Both β
 2
 - and β
 1
 -Adrenergic Receptors Mediate Hastened Relaxation and Phosphorylation of Phospholamban and Troponin I in Ventricular Myocardium of Fallot Infants, Consistent With Selective Coupling of β
 2
 -Adrenergic Receptors to G
 s
 -Protein

Molenaar, Peter; Bartel, Sabine; Cochrane, Andrew; Vetter, Donathe; Jalali, Homayoun; Pohlner, Peter; Burrell, Kylie M.; Karczewski, Peter; Krause, Ernst‐Georg; Kaumann, Alberto J.

doi:10.1161/01.cir.102.15.1814

Cited by 66 publications

(58 citation statements)

References 26 publications

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“…In cardiomyocytes, the extrusion and sequestration of free calcium during diastole is dependent on cyclic AMP, is modulated by b-receptors, and is influenced by several ion transport mechanisms including the Na + /H + exchanger. [30][31][32][33][34][35][36] Cardiac b-receptors couple to a G-protein-stimulated adenylcyclase, which in turn stimulates cyclic AMP-dependent regulatory mechanisms. 30,31,33,37 Recent studies in rodent cardiomyocytes revealed that b 2 -receptors couple to G-proteins, which lead to inhibition of cyclic AMP formation downstream.…”

Section: Discussionmentioning

confidence: 99%

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

et al. 2003

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The 825T allele of the G-protein b 3 -subunit is associated with increased intracellular signalling. Its association with hypertension is inconsistent. We, therefore, studied the C825T polymorphism in relation to ambulatory blood pressure as well as left ventricular structure and function in two European populations. We genotyped 248 parents and 318 offspring, enrolled in the European Project on Genes in Hypertension in Cracow, Poland (n ¼ 286) and in Novosibirsk, Russian Federation (n ¼ 280). The 24-h ambulatory blood pressure was recorded using oscillometric SpaceLabs 90207 monitors. Within each centre, a single observer performed two-dimensionally guided M-mode echocardiography and Doppler sonography to measure left ventricular structure (American Society of Echocardiography conventions) and diastolic function: early (E) and late (A) peak diastolic inflow velocities. We used analysis of covariance and generalized estimating equations to allow for covariables and nonindependence among related subjects. Genotype frequencies were similar (P ¼ 0.25) in Cracow and Novosibirsk and amounted to 44.7% for CC, 47.2% for CT, and 8.1% for TT. Among parents (mean age: 51.3 years)Fbut not among offspring (mean age 25.1 years)F24-h, daytime and night time systolic blood pressures were 5-6 mmHg higher in TT homozygotes than in C allele carriers. In TT homozygous parents (À8.2 cm/sec, P ¼ 0.004) as well as in TT homozygous offspring (À7.5 cm/sec, P ¼ 0.02), the E-wave was significantly reduced, which in offspring also resulted in a lower E/A ratio (-0.25, P ¼ 0.002). Neither in parents nor in offspring, left ventricular mass index was associated with the C825T polymorphism. In conclusion, in TT homozygotes of both generations, early left ventricular relaxation was reduced. In TT homozygous parents, the latter observation might be because of the higher systolic pressure associated with the TT genotype.

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Section: Discussionmentioning

confidence: 99%

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

et al. 2003

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“…Two groups found only ␤ 1 -induced troponin I phosphorylation in rats, 54,55 whereas others described phosphorylation via both subtypes in human heart. 56 Phospholamban phosphorylation has been reported after ␤ 1 -but not ␤ 2 -receptor activation in canine and human cardiomyocytes, 54,57 while in other studies, particularly in human heart, both subtypes caused phosphorylation. 55,56 ␤ 1 -Receptor stimulation increased PKA activity in the particulate fraction of cardiomyocytes, whereas after ␤ 2 -receptor stimulation this increase was limited to the soluble fraction.…”

Section: Compartmentation Of ␤-Adrenergic Signalingmentioning

confidence: 91%

What Is the Role of β-Adrenergic Signaling in Heart Failure?

Lohse

Engelhardt²,

Eschenhagen³

2003

Circulation Research

708

583

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Abstract-This review addresses open questions about the role of ␤-adrenergic receptors in cardiac function and failure.Cardiomyocytes express all three ␤-adrenergic receptor subtypes-␤ 1 , ␤ 2 , and, at least in some species, ␤ 3 . The ␤ 1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The ␤ 2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the ␤ 1 subtype. In heart failure, the sympathetic system is activated, cardiac ␤-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, ␤-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the ␤-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.

