Powerful Technique to Test Selectivity of Agents Acting on Cardiac Ion Channels: The Action Potential Voltage-Clamp
Authors: Szentandrassy, N.; Nagy, D.; Ruzsnavszky, F.; Harmati, G.; Banyasz, T.; Magyar, J.; J. Szentmiklosi, A.; P. Nanasi, P.
Source: Current Medicinal Chemistry, Volume 18, Number 24, August 2011 , pp. 3737-3756(20)
Publisher: Bentham Science Publishers
Abstract:Action potential voltage-clamp (APVC) is a technique to visualize the profile of various currents during the cardiac action potential. This review summarizes potential applications and limitations of APVC, the properties of the most important ion currents in nodal, atrial, and ventricular cardiomyocytes. Accordingly, the profiles (“fingerprints) of the major ion currents in canine ventricular myocytes, i.e. in cells of a species having action potential morphology and set of underlying ion currents very similar to those found in the human heart, are discussed in details. The degree of selectivity of various compounds, which is known to be a critical property of drugs used in APVC experiments, is overviewed. Thus the specificity of agents known to block sodium (tetrodotoxin, saxitoxin), potassium (chromanol 293B, HMR 1556, E-4031, dofetilide, sotalol, 4-aminopyridine, BaCl2), calcium (nifedipine, nisolpidine, nicardipine, diltiazem, verapamil, gallopamil), and chloride (anthracene-9-carboxylic acid, DIDS) channels, the inhibitor of the sodium-calcium exchanger (SEA0400), and the activator of sodium current (veratridine) are accordingly discussed. Based on a theory explaining how calcium current inhibitors block calcium channels, the structural comparison of the studied substances usually confirmed the results of the literature. Using these predictions, a hypothetical super-selective calcium channel inhibitor structure was designed. APVC is a valuable tool not only for studying the selectivity of the known ion channel blockers, but is also suitable for safety studies to exclude cardiac ion channel actions of any agent under development.
Keywords: Action potential; action potential voltage-clamp; calcium channel; chemical structure; ion current; ion channel blocker; selective calcium channel blocker; APVC experiments; dofetilide; 4-aminopyridine; BaCl2
Document Type: Research article
Publication date: 2011-08-01
- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.