Differential Activation of Protein Kinase A in Various Regions of Myocardium during Sepsis

Hsu, Chin; Yang, Shaw Lang; Hsu, Sung Po; Hsu, Hseng Kuang; Liu, Maw Shung

doi:10.1006/jsre.1997.5143

Cited by 4 publications

(3 citation statements)

References 24 publications

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“…al, 1997). Additionally PKA-C has been demonstrated to be activated in the right atrium early in the septic process (Hsu et. al., 1997).…”

Section: Discussionmentioning

confidence: 99%

“…The laboratory of Fleming and Taylor has shown differences in the development of supersensitivity between the right and left atria as well as the ventricle of the guinea pig in response to chronic reserpine treatment (Fleming, 1984;Fleming and Taylor, 1991;. Recently, in a study also using rat cecal ligation and puncture, a significant increase in type II protein kinase A (PKA, also called cAMP dependent protein kinase) was observed in the right atrium that was not present in either the left atrium or ventricle (Hsu et. al., 1997).…”

Section: Evidence For a Difference In The Chronotropic Responsementioning

confidence: 99%

“…Additionally, levels of PKA activity have been demonstrated to be variable in a rat model of sepsis depending upon the location in the heart and the duration of the septic process (Hsu et. al., 1997).…”

Section: Time Course Of Changes In the Catalytic Subunit Of Protein Kmentioning

confidence: 99%

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Alterations in intrinsic heart rate in endotoxemia

Wearden¹

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After much early debate, it is now well recognized that the origin of the heart beat is myogenic, or intrinsic, to the heart. It has been felt that the intrinsic heart rate (IHR) is constant and that the observed heart rate is controlled by tonal alterations in the activity of the autonomic nervous system in response to various stimuli. Some investigators have recognized, however, that the intrinsic heart rate (IHR) can be altered in certain conditions. Sepsis, or the host response to bacterial infection, is recognized as a stress to the host that results in decreased myocardial contractility and tachycardia. Some previous work has suggested that this tachycardia may exist outside the tonal regulation of the autonomic nervous system, raising the possibility of an elevation of the IHR. Utilizing an E. coli lipopolysaccharide (LPS) endotoxin model of sepsis in the rat, this work demonstrates an elevation of the IHR in sepsis. The experimental evidence further suggests that the β-adrenoceptor participates in the induction of the elevation in IHR early in the septic process. By sixteen hours after LPS administration the β-adrenoceptor is, however, no longer required for the ongoing elevation of IHR. It is also demonstrated that the elevation in IHR is more prolonged than the contractile dysfunction induced by LPS. iii Dedication To Andrea, Andrew, Mara and Luke Without your support this would not have been possible Without your unconditional love this would all be meaningless

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“…al, 1997). Additionally PKA-C has been demonstrated to be activated in the right atrium early in the septic process (Hsu et. al., 1997).…”

Section: Discussionmentioning

confidence: 99%

Section: Evidence For a Difference In The Chronotropic Responsementioning

confidence: 99%

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Alterations in intrinsic heart rate in endotoxemia

Wearden¹

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Adrenergic regulation of the rapid component of the cardiac delayed rectifier potassium current, IKr, and the underlying hERG ion channel

et al. 2004

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Ventricular arrhythmias are often precipitated by physical or emotional stress, in particular in patients with ischemic heart disease or hereditary long QT syndrome. Stimulation of the sympathetic nervous system in response to exercise or emotional stress causes activation of cardiac alpha- and beta-adrenoceptors. The rapid component of the delayed rectifier potassium current, I(Kr), and the underlying hERG potassium channel are critical for the regulation of heart rhythm. Recent experimental studies revealed that hERG/I(Kr) currents are modulated by alpha- and beta-adrenergic stimulation, providing a pathophysiological explanation for the increased incidence of arrhythmias during stress. This review summarizes the current knowledge on hERG/I(Kr) channel modulation by adrenergic activity. In addition, therapeutic approaches to future effective, more genotype-specific antiarrhythmic therapies are discussed.

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HERG Potassium Channel Activation Is Shifted by Phorbol Esters via Protein Kinase A-dependent Pathways

Kiehn

Karle

Thomas

et al. 1998

Journal of Biological Chemistry

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We investigated the effects of the phorbol ester phorbol 12-myristate 13-acetate (PMA) on the rapid component of the delayed rectifier potassium current, I Kr , in guinea pig cardiomyocytes and found that the I Kr current amplitude was reduced by 20% with 10 nM PMA and 44% with 100 nM PMA. The ether-a-go-go-related gene (HERG) encodes I Kr in human heart. We expressed HERG heterologously in Xenopus oocytes and investigated the effects of PMA on the delayed rectifier potassium current. Upon application of PMA in a concentration of 100 nM, we found a similar reduction of HERG outward current amplitude by 59%. This reduction was due to a shift in the HERG activation curve by 37 mV. The ED 50 for the PMA-induced shift was 9.0 nM. The inactive 4␣-phorbol 12-myristate 13-acetate (4␣-PMA) had no effect. PMA is known to act by stimulating distinct protein kinase cascades. Additional application of the specific protein kinase C inhibitors chelerythrine (10 M) or bisindolylmaleimide (1 M) could not attenuate the PMA-induced shift. In contrast, the shift by PMA was reduced significantly when the specific protein kinase A (PKA) inhibitors H89 (50 M) or KT5720 (2.5 M) were applied. Forskolin (400 M), an activator of the adenylate cyclase that results in PKA activation, shifted the HERG activation curve by 14 mV. Moreover the specific protein kinase C activator 1-stearoyl-2-arachidonylglycerol (10 M) showed no effect. Our data suggest that mainly PKA is mediating the shift of the HERG activation kinetics.Repolarization of the cardiac action potential involves many potassium currents (1). One crucial repolarizing potassium current is the rapid component of the delayed rectifier potassium current (I Kr ) 1 (2-4). Recently, it has been shown that the underlying gene of the I Kr current is the human ether-a-go-gorelated gene (HERG) (5,6). HERG expressed in Xenopus oocytes produces a potassium current largely indistinguishable from native cardiac I Kr (6, 7). The HERG channel is the molecular target of antiarrhythmic therapy with Class III antiarrhythmic drugs, with the result that I Kr is blocked, and the cardiac action potential is prolonged (7,8). Congenital mutations in the HERG gene produce one form of the congenital long QT syndrome (LQT2) (9). Electrophysiological studies have shown that these HERG mutations result in a reduced HERG current with the consequence that the cardiac action potential and QT interval on the surface electrocardiogram of this patients is prolonged (10). These patients have a high risk for sudden cardiac death because of torsade de pointes ventricular arrhythmias (11).Protein kinases have been found in almost all cell membranes, and it has been demonstrated that they regulate ion channels (12-16). The biophysical properties of ion channels can be affected by protein kinases in native tissue (12,14) and when ion channels were expressed heterologously in Xenopus oocytes (13,16). Among the various protein kinases that have been found in almost all cells are protein kinase C (PKC) and protein kinase A (P...

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Differential Activation of Protein Kinase A in Various Regions of Myocardium during Sepsis

Cited by 4 publications

References 24 publications

Alterations in intrinsic heart rate in endotoxemia

Alterations in intrinsic heart rate in endotoxemia

Adrenergic regulation of the rapid component of the cardiac delayed rectifier potassium current, IKr, and the underlying hERG ion channel

HERG Potassium Channel Activation Is Shifted by Phorbol Esters via Protein Kinase A-dependent Pathways

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