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“…Suggested explanations for the compartmentation in rodents include localization of b2-adrenoceptors inside caveolae in cardiomyocytes or coupling of b2-adrenoceptors to Gi-dependent pathways, acting as negative regulators of contractility (Jo et al, 2002;Xiang et al, 2002;Pavoine and Defer, 2005). The stimulation of b1-adrenoceptors hastens the relaxation (lusitropic response, LR) along with increasing the contraction (PIR) while b2-adrenoceptor stimulation has been found to evoke a PIR with no LR in cardiac tissue from rodents, cat and sheep (Xiao et al, 1999), but not human (Kaumann et al, 1999;Molenaar et al, 2000; and canine hearts (Xiao et al, 1999). In accordance with the suggestion that Gi is able to compartmentalize downstream b2-adrenoceptor signalling, inhibition of Gi by Pertussis toxin disclosed an LR to b2-adrenoceptor stimulation along with increased phosphorylation of phospholamban .…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of β₂‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle

Afzal¹,

Aronsen

Moltzau³

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSEb-Adrenoceptors play a major role in regulating myocardial function through cAMP-dependent pathways. Different phosphodiesterases (PDEs) regulate intracellular cAMP-pools and thereby contribute to the compartmentalization of cAMP-dependent effects. We explored the involvement of PDEs in limiting the b2 adrenoceptor-mediated positive inotropic (PIR) and lusitropic (LR) responses in sham-operated (Sham) and failing rat hearts. EXPERIMENTAL APPROACHExtensive myocardial infarctions were induced by coronary artery ligation in Wistar rats. Rats developing heart failure were studied 6 weeks after surgery. Contractility was measured in left ventricular strips from failing and Sham hearts. cAMP was quantified by RIA. KEY RESULTSIn ventricular strips, stimulation of b2-adrenoceptors with (-)-adrenaline (300 nM CGP20712A present) exerted a small PIR and LR. In Sham hearts, b2-adrenoceptor-mediated as well as b1-adrenoceptor-mediated PIR and LR were increased by selective inhibition of either PDE3 (1 mM cilostamide) or PDE4 (10 mM rolipram). In failing rat hearts, PDE3 inhibition enhanced PIR and LR to both b1-and b2-adrenoceptor stimulation while PDE4 inhibition had no effect on these responses despite a significant increase in cAMP levels. Combined PDE3/4 inhibition further enhanced the PIR and LR of b2-and b1-adrenoceptor activation both in Sham and failing hearts, compared with PDE3 inhibition alone. PDE4 enzyme activity was reduced in failing hearts. CONCLUSIONS AND IMPLICATIONSBoth PDE3 and PDE4 attenuated b2-and b1-adrenoceptor-mediated contractile responses in Sham hearts. In failing hearts, these responses are attenuated solely by PDE3 and thus even selective PDE3 inhibitors may provide a profound enhancement of b-adrenoceptor-mediated responses in heart failure. AbbreviationsEHNA, erythro-9-(2-hydroxy-3-nonyl) adenine; HF, heart failure; LR, lusitropic response; PIR, positive inotropic response; RT, relaxation time BJP British Journal of Pharmacology

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Both β ₂ - and β ₁ -Adrenergic Receptors Mediate Hastened Relaxation and Phosphorylation of Phospholamban and Troponin I in Ventricular Myocardium of Fallot Infants, Consistent With Selective Coupling of β ₂ -Adrenergic Receptors to G _s -Protein

Abstract: Despite their low density, beta(2)-adrenergic receptors are nearly as effective as beta(1)-adrenergic receptors of infant Fallot ventricle in enhancing contraction, relaxation, and phosphorylation of phospholamban and troponin I, consistent with selective coupling to G(s)-protein.

Cited by 66 publications

References 26 publications

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

What Is the Role of β-Adrenergic Signaling in Heart Failure?

Differential regulation of β₂‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle

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Both β 2 - and β 1 -Adrenergic Receptors Mediate Hastened Relaxation and Phosphorylation of Phospholamban and Troponin I in Ventricular Myocardium of Fallot Infants, Consistent With Selective Coupling of β 2 -Adrenergic Receptors to G s -Protein

Abstract: Despite their low density, beta(2)-adrenergic receptors are nearly as effective as beta(1)-adrenergic receptors of infant Fallot ventricle in enhancing contraction, relaxation, and phosphorylation of phospholamban and troponin I, consistent with selective coupling to G(s)-protein.

Cited by 66 publications

References 26 publications

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

What Is the Role of β-Adrenergic Signaling in Heart Failure?

Differential regulation of β2‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle

Contact Info

Product

Resources

About

Both β ₂ - and β ₁ -Adrenergic Receptors Mediate Hastened Relaxation and Phosphorylation of Phospholamban and Troponin I in Ventricular Myocardium of Fallot Infants, Consistent With Selective Coupling of β ₂ -Adrenergic Receptors to G _s -Protein

Differential regulation of β₂‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle