Enhanced Inhibition of L-type Ca<sup>2+</sup> Current by β<sub>3</sub>-Adrenergic Stimulation in Failing Rat Heart

Zhang, Zhu-Shan; Cheng, Heng-Jie; Onishi, Katsuya; Ohte, Nobuyuki; Wannenburg, Thomas; Cheng, Che‐Ping

doi:10.1124/jpet.105.089672

Cited by 70 publications

(69 citation statements)

References 29 publications

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“…The previously reported changes in atrial intracellular cGMP production together with the increased effect of phosphodiesterase inhibition on I CaL are consistent with the proposal that changes in NO/cGMP-dependent regulation of Ltype Ca 2ϩ channels may underlie both the reduced basal current and increased sensitivity to noradrenergic agonism in heart failure (4,19). On the other hand, whereas it has previously been shown that the effect of NE on I CaL is almost exclusively mediated via ␤ 1 -adrenoceptors in atrial myocytes from normal hearts (6), the contribution of ␣ 1 -, ␤ 2 -, and ␤ 3 -adrenoceptors in heart failure cannot be ruled out (44,45,52). Thus future studies using selective adrenoceptor ligands and inhibitors of signaling cascades will be important to establish the mechanism underlying the remodeling of atrial I CaL regulation in heart failure.…”

Section: Discussionmentioning

confidence: 87%

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Bond

Bryant

Watson

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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Bond RC, Bryant SM, Watson JJ, Hancox JC, Orchard CH, James AF. Reduced density and altered regulation of rat atrial L-type Ca 2ϩ current in heart failure. Am J Physiol Heart Circ Physiol 312: H384 -H391, 2017. First published December 6, 2016; doi:10.1152/ ajpheart.00528.2016.-Constitutive regulation by PKA has recently been shown to contribute to L-type Ca 2ϩ current (ICaL) at the ventricular t-tubule in heart failure. Conversely, reduction in constitutive regulation by PKA has been proposed to underlie the downregulation of atrial ICaL in heart failure. The hypothesis that downregulation of atrial ICaL in heart failure involves reduced channel phosphorylation was examined. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, Nϭ10) or equivalent sham-operation (Sham, Nϭ12). Left atrial myocytes were isolated~18 wk postsurgery and whole cell currents recorded (holding potentialϭ-80 mV). ICaL activated by depolarizing pulses to voltages from -40 to ϩ50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cell capacitances were~1.67-fold greater than Sham (P Յ 0.0001). Maximal ICaL conductance (Gmax) was downregulated more than 2-fold in CAL vs. Sham myocytes (P Ͻ 0.0001). Norepinephrine (1 mol/l) increased Gmax Ͼ50% more effectively in CAL than in Sham so that differences in ICaL density were abolished. Differences between CAL and Sham Gmax were not abolished by calyculin A (100 nmol/l), suggesting that increased protein dephosphorylation did not account for ICaL downregulation. Treatment with either H-89 (10 mol/l) or AIP (5 mol/l) had no effect on basal currents in Sham or CAL myocytes, indicating that, in contrast to ventricular myocytes, neither PKA nor CaMKII regulated basal ICaL. Expression of the L-type ␣1C-subunit, protein phosphatases 1 and 2A, and inhibitor-1 proteins was unchanged. In conclusion, reduction in PKA-dependent regulation did not contribute to downregulation of atrial ICaL in heart failure. NEW & NOTEWORTHY Whole cell recording of L-type Ca 2ϩcurrents in atrial myocytes from rat hearts subjected to coronary artery ligation compared with those from sham-operated controls reveals marked reduction in current density in heart failure without change in channel subunit expression and associated with altered phosphorylation independent of protein kinase A. atrial remodeling; coronary artery ligation; voltage-gated Ca 2ϩ channel ATRIAL FIBRILLATION (AF) is the most common clinical arrhythmia and is associated with significant mortality, primarily through stroke and heart failure (2, 3). There are many causes of AF and although patients generally show multiple predisposing risk factors, Ͼ70% of patients have some form of underlying structural heart disease (2, 3). Evidence from animal models of heart diseases that predispose to AF indicates that disease-associated remodeling of the atria, presumably due to mechanical overload of the atrial wall, creates an arrhythmic substrate in which AF is more likely to arise and be sustained ...

