Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 22, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn100
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Enhancement of Ventricular Gap Junction Coupling By Rotigaptide
1 Department of Pharmacology, SUNY Upstate Medical University, 750 East Adams Street Syracuse, NY 13210
2 Cardiovascular and Metabolic Disease, Wyeth Research, Collegeville, PA 19426
3 Zealand Pharma A/S, Department of Pharmacology, Glostrup, Denmark
* Corresponding Author Richard D. Veenstra, Ph.D. Department of Pharmacology SUNY Upstate Medical University 750 East Adams Street Syracuse, NY 13210 Phone: 315-464-5145 Fax: 315-464-8014 E-mail: veenstrr{at}upstate.edu
Aim: Rotigaptide is proposed to exert its anti-arrhythmic effects by improving myocardial gap junction communication. To directly investigate the mechanisms of rotigaptide action, we treated cultured neonatal murine ventricular cardiomyocytes with clinical pharmacological doses of rotigaptide and directly determined its effects on gap junctional currents.
Methods: Neonatal murine ventricular cardiomyocytes were enzymatically isolated and cultured for 1-4 days. Primary culture cell pairs were subjected to dual whole cell patch clamp procedures to directly measure gap junctional currents (Ij) and voltage (Vj). Rotigaptide (0 - 350 nM) was applied overnight or acutely perfused into 35-mm culture dishes.
Results: Rotigaptide (35 – 100 nM) acutely and chronically increased the resting gap junction conductance (gj) and normalized steady state minimum gj (Gmin) by 5-20%. Higher concentrations produced a diminishing response, which mimics the observed therapeutic efficacy of the drug. The inactivation kinetics were similarly slowed in a therapeutic concentration-dependent manner without affecting the Vj dependence of inactivation or recovery. The effects of 0 – 100 nM rotigaptide on ventricular gj during cardiac action potential propagation were accurately modeled by computer simulations which demonstrate that clinically effective concentrations of rotigaptide can partially reverse conduction slowing due to decreases in gj and inactivation.
Conclusions: These results demonstrate that therapeutic concentrations of rotigaptide increase the resting gap junction conductance and reduce the magnitude and kinetics of steady state inactivation in a concentration-dependent manner. Rotigaptide may be effective in treating reentrant forms of cardiac arrhythmias by improving conduction and preventing the formation of reentrant circuits in partially uncoupled myocardium.
Time for primary review: 23 days
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