Swelling-activated chloride channels in cardiac physiology and pathophysiology

Abstract

Characteristics and functions of the cardiac swelling-activated Cl current (I(Cl,swell)) are considered in physiologic and pathophysiologic settings. I(Cl,swell) is broadly distributed throughout the heart and is stimulated not only by osmotic and hydrostatic increases in cell volume, but also by agents that alter membrane tension and direct mechanical stretch. The current is outwardly rectifying, reverses between the plateau and resting potentials (E(m)), and is time-independent over the physiologic voltage range. Consequently, I(Cl,swell) shortens action potential duration, depolarizes E(m), and acts to decrease cell volume. Because it is activated by stimuli that also activate cation stretch-activated channels, I(Cl,swell) should be considered as a potential effector of mechanoelectrical feedback. I(Cl,swell) is activated in ischemic and non-ischemic dilated cardiomyopathies and perhaps during ischemia and reperfusion. I(Cl,swell) plays a role in arrhythmogenesis, myocardial injury, preconditioning, and apoptosis of myocytes. As a result, I(Cl,swell) potentially is a novel therapeutic target.

New Molecular Mechanisms for Cardiovascular Disease: Cardiac Hypertrophy and Cell-Volume Regulation

“…Thus, membrane Cl − channels have the unique ability, compared with cation channels, to contribute both inward as well as outward current during cardiac action potential (9,13,14). Consequently, activation of VRAC current should decrease the action potential duration (APD) and thereby the effective refractory period (ERP), and should depolarize membrane potential (15); it may also contribute to the development of stretchinduced membrane depolarizations and arrhythmias (9,14).…”

The Functional Role of Chloride Channels in Cardiac Pacemaker Activity

“…Patch-clamp studies have now identified at least eight types of Cl -currents in cardiac cells from different regions of the heart and in different species. The biophysical, pharmacological and molecular properties of these Clchannels have been well characterized and are summarized in Table 1 Hume et al, 2000;Baumgarten & Clemo, 2003;Duan et al, 2005;Duan, 2009). Several of these Cl -channels have been found to be expressed in SAN of different species (Table 1).…”

“…Although it has been suggested that stretch and swelling activate the same anion channel in some non-cardiac cells, further study is needed to determine whether this is true in cardiac myocytes. Baumgarten's laboratory has recently demonstrated that I Cl,swell in ventricular myocytes can be directly activated by mechanical stretch through selectively stretching β1-integrins with mAb-coated magnetic beads (Browe & Baumgarten, 2003;Baumgarten & Clemo, 2003;Browe & Baumgarten, 2004;Browe & Baumgarten, 2006). The stretch-activated Cl -current may contribute to the pacemaker rhythm under physiological conditions, since the stimulus is almost continuously present in the intact heart (Hagiwara et al, 1992).…”

“…The stretch-activated Cl -current may contribute to the pacemaker rhythm under physiological conditions, since the stimulus is almost continuously present in the intact heart (Hagiwara et al, 1992). I Cl,vol may also serve as a mediator of mechanotransduction and volume regulation and play a significant role in the pacemaker function if they act as both the stretch activated channels and cell swelling activated channels in these cells (Hagiwara et al, 1992;Kohl et al, 1994;Arai et al, 1996;Lei & Kohl, 1998;Baumgarten & Clemo, 2003). The short isoform of ClC-3 (sClC-3), a member of the ClC superfamily of voltage-dependent Cl -channels, has been proposed to be the molecular correlate of a key component of the www.intechopen.com native I Cl,vol in cardiac myocytes.…”

“…Several recent review articles have summarized the biophysical, pharmacological and molecular properties and the potential functional role of Cl -channels in the heart Hume et al, 2000;Baumgarten & Clemo, 2003;Duan et al, 2005;Duan, 2009). In this chapter, we will highlight the major findings and recent advances in the studies of Cl -channels in the regulation of cardiac pacemaker activity.…”