Beta-adrenoceptors in cardiac disease

Brodde, Otto‐Erich

doi:10.1016/0163-7258(93)90030-h

Cited by 240 publications

(116 citation statements)

References 130 publications

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“…␤ 1 and ␤ 2 -ARs have been identified in rat, dog and human hearts and both receptor subtypes are involved in regulation of inotropic and chronotropic responses via functional coupling to the adenylyl cyclase system through the heterotrimeric G protein, Gs. 20 Our laboratory has recently reported that adenovirus-mediated gene transfer of ␤ 2 -ARs to normal and failing adult rabbit ventricular myocytes in culture leads to potentiation of ␤-adrenergic signaling including the restoration of ␤-AR signaling in myocytes isolated from rabbits in congestive heart failure where ␤-AR function is defective. 12,21 This work in myocytes as well as the current study, was formulated after studies in transgenic mice found that cardiac-targeted overexpression of the human ␤ 2 -AR to a density Ͼ100-fold over native myocardial ␤-AR levels led to enhanced in vivo cardiac contractility.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated gene transfer of the β2-adrenergic receptor to donor hearts enhances cardiac function

et al. 1999

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Gene transfer to modify donor heart function during transthe ␤ 2 -AR agonist, zinterol. Treatment with the ␤ 2 -AR virus plantation has significant therapeutic implications. Recent resulted in global myocardial gene transfer with a six-fold studies by our laboratory in transgenic mice have shown increase in mean ␤-AR density which corresponded to a that overexpression of ␤ 2 -adrenergic receptors (␤ 2 -ARs) significant increase in basal contractility (LV + dP/dt max , leads to significantly enhanced cardiac function. Thus, we control: 3152.1 ± 286 versus ␤ 2 -AR, 6250.6* ± 432.5 investigated the functional consequences of adenovirusmmHg/s; n = 10, *P Ͻ 0.02). ␤ 2 -AR overexpressing hearts mediated gene transfer of the human ␤ 2 -AR in a rat heteroalso had higher contractility after zinterol administration topic heart transplant model. Donor hearts received 1 ml compared with control hearts. Our results indicate that of solution containing 1 × 10 10 p.f.u. of adenovirus encomyocardial function of the transplanted heart can be ding the ␤ 2 -AR or an empty adenovirus as a control. Five enhanced by the adenovirus-mediated delivery of ␤ 2 -ARs. days after transplantation, basal left ventricular (LV) pressThus, genetic manipulation may offer a novel therapeutic ure was measured using an isolated, isovolumic heart perstrategy to improve donor heart function in the postfusion apparatus. A subset of hearts was stimulated with operative setting.

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Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated gene transfer of the β2-adrenergic receptor to donor hearts enhances cardiac function

et al. 1999

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“…Because the human heart contains only a few spare β-AR (for references, see Brodde 1993), any decrease in number of available surface receptors must automatically lead to a decreased functional response. Thus, a β-AR blocker-evoked up-regulation would be helpful in restoring maximal contractile responses to β-AR stimulation.…”

Section: Effects On β-Adrenoceptor Densitymentioning

confidence: 99%

β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure

Brodde

2007

Naunyn-Schmied Arch Pharmacol

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“…In response to acute physical or emotional stress, stimulation of myocardial ␤AR by circulating epinephrine or locally released norepinephrine increases cardiac contractility, heart rate, and blood flow to vital organs (1). In chronic heart failure, activation of this pathway to compensate for cardiac insufficiency is defective, resulting in further increased sympathetic outflow and myocardial catecholamine toxicity (2,3). Specific ␤AR abnormalities that have been identified in heart failure include receptor down-regulation and uncoupling from signaling effectors (4,5).…”

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confidence: 99%

Regulation of cardiac contractility by Rab4-modulated β2-adrenergic receptor recycling

Odley

Hahn

Lynch

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Catecholaminergic activation of myocardial ␤-adrenergic receptors (␤AR) is the principle mechanism regulating cardiac function. Agonists desensitize ␤AR through G protein-coupled receptor kinase-mediated uncoupling and ␤-arrestin-mediated internalization. Although inhibition of myocardial G protein-coupled receptor kinase-2 enhances cardiac function and reverses heart failure, pathophysiological effects of modulated ␤AR internalization͞re-cycling are unknown. We used mutation and transgenic expression of Rab4, which regulates vesicular transport of heptahelical receptors to plasma membranes, to interrogate in vivo ␤AR trafficking and cardiac function. Expression of constitutively active Rab4 Q72L had no effects on cardiac structure or function, but dominant inhibitor Rab4 S27N impaired responsiveness to endogenous and exogenous catecholamines. To relate ␤AR trafficking to diminished cardiac function, Rab4 mutant mice were crossbred with mice overexpressing human ␤2AR. In unstimulated ␤2AR overexpressors, ␤2AR localized to heavier endosomes and translocated to lighter, caveolin-rich fractions after isoproterenol stimulation. Coexpression of ␤2AR with activated Rab4 Q72L caused loss of receptors from heavier endosomes while retaining normal inotropy. In contrast, coexpression of ␤2AR with inhibitory Rab4 S27N mimicked isoproterenol-induced receptor redistribution to caveolae, with diminished cardiac inotropy. Rab4 inhibition alone prevented resensitization after isoproterenol-induced in vivo adrenergic desensitization. Confocal and ultrastructural analyses revealed bizarre vesicular structures and abnormal accumulation of ␤2AR in the sarcoplasm and subsarcollema of Rab4 S27N, but not Q72L, mice. These data provide evidence for constant bidirectional sarcollemal-vesicular ␤AR trafficking in the in vivo heart and show that Rab4-mediated recycling of internalized ␤AR is necessary for normal cardiac catecholamine responsiveness and resensitization after agonist exposure.

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Beta-adrenoceptors in cardiac disease

Cited by 240 publications

References 130 publications

Adenovirus-mediated gene transfer of the β2-adrenergic receptor to donor hearts enhances cardiac function

Adenovirus-mediated gene transfer of the β2-adrenergic receptor to donor hearts enhances cardiac function

β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure

Regulation of cardiac contractility by Rab4-modulated β2-adrenergic receptor recycling

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