Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

49-POS Board 49 Deciphering the Functional Impact of Pirfenidone-Induced Potentiation of L-type Ca 2+ Channels

Adrian Monsalvo-Villegas , Guillermo Avila. CINVESTAV, IPN, Mexico, Mexico.

INTRODUCTION: A synthetic compound termed pirfenidone (PFD) is well known for its ability to prevent and/or revert the excess deposition of extracellular matrix proteins (fibrosis). Thus, it is frequently used to restore alterations thought to originate from an exacerbated fibrosis in several tissues. For example, in the mouse ventricle PFD attenuates sequels of myocardial infarction. More specifically, a previous treatment with this compound decreases the area of infarct, inhibits the inducibility of tachycardia, increases electrical conduction velocity and enlarges the ejection fraction. Interestingly, our laboratory recently reported that PFD also chronically stimulates the activity of cardiac L-type Ca 2+ channels (LTCCs; Cardiovascular Research, 2012 96:244-54). OBJETIVES AND METHODS: Using primary cultures of adult rat ventricular myocytes, we have now investigated the downstream consequences of the pirfenidone-induced potentiation of LTCCs. Ca 2+ currents (I Ca ) and transients were measured simultaneously, using the whole-cell patch-clamp technique. In addition, parallel measurements of contractility and Ca 2+ transients were performed, in intact (non-patch-clamped) myocytes. RESULTS: A chronic treatment (1-2 d) with PFD led to increases in the magnitude of ICa, Ca 2+ transients, percentage of cell and sarcomere shortening, and velocity of contraction and relaxation. In contrast, this drug did not alter the levels of diastolic Ca 2+ , velocity of Ca 2+ transient decay, sarcoplasmic reticulum (SR) Ca 2+ content nor the gain of excitation-contraction coupling (i.e. the amount of Ca 2+ released through ryanodine receptors, divided by I Ca ). CONCLUSIONS: The PFD-dependent stimulation of LTCCs up-regulates Ca 2+ -induced Ca 2+ - release, which in turn accelerates contraction (positive inotropy). The stimulated relaxation is not explained by changes in the kinetics of Ca 2+ transient decay, suggesting a positive lusitropy that likely originates from modulation of the contractile apparatus. Clearly, PFD enhances the ventricular function, not only via anti-fibrotic mechanisms, but also by promoting electrophysiological effects.

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