Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

Matsumoto, Yasunori; Aihara, Hidenori; Yamauchi-Kohno, Rikako; Reien, Yoshie; Ogura, Takehiko; Yabana, Hideo; Masuda, Yoshiaki; Sato, Toshiaki; Komuro, Issei; Nakaya, Haruaki

doi:10.1161/01.cir.0000023526.45800.8e

Cited by 37 publications

(20 citation statements)

References 39 publications

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“…Whole-cell membrane current recordings were performed by the patch-clamp method, as described previously (22,23). HEK293 cells were placed in a recording chamber (1-ml volume) attached to an inverted microscope (IMT-2; Olympus, Tokyo), and superfused with the HEPES-Tyrode solution at a rate of 3 ml/min.…”

Section: Electrophysiologymentioning

confidence: 99%

Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

et al. 2009

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Abstract. After the report of the Cardiac Arrhythmia Suppression Trial, a tabular framework of the Sicilian Gambit has been proposed to display actions of antiarrhythmic drugs on ion channels and receptors and to provide more rational pharmacotherapy of arrhythmias. However, because effects of antiarrhythmic drugs on I f have not been thoroughly examined, we used patch clamp techniques to determine the effects of various antiarrhythmic drugs on the HCN (hyperpolarization-activated cyclic nucleotide-gated) channel currents. HCN4 channels, a dominant isoform of HCN channels in the heart, were expressed in HEK293 cells. Amiodarone and bepridil potently inhibited the HCN4 channel current with IC 50 values of 4.5 and 4.9 μM, respectively, which were close to their therapeutic concentrations. The inhibitory effects of quinidine, disopyramide, cibenzoline, lidocaine, mexiletine, aprindine, propafenone, flecainide, propranolol, and verapamil on the HCN4 channel current were weak in their therapeutic concentrations, with IC 50 values of 78.3, 249, 46.8, 276, 309, 43.7, 14.3, 1700, 50.5, and 44.9 μM, respectively, suggesting that the inhibitory effects on I f would be clinically small. d,l-Sotalol hardly affected the HCN4 channel current. Information about the HCN4-channel effects of many antiarrhythmic drugs may be useful for determining the appropriate drug for treatment of various arrhythmias while minimizing adverse effects.

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Section: Electrophysiologymentioning

confidence: 99%

Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

et al. 2009

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“…ET A receptor antagonists also have an antiarrhythmic effect in pathological hearts, although the mechanism remains unclear (33). Neural remodeling in sympathetic nerve sprouting results in ventricular tachyarrhythmia in diseased human hearts and in animal models (7,8).…”

Section: Figurementioning

confidence: 99%

Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression

Ieda¹,

Fukuda²,

Hisaka³

et al. 2004

J. Clin. Invest.

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IntroductionCardiac tissues are extensively innervated by autonomic nerves. The cardiac sympathetic nerve plays an important role in modulating heart rate, conduction velocity, myocardial contraction, and relaxation. Although several molecules that regulate the development of the heart have been well characterized, little is known about the mechanism that regulates sympathetic innervation of the heart. The cardiac sympathetic nerve extends from the sympathetic neuron in stellate ganglia (SG), which is derived from the neural crest (1). Nerve growth factor (NGF) is a prototypic member of the neurotrophin family, members of which are critical for the differentiation, survival, and synaptic activity of the peripheral sympathetic and sensory nervous systems (2, 3). Levels of NGF expression within innervated tissues roughly correspond to innervation density (4). The volume of sympathetic ganglion is reduced by at least 80% at postnatal day 3 in mice with a disruption of the NGF gene. In mice that lack the NGF receptor TrkA, no neurons remain at postnatal day 9 (2). Deletion of a single copy of the NGF gene results in a 50% reduction in sympathetic neurons (5), while overexpression of NGF in the heart results in cardiac hyperinnervation and hyperplasia in SG neurons (6). These results demonstrate the importance of NGF in the regulation of sympathetic neuron development and innervation.In pathological states, NGF production in the heart is variable. In ischemic hearts, an increase in cardiac NGF leads to regeneration of sympathetic nerves (7,8). In a previous experiment, we found that NGF was upregulated in streptozotocin-induced diabetic murine hearts (9). In contrast, it was reported that NGF and sympathetic innervation were reduced in congestive heart failure (10). Despite their importance, the molecular mechanisms that regulate NGF expression and sympathetic innervation in the heart remain poorly understood.Endothelin-1 (ET-1) is believed to play a critical role in the pathogenesis of cardiac hypertrophy, hypertension, and atherosclerosis. Gene targeting of ET-1 and its receptor endothelin-A (ET A ) resulted in unexpected craniofacial and cardiovascular abnormalities. These phenotypes are consistent with interference of neural crest differentiation. The influence of ET-1 on neural crest development remains undetermined (11-13).We hypothesized that ET-1 could affect the induction of neurotrophic factors, and that its disruption might contribute to the immature development of neural crest-derived cells. In this study, we found ET-1-specific induction of NGF in cardiomyocytes, idenEndothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression The cardiac sympathetic nerve plays an important role in regulating cardiac function, and nerve growth factor (NGF) contributes to its development and maintenance. However, little is known about the molecular mechanisms that regulate NGF expression and sympathetic innervation of the heart. In an effort to identify regulato...

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“…28 Long-term ET A receptor blockade significantly ameliorates LV dysfunction, prevents histological and electrical ventricular remodeling, suppresses ventricular arrhythmias, and therefore greatly improves survival in various models of experimental heart failure. 29,30 In addition to ET-1, combined administration of Ang II and PD123319 significantly elevated the mRNA level of IGF-1, a peptide growth factor involved in cardiomyocyte proliferation and differentiation. 31 It was demonstrated previously that Ang II-induced arteriolar growth was blunted by PD123319 in the hypertrophied heart.…”

Section: Lakó-futó Et Al Role Of At 2 Receptor In the Cardiac Hypertrmentioning

confidence: 99%

Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac Hypertrophic Process In Vivo in the Rat Heart

et al. 2003

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Background-The precise function of angiotensin II type 2 receptor (AT 2 -R) in the mammalian heart in vivo is unknown.Here, we investigated the role of AT 2 -R in cardiac pressure overload. Methods and Results-Rats were infused with vehicle, angiotensin II (Ang II), PD123319 (an AT 2 -R antagonist), or the combination of Ang II and PD123319 via subcutaneously implanted osmotic minipumps for 12 or 72 hours. Ang II-induced increases in mean arterial pressure, left ventricular weight/body weight ratio, and elevation of skeletal ␣-actin and ␤-myosin heavy chain mRNA levels were not altered by PD123319. In contrast, AT 2 -R blockade resulted in a marked increase in the gene expression of c-fos, endothelin-1, and insulin-like growth factor-1 in Ang II-induced hypertension. In parallel, Ang II-stimulated mRNA and protein expression of atrial natriuretic peptide were significantly augmented by AT 2 -R blockade. Moreover, PD123319 markedly increased the synthesis of B-type natriuretic peptide. Furthermore, the expression of vascular endothelial growth factor and fibroblast growth factor-1 was downregulated by Ang II only in the presence of AT 2 -R blockade. Conclusions-Our

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Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

Cited by 37 publications

References 39 publications

Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide–Gated Channel Current

Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression

Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac Hypertrophic Process In Vivo in the Rat Heart

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