EP News: Basic and Translational Penelope A. Boyden, PhD From the Department of Pharmacology, Columbia University, New York, New York.
Attenuated response of L-type calcium current to nitric oxide in atrial fibrillation
Mechanism underlying hypothermia-induced VT/VF in the setting of early repolarization
Nitric oxide (NO) synthesized by cardiomyocytes plays an important role in the regulation of cardiac function. Rozmaritsa et al (Cardiovasc Res 2014; PMID 24336332) studied the impact of NO on calcium influx and its relation to atrial fibrillation (AF). Right atrial appendages were obtained from patients in sinus rhythm (SR) and AF. The biotin-switch technique was used to evaluate endogenous S-nitrosylation of the L-type Ca channels. Comparing SR to AF, S-nitrosylation was similar. Direct effects of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) on the L-type calcium current (ICa,L) were studied using voltage-clamp techniques. In SR, ICa,L increased with SNAP by 48%. Specific inhibition of phosphodiesterase 3 (PDE3) increased ICa,L to a similar extent as SNAP. However, when cAMP was elevated by PDE3 inhibition, SNAP reduced ICa,L, pointing to cGMP-cAMP cross-regulation. In AF, the stimulatory effect of SNAP on ICa,L was attenuated while its inhibitory effect on isoprenaline-stimulated current was preserved. NO exerts dual effects on ICa,L in SR cells with an increase of basal and inhibition of cAMP-stimulated current. In AF cells, NO inhibits only stimulated ICa,L. The authors conclude that in AF, the cGMP regulation of PDE2 is preserved but the regulation of PDE3 is lost.
Hypothermia has been reported to induce ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with early repolarization (ER) pattern. Gurabi et al (Circ Arrhythm Electrophysiol 2014; PMID 24429494) examined the cellular mechanisms underlying VT/VF associated with hypothermia in an experimental model of ER syndrome. Action potentials (APs) were simultaneously recorded from epicardial and endocardial sites of LV wedges. NS5806 and verapamil were used to pharmacologically model the genetic mutations responsible for ER. Acetylcholine was used to simulate increased parasympathetic tone, which promotes ER. In control, mild hypothermia resulted in increased J-wave area on the electrocardiogram and accentuated epicardial AP notch but no arrhythmic activity. In ER, hypothermia caused further accentuation of the epicardial AP notch, creating the substrate for the development of VT/VF. The addition of quinidine or phosphodiesterase 3 inhibitors prevented the hypothermia-induced VT/VF. The authors conclude that hypothermia leads to VT/VF in the setting of ER by exaggerating repolarization abnormalities.
βIV-Spectrin regulates 2-pore channel, TREK-1, membrane targeting in the heart
Nav1.8 channels in ganglionated plexi modulate atrial fibrillation inducibility
Little is known about the regulation and/or targeting of 2-pore Kþ channel family members, despite their potential importance in the modulation of atrial electrophysiology. Hund et al (Cardiovasc Res 2014; PMID 24445605) reported a pathway for membrane targeting of TREK-1, a mechano-sensitive 2-pore Kþ channel regulated by factors including membrane stretch and pH. βIV-spectrin, an actin-associated protein, colocalizes with TREK-1 at the intercalated disc, associates with TREK-1, and is required for TREK-1 membrane targeting. Mice-expressing βIV-spectrin lacking TREK-1 binding display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without defects in localization/function of other cardiac K channels. These authors provide insight into membrane targeting of cardiac TREK-1 thus establishing a broader role for βIV-spectrin in organizing functional membrane domains critical for normal EP function.
SCN10A/NaV1.8 is associated with cardiac conduction and AF, but the role of NaV1.8 in cardiac electrophysiology remains understood. Qi et al (Cardiovasc Res 2014; PMID 24419303) investigated the effects of blockade of NaV1.8 channels of cardiac ganglionated plexi (GPs) on AF inducibility in the canine. Right cervical vagus nerve stimulation (VNS) was applied to determine its effects on the sinus rate, ventricular rate during AF, PR interval, and atrial effective refractory period. The NaV1.8 blocker A-803467 or dimethyl sulfoxide/polyethylene glycol (control) was injected into the anterior and inferior right GPs. The effects of VNS on electrophysiological variables above were significantly eliminated at 10, 35, and 90 minutes after A-803467 injection. The authors conclude that the blockade of NaV1.8 channels suppresses the effects of VNS on cardiac conduction and AF inducibility most likely by inhibiting the neural activity of cardiac GPs.
Address reprint requests and correspondence: Dr Penelope A. Boyden, Department of Pharmacology, Columbia University, 630 W 186th St, New York, NY 10032. E-mail address: [email protected].
1547-5271/$-see front matter
http://dx.doi.org/10.1016/j.hrthm.2014.03.004
Attenuated response of L-type calcium current to nitric oxide in atrial fibrillation
Mechanism underlying hypothermia-induced VT/VF in the setting of early repolarization
Nitric oxide (NO) synthesized by cardiomyocytes plays an important role in the regulation of cardiac function. Rozmaritsa et al (Cardiovasc Res 2014; PMID 24336332) studied the impact of NO on calcium influx and its relation to atrial fibrillation (AF). Right atrial appendages were obtained from patients in sinus rhythm (SR) and AF. The biotin-switch technique was used to evaluate endogenous S-nitrosylation of the L-type Ca channels. Comparing SR to AF, S-nitrosylation was similar. Direct effects of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) on the L-type calcium current (ICa,L) were studied using voltage-clamp techniques. In SR, ICa,L increased with SNAP by 48%. Specific inhibition of phosphodiesterase 3 (PDE3) increased ICa,L to a similar extent as SNAP. However, when cAMP was elevated by PDE3 inhibition, SNAP reduced ICa,L, pointing to cGMP-cAMP cross-regulation. In AF, the stimulatory effect of SNAP on ICa,L was attenuated while its inhibitory effect on isoprenaline-stimulated current was preserved. NO exerts dual effects on ICa,L in SR cells with an increase of basal and inhibition of cAMP-stimulated current. In AF cells, NO inhibits only stimulated ICa,L. The authors conclude that in AF, the cGMP regulation of PDE2 is preserved but the regulation of PDE3 is lost.
Hypothermia has been reported to induce ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with early repolarization (ER) pattern. Gurabi et al (Circ Arrhythm Electrophysiol 2014; PMID 24429494) examined the cellular mechanisms underlying VT/VF associated with hypothermia in an experimental model of ER syndrome. Action potentials (APs) were simultaneously recorded from epicardial and endocardial sites of LV wedges. NS5806 and verapamil were used to pharmacologically model the genetic mutations responsible for ER. Acetylcholine was used to simulate increased parasympathetic tone, which promotes ER. In control, mild hypothermia resulted in increased J-wave area on the electrocardiogram and accentuated epicardial AP notch but no arrhythmic activity. In ER, hypothermia caused further accentuation of the epicardial AP notch, creating the substrate for the development of VT/VF. The addition of quinidine or phosphodiesterase 3 inhibitors prevented the hypothermia-induced VT/VF. The authors conclude that hypothermia leads to VT/VF in the setting of ER by exaggerating repolarization abnormalities.
βIV-Spectrin regulates 2-pore channel, TREK-1, membrane targeting in the heart
Nav1.8 channels in ganglionated plexi modulate atrial fibrillation inducibility
Little is known about the regulation and/or targeting of 2-pore Kþ channel family members, despite their potential importance in the modulation of atrial electrophysiology. Hund et al (Cardiovasc Res 2014; PMID 24445605) reported a pathway for membrane targeting of TREK-1, a mechano-sensitive 2-pore Kþ channel regulated by factors including membrane stretch and pH. βIV-spectrin, an actin-associated protein, colocalizes with TREK-1 at the intercalated disc, associates with TREK-1, and is required for TREK-1 membrane targeting. Mice-expressing βIV-spectrin lacking TREK-1 binding display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without defects in localization/function of other cardiac K channels. These authors provide insight into membrane targeting of cardiac TREK-1 thus establishing a broader role for βIV-spectrin in organizing functional membrane domains critical for normal EP function.
SCN10A/NaV1.8 is associated with cardiac conduction and AF, but the role of NaV1.8 in cardiac electrophysiology remains understood. Qi et al (Cardiovasc Res 2014; PMID 24419303) investigated the effects of blockade of NaV1.8 channels of cardiac ganglionated plexi (GPs) on AF inducibility in the canine. Right cervical vagus nerve stimulation (VNS) was applied to determine its effects on the sinus rate, ventricular rate during AF, PR interval, and atrial effective refractory period. The NaV1.8 blocker A-803467 or dimethyl sulfoxide/polyethylene glycol (control) was injected into the anterior and inferior right GPs. The effects of VNS on electrophysiological variables above were significantly eliminated at 10, 35, and 90 minutes after A-803467 injection. The authors conclude that the blockade of NaV1.8 channels suppresses the effects of VNS on cardiac conduction and AF inducibility most likely by inhibiting the neural activity of cardiac GPs.
Address reprint requests and correspondence: Dr Penelope A. Boyden, Department of Pharmacology, Columbia University, 630 W 186th St, New York, NY 10032. E-mail address: [email protected].
1547-5271/$-see front matter
http://dx.doi.org/10.1016/j.hrthm.2014.03.004
