Experimental study Electrophysiological effect of rotigaptide in rabbits with heart failure

Abstract

IntroductionRotigaptide is a new anti-arrhythmic peptide, which has recently been found to increase junctional conductance and prevent ischemia-induced ventricular tachycardia. In this study, we attempted to investigate the effects and mechanisms of rotigaptide on the vulnerability to ventricular arrhythmias in rabbits with heart failure (HF).Material and methodsChronic volume-pressure overload was used to induce HF. After rotigaptide infusion, an electrophysiological study was performed to record monophasic action potential (MAP), determine the effective refractory period (ERP) and ventricular fibrillation threshold (VFT), and assess the susceptibility to ventricular arrhythmia. Finally, real-time PCR was used to detect the changes of connexin 43 (Cx43) mRNA expression.ResultsHF rabbits exhibited significant down-regulation of Cx43 mRNA, increase of effective refractory period (ERP) and decrease of VFT (p < 0.05, respectively). These changes resulted in an increase of vulnerability to ventricular tachyarrhythmias (VT/VF). Rotigaptide administration shortened ERP (113.3 ±8.6 ms vs. 131.7 ±12.5 ms, p < 0.05), restored VFT (15.0 ±2.0 V vs. 6.3 ±1.4 V, p < 0.05), and decreased the vulnerability to VT/VF. However, short-term rotigaptide treatment had no significant effect on MAP duration (MAP duration at 90% repolarization: 169.3 ±6.0 ms vs. 172.7 ±6.2 ms, p > 0.05) or connexin 43 mRNA expression (p > 0.05).ConclusionsRotigaptide decreases the ERP, elevates VFT, and reduces the vulnerability to ventricular arrhythmias without changing Cx43 expression in rabbits with HF. It may be a promising antiarrhythmic drug for preventing ventricular arrhythmia in HF.

Compartmentalized Structure of the Moderator Band Provides a Unique Substrate for Macroreentrant Ventricular Tachycardia

“…However, considering the variability of MB thickness, complexity of the MB macrostructure (Figure 1 ), and variability of muscle/Purkinje fiber ratios (Figure IV in the Data Supplement ), the ERP may be influenced by variations of electrotonic loading, which is sensitive to tissue mass 15 and coupling. 16 Therefore, ERP of the MB was compared against MB thickness (Figure 7 C). A strong linear relationship was identified, whereby thicker MBs were associated with shorter ERP.…”

Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis

“…What is more, sole alterations in Cx43 function have been shown to impact on arrhythmogenesis [ 19 , 20 ]. Interestingly, despite not exhibiting an increase in fibrosis compared to WT and presenting with only 10.9% of abnormal distribution of Cx43, Cap2 gt/+ mice showed marked reductions in conduction velocities.…”

Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications

“…The dephosphorylation of Ser-297 and Ser-368 can be prevented by rotigaptide (Axelsen et al, 2006). Cx43 synthesis was not affected by rotigaptide (Liu et al, 2014). In contrast, AAP10 led to an increase in Cx43 mRNA expression (Easton et al, 2009).…”

“…Accordingly, it was also shown that AAP10 could significantly decrease the incidence of ventricular tachycardia and ventricular fibrillation in acute ischemia (coronary ligation) (Ni et al, 2015;Sun et al, 2015a). Similarly, rotigaptide (ZP123) also reduced the incidence of ventricular fibrillation and ventricular tachycardia in acute coronary ischemia in various animal models (Hennan et al, 2006;Kjølbye et al, 2008;Su et al, 2015), prevented ischemia-induced conduction velocity slowing (Shiroshita-Takeshita et al, 2007) and suppressed arrhythmia in volumepressure overload heart failure (Liu et al, 2014). Spiral wave reentry circuits became destabilized by enhancement of GJ coupling (Takemoto et al, 2012).…”