Hypersensitivity of Gi protein mediated muscarinic receptor adenylyl cyclase in chronic ischaemic heart failure in the rat

Fu, Lei; Feng, Qingping; Liang, Qi-Ming; Sun, Xingshu; Hedner, Thomas; Hoebeke, Johan; Hjalmarson, Åke

doi:10.1093/cvr/27.11.2065

Cited by 17 publications

(6 citation statements)

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“…Second, whereas rapid atrial pacing has been shown to cause dramatic effects on sinus node function, no differences were found in sinus node function with rapid ventricular pacing (11). Finally, and perhaps most convincing that the effects seen here are not related to the pacing model per se, are the findings by other investigators that changes in muscarinic receptor function involving G proteins are consistent across pacing-induced HF in dogs (42) and dilated idiopathic cardiomyopathy in humans (15,16,23). Therefore, whereas we cannot exclude the effects of tachycardia alone, these results are more consistent with an effect due to the HF state itself.…”

Section: Limitations Of Studysupporting

confidence: 60%

Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity

Dunlap

Bibevski

Rosenberry

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Parasympathetic control of the heart is attenuated in heart failure (HF). We investigated possible mechanisms and sites of altered vagal control in dogs with HF induced by rapid pacing. Muscarinic blockade reduced the R-R interval by 308 ms in controls but only by 32 ms in HF, indicating low levels of resting vagal tone. Vagomimetic doses of atropine sulfate prolonged the R-R interval by 109 ms in controls and increased standard deviation of the R-R interval by 66 ms but only by 46 and 16 ms, respectively, in HF. Bradycardia elicited by electrical stimulation of the vagus nerve was also attenuated in the HF group. Conversely, muscarinic receptor activation by bethanechol, and indirectly by neostigmine, elicited exaggerated R-R interval responses in HF. To investigate possible mechanisms, we measured muscarinic receptor density (B max) and acetylcholinesterase activity in different areas of the heart. In sinoatrial nodes, B max was increased (230 Ϯ 75% of control) and acetylcholinesterase decreased (80 Ϯ 6% of control) in HF. We conclude that muscarinic receptors are upregulated and acetylcholinesterase is reduced in the sinus node in HF. Therefore, reduced vagal control in HF is most likely due to changes of presynaptic function (ganglionic), because postsynaptic mechanisms augment vagal control in HF.cholinergic; parasympathetic; autonomic ABNORMAL BAROREFLEX CONTROL of heart rate in patients with cardiac dysfunction has been recognized for over 30 years (10). Abnormalities in this reflex could be located in the afferent limb, centrally, or in efferent control mechanisms. We (7), as well as other investigators (43), have found reduced sensitivity of baroreceptor afferent fibers in a dog model of heart failure (HF) induced by rapid ventricular pacing; however, less is known about efferent vagal control mechanisms in HF. Vagal control of heart rate is a complex process involving many different components. These include central impulse generation, synapses at peripheral ganglia, synthesis and release of ACh into the synaptic cleft, uptake of ACh by muscarinic receptors, postreceptor mechanisms (including interaction with membrane proteins and intracellular signaling), and hydrolysis of ACh by acetylcholinesterase (37). Parasympathetic dysfunction could therefore be due to abnormalities at any of these sites.We recently reported that synaptic transmission involving nicotinic ACh receptors across the parasympathetic ganglion contributes to parasympathetic dysfunction in the rapid pacing model of HF in dogs (1). In that report, we showed that stimulation of preganglionic fibers resulted in attenuated end-organ sinus cycle length (SCL) responses, but bypass of the ganglion through direct stimulation of postganglionic fibers resulted in augmented SCL responses. This observation suggested that sufficient ACh could be released from postganglionic nerve fibers to interact with postsynaptic mechanisms to elicit the exaggerated response in HF. This augmented postsynaptic response in HF is likely to involve upregulated sign...

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Section: Limitations Of Studysupporting

confidence: 60%

Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity

Dunlap

Bibevski

Rosenberry

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…Since muscarinic receptor-mediated inhibition of adenylyl cyclase to some extent balances the effect of P-adrenergic-mediated stimulation of the adenylyl cyclase system in myocardium, changes in any of the various components in the inhibitory G-protein (Gi)-mediated muscarinic receptor signaling system could therefore be expected to also occur in cardiomyopathy or diabetes induced cardiac dysfunction. We and others have previously demonstrated an increase in Gi function not only in failing human heart due to dilated cardiomyopathy but also in failing rat heart due to chronic ischemia (Bohm et al 1990;Fu et al 1992bFu et al & 1993. The first ojective of the present study was, therefore, to examine the biochemical changes in the Gi-mediated muscarinic receptor-adenylyl cyclase system in diabetes induced cardiac dysfunction.…”

mentioning

confidence: 78%

“…The reaction was linear within 10 min. and with respect to a protein content of 20-50 pgi25 p1 (Fu et al 1992b(Fu et al & 1993.…”

