Increased Response to [beta].sub.2-Adrenoreceptor Stimulation Augments Inhibition of I.sub.Kr in Heart Failure Ventricular Myocytes

Citation metadata

Date: Sept. 28, 2012
From: PLoS ONE(Vol. 7, Issue 9)
Publisher: Public Library of Science
Document Type: Report
Length: 5,306 words
Lexile Measure: 1400L

Document controls

Main content

Article Preview :

Author(s): Hegui Wang 1 , Yanhong Chen 2 , Hongjun Zhu 2 , Sen Wang 2 , Xiwen Zhang 2 , Dongjie Xu 2 , Kejiang Cao 2 , Jiangang Zou 2 , *

Introduction

Heart failure (HF) is associated with significant mortality, with nearly 50% of deaths occurring suddenly, primarily from ventricular tachycardia to ventricular fibrillation [1]. Sympathetic nerve activity is increased in HF [2]. It is widely accepted that the cardiac response to catecholamines is mediated primarily by [beta]-adrenoreceptors ([beta]-ARs). Arrhythmogenesis in HF is enhanced by [beta]-adrenergic stimulation [3].

The human ether-a-go-go-related gene (hERG or KCNH2 ) [4] encodes the [alpha] subunit of the channel underlying IKr [5], which is crucial for the repolarization of cardiac action potentials (AP). IKr is modulated by catecholamines. There is increasing evidence that hERG/I Kr channels are modulated by various G protein-coupled receptors including [alpha]- and [beta]-ARs, which act through the intracellular signaling modulators cAMP, protein kinase A (PKA), and protein kinase C (PKC) [6], [7], [8], [9]. Stimulation of [beta]-AR by 10 [micro]M isoprenaline decreased I Kr tail currents in guinea pig ventricular myocytes [7]. Similarly, PKA-mediated phosphorylation of expressed hERG channels significantly decreased hERG currents [10]. However, recent studies have revealed that I Kr tail currents are enhanced by 100 nM isoprenaline in canine ventricular myocytes [11]. It is well known that [beta]1 -AR is downregulated and [beta]2 -AR is relatively preserved in HF. In addition, experimental studies have demonstrated that canine ventricular response to [beta]2 -agonists is increased in tachypacing failure [12]. The responsiveness of cardiac L -type calcium current to [beta]2 -AR stimulation is increased in rats with HF induced by ligation of the coronary artery [13]. However, the role and mechanism of [beta]2 -AR activation in IKr in HF have not been previously assessed. Accordingly, the present study was designed to examine the role and possible mechanisms of [beta]2 -AR activation in IKr in left ventricular (LV) myocytes from HF guinea pigs using the whole cell patch clamp technique.

Results

Validity of the Guinea Pig Model

Following 12 weeks of thoracic aortic banding, the ejection fraction (EF) and fractional shortening (FS) of the heart of guinea pigs were significantly decreased; LV end-diastolic diameter, LV end-systolic diameter, the QT interval, and corrected QT interval were significantly increased while there were no changes in heart rate (Table 1). Cell capacitance of HF LV myocytes (n = 35 cells; 20 animals) and control LV myocytes (n = 35 cells; 16 animals) was 163±7 and 121±3 pF, respectively (P<0.001). Cell capacitance was increased in HF LV myocytes. All guinea pigs with HF developed ascites and pleural effusion. Thus, the HF model of guinea pigs induced by pressure overload is valid.

HF Reduces Ikr Tail Current Density

Ikr tail currents of guinea pig LV myocyte were completely abolished by the specific Ikr blocker, dofetilide (1 [micro]m) (Figure 1A), indicating that Ikr tail currents were measured free of contamination by other currents under the...

Source Citation

Source Citation   

Gale Document Number: GALE|A498244597