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Section: Discussionmentioning

confidence: 87%

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Bond

Bryant

Watson

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…It is about 100-fold less potent at the rat β 3 -adrenoceptor (Candelore et al 1999). Nevertheless, it was reported to abolish some nadololinsensitive β-adrenoceptor responses in rat heart (Zhang et al 2005) or aorta (Mallem et al 2004) and also to inhibit propranolol-resistant responses in the opossum esophagus (Sarma et al 2003) or anal sphincter . L-748,337 distinguishes the β 3 -adrenoceptor from the propranolol-resistant site of the β 1 -adrenoceptor (Joseph et al 2003).…”

Section: Cell Linesmentioning

confidence: 99%

Tools to study β3-adrenoceptors

Vrydag

Michel

2007

Naunyn-Schmied Arch Pharmacol

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β 3 -adrenoceptors mediate some of the effects of catecholamines on tissues such as blood vessels or the urinary bladder and are putative targets for the treatment of diseases such as the overactive bladder syndrome. Progress in the understanding of the presence, function, and regulation of β 3 -adrenoceptors has been hampered by a lack of highly specific tools. "Classical" is not selective for β 3 -adrenoceptors, at least in humans, and may actually be a partial agonist. Radioligands, which are suitable either for the selective labeling of β 3 -adrenoceptors or for the nonselective labeling of all β-adrenoceptor subtypes, are also missing. β 3 -and β 1 /β 2 double knockout mice have been reported, but their usefulness for extrapolations in humans is questionable based upon major differences between humans and rodents with regard to the ligand recognition and expression profiles of β 3 -adrenoceptors. While the common availability of more selective agonists and antagonists at the β 3 -adrenoceptor is urgently awaited, the limitations of the currently available tools need to be considered in studies of β 3 -adrenoceptor for the time being.

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“…In the heart, PTx-sensitive G proteins, located at the interface between receptor-response coupling, are involved in various inhibitory transduction cascades triggered by both chemical and physical stimuli (Hare et al, 1998). In the rat heart, ␤3-ARs, acting through a G i protein, mediate the inhibitory effect of BRL on L-type Ca 2+ current (Zhang et al, 2005). Moreover, in human heart the PTx-sensitive-␤3-ARinduced negative inotropic effect was associated with decreased action potential amplitude and reduced action potential duration (Gauthier et al, 1996).…”

Section: Transduction Mechanism G-proteins Interactionmentioning

confidence: 99%

Beta3-Adrenoceptor in the eel (Anguilla anguilla) heart:negative inotropy and NO-cGMP-dependent mechanism

Imbrogno

Angelone

Adamo

et al. 2006

Journal of Experimental Biology

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Enhanced Inhibition of L-type Ca²⁺ Current by β₃-Adrenergic Stimulation in Failing Rat Heart

Cited by 70 publications

References 29 publications

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Tools to study β3-adrenoceptors

Beta3-Adrenoceptor in the eel (Anguilla anguilla) heart:negative inotropy and NO-cGMP-dependent mechanism

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Enhanced Inhibition of L-type Ca2+ Current by β3-Adrenergic Stimulation in Failing Rat Heart

Cited by 70 publications

References 29 publications

Reduced density and altered regulation of rat atrial L-type Ca2+current in heart failure

Reduced density and altered regulation of rat atrial L-type Ca2+current in heart failure

Tools to study β3-adrenoceptors

Beta3-Adrenoceptor in the eel (Anguilla anguilla) heart:negative inotropy and NO-cGMP-dependent mechanism

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Product

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Enhanced Inhibition of L-type Ca²⁺ Current by β₃-Adrenergic Stimulation in Failing Rat Heart

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure

Reduced density and altered regulation of rat atrial L-type Ca²⁺current in heart failure