maximum number of binding sites = 4.8 +/- 0.72 vs. 4.5 +/- 0.81 fmol/mg protein, control vs. treated, respectively). Adenylyl cyclase activities in response to prostaglandin E1, NaF, or forskolin were not different in treated and untreated cells. These results demonstrate that a cytokine known to be increased during exacerbation of asthmatic symptoms directly impairs beta-adrenergic function in ASM cells and suggests a mechanism by which inflammation impairs beta-adrenergic receptor signal transduction in asthma.

Dependence of changes in β-adrenoceptor signal transduction on type and stage of cardiac hypertrophy

2007 ◽  
Vol 102 (3) ◽  
pp. 978-984 ◽  
Author(s):  
Rajat Sethi ◽  
Harjot K. Saini ◽  
Xiaobing Guo ◽  
Xi Wang ◽  
Vijayan Elimban ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Adenylyl Cyclase ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Cyclase Activity ◽  
Adenylyl Cyclase Activity ◽  
Hemodynamic Assessment ◽  
Intracellular Ca

To examine whether cardiac hypertrophy is associated with changes in β-adrenoceptor signal transduction mechanisms, pressure overload (PO) was induced by occlusion of the abdominal aorta and volume overload (VO) by creation of an aortocaval shunt for 4 and 24 wk in rats. After hemodynamic assessment of the animals, the left ventricular (LV) particulate fraction was isolated for measurement of β1-adrenoceptors and adenylyl cyclase activity, and cardiomyocytes were isolated for monitoring of the intracellular Ca2+ concentration. Although PO and VO produced cardiac hypertrophy and increased LV end-diastolic pressure at 4 wk, cardiac function was increased in animals subjected to PO but remained unaltered in animals subjected to VO. Cardiac hypertrophy and increased LV end-diastolic pressure were associated with depressed cardiac function at 24 wk of PO or VO, but clinical signs of congestive heart failure were evident only in animals subjected to VO. Isoproterenol-induced increases in cardiac function, activation of adenylyl cyclase activity, and increase in intracellular Ca2+ concentration, as well as β1-adrenoceptor density, were unaltered by PO at 4 wk, augmented by VO at 4 wk, and attenuated by PO and VO at 24 wk. These results suggest that alterations in β1-adrenoceptor signal transduction are dependent on the type and stage of cardiac hypertrophy.

β-Adrenergic receptor desensitization in the early stage of hereditary cardiomyopathy in hamsters

1994 ◽  
Vol 72 (8) ◽  
pp. 875-883 ◽  
Author(s):  
Stéphane St-Onge ◽  
Peter Chidiac ◽  
Léa Brakier-Gingras ◽  
Michel Bouvier
Keyword(s):  
Adenylyl Cyclase ◽  
Adrenergic Receptor ◽  
Early Stage ◽  
Signalling Pathway ◽  
Cyclase Activity ◽  
Receptor Desensitization ◽  
Adenylyl Cyclase Activity ◽  
Sequence Of Events ◽  
Hereditary Cardiomyopathy ◽  
Cardiomyopathic Hamsters

The β-adrenergic receptor (βAR)/adenylyl cyclase signalling pathway was examined in cardiac membranes from cardiomyopathic Syrian hamsters. Three stages were examined during the progression of this hereditary cardiomyopathy (30 days old, prenecrotic phase; 60 days old, necrotic phase; and 120 days old, compensatory phase). Isoproterenol-stimulated adenylyl cyclase activity was decreased by 32 ± 16% in 30-day-old cardiomyopathy hamsters, compared with age-matched controls. This was not accompanied by any change in the fluoride- or forskolin-stimulated activities, suggesting that the decrease reflects a perturbation of the receptor-mediated stimulation. Neither the density nor the subcellular distribution of the βAR, as assessed by [125I]iodocyanopindolol binding assays, was affected in these animals. However, the agonist binding properties of the βAR were significantly affected. Indeed, the effect of guanyl nucleotides on isoproterenol binding was decreased in 30-day-old cardiomyopathic hamsters. Given that guanyl nucleotide sensitivity is correlated with the ability of the βAR to productively interact with Gs protein, these results suggest that the decreased β-adrenergic-stimulated adenylyl cyclase activity results from a functional uncoupling of the βAR with no change in receptor density. The desensitization of the β-adrenergic-stimulated adenylyl cyclase was transient, since no change in isoproterenol-stimulated adenylyl cyclase was detected in 60- and 120-day-old hamsters, compared with age-matched controls. Similarly, the receptor number and distribution were not affected at those ages. The desensitization in the βAR/adenylyl cyclase signalling pathway, occurring early in the development of the pathology, may result from the increased sympathetic tone associated with this pathology and may be part of the sequence of events leading to the progression of the cardiomyopathy in hamsters.Key words: β-adrenergic receptor, desensitization, cardiomyopathic hamsters.

Sign in / Sign up

Export Citation Format

Share Document