Section: Peptide Synthesis and Antibody Purijicationmentioning

confidence: 99%

Diabetes‐Induced Changes in the Gi‐Modulated Muscarinic Receptor‐Adenylyl Cyclase System in Rat Myocardium^*

Bergh²,

Liang³

et al. 1994

Pharmacology & Toxicology

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The inhibitory guanine nucleotide binding regulatory protein (Gi)-mediated muscarinic receptor-adenylyl cyclase system was studied in myocardium from adult male Wistar rats with 10 weeks of diabetes induced by a single intravenous injection of streptozotocin (60 mg/kg). Neither the messenger ribonucleic acid level nor the amount of Gi was changed in the streptozotocin diabetic group as compared to the control group. The activity of the adenylyl cyclase stimulated by guanyliminodiphosphate was decreased by 48% in the streptozotocin diabetic group whereas stimulated activities of adenylyl cyclase by sodium fluoride and forskolin remained unchanged. The inhibition of forskolin-stimulated adenylyl cyclase activity by carbachol was more potent in membranes from the streptozotocin diabetic group than that in membranes from the control group. The competition binding curve between (3H)- quinuclidinyl benzilate and carbachol obtained from the streptozotocin diabetic group was shifted to the left as compared to the control group. These results suggest that the myocardium of streptozotocin-induced diabetic rats exhibited an increase in Gi function as demonstrated by the increased inhibition of guanyliminodiphosphate-mediated adenylyl cyclase and the superhigh affinity for carbachol of the muscarinic receptors. As there were signs, similar to those seen in clinical heart failure, in the streptozotocin diabetic group, these results demonstrate that functional alteration of Gi might underlie, at least in part, the cardiac dysfunction that is associated with diabetes.

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“…11–13 However, it is unclear whether GRK-mediated phosphorylation of β 2 AR is involved in the regulation of β 2 AR-coupled G i signaling in heart. Because both GRK2 and G i proteins are significantly elevated in HF caused by a multitude of etiologies, 14–19 we hypothesize that the well-documented detrimental effects of GRK2 in the failing heart may causatively link to enhanced β 2 AR-coupled G i signaling.…”

Section: Introductionmentioning

confidence: 99%

G _i -Biased β ₂ AR Signaling Links GRK2 Upregulation to Heart Failure

Zhu

Petrashevskaya

Ren

et al. 2012

Circulation Research

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Rationale Phosphorylation of β2-adrenergic receptor (β2AR) by a family of serine/threonine kinases known as G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) is a critical determinant of cardiac function. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is a well-established causal factor of heart failure, but the underlying mechanism is poorly understood. Objective We seek to determine the relative contribution of PKA- and GRK-mediated phosphorylation of β2AR to the receptor coupling to Gi signaling that attenuates cardiac reserve and contributes to the pathogenesis of heart failure in response to pressure overload. Methods and Results Overexpression of GRK2 led to a Gi-dependent decrease of contractile response to βAR stimulation in cultured mouse cardiomyocytes and in vivo. Importantly, cardiac-specific transgenic overexpression of a mutant β2AR lacking PKA phosphorylation sites (PKA- TG), but not the wild type β2AR (WT TG) or a mutant β2AR lacking GRK sites (GRK- TG), led to exaggerated cardiac response to pressure overload, as manifested by markedly exacerbated cardiac maladaptive remodeling and failure, and early mortality. Furthermore, inhibition of Gi signaling with pertussis toxin restores cardiac function in heart failure associated with increased β2AR to Gi coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of β2AR by GRK and resultant increase in Gi-biased β2AR signaling play an important role in the development of heart failure. Conclusions Our data show that enhanced β2AR phosphorylation by GRK, in addition to PKA, leads the receptor to Gi-biased signaling which, in turn, contributes to the pathogenesis of heart failure, marking Gi-biased β2AR signaling as a primary event linking upregulation of GRK to cardiac maladaptive remodeling, failure and cardiodepression.

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Hypersensitivity of Gi protein mediated muscarinic receptor adenylyl cyclase in chronic ischaemic heart failure in the rat

Cited by 17 publications

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Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity

Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity

Diabetes‐Induced Changes in the Gi‐Modulated Muscarinic Receptor‐Adenylyl Cyclase System in Rat Myocardium^*

G _i -Biased β ₂ AR Signaling Links GRK2 Upregulation to Heart Failure

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Hypersensitivity of Gi protein mediated muscarinic receptor adenylyl cyclase in chronic ischaemic heart failure in the rat

Cited by 17 publications

References 0 publications

Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity

Mechanisms of altered vagal control in heart failure: influence of muscarinic receptors and acetylcholinesterase activity

Diabetes‐Induced Changes in the Gi‐Modulated Muscarinic Receptor‐Adenylyl Cyclase System in Rat Myocardium*

G i -Biased β 2 AR Signaling Links GRK2 Upregulation to Heart Failure

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Diabetes‐Induced Changes in the Gi‐Modulated Muscarinic Receptor‐Adenylyl Cyclase System in Rat Myocardium^*

G _i -Biased β ₂ AR Signaling Links GRK2 Upregulation to Heart Failure