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Emerging Concepts in Ion Channel Biophysics
Poster Abstracts
55
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.