Zatebradine hydrochloride

Pirfenidone (PFD), a pyridone compound, is well recognized as an antifibrotic agent tailored for the treatment of idiopathic pulmonary fibrosis. Recently, through its anti-inflammatory and anti-oxidant effects, PFD based clinical trial has also been launched for the treatment of coronavirus disease (COVID-19). To what extent this drug can perturb membrane ion currents remains largely unknown. Herein, the exposure to PFD was observed to depress the amplitude of hyperpolarization-activated cation current (I_h) in combination with a considerable slowing in the activation time of the current in pituitary GH₃ cells. In the continued presence of ivabradine or zatebradine, subsequent application of PFD decreased I_h amplitude further. The presence of PFD resulted in a leftward shift in I_h activation curve without changes in the gating charge. The addition of this compound also led to a reduction in area of voltage-dependent hysteresis evoked by long-lasting inverted triangular (downsloping and upsloping) ramp pulse. Neither the amplitude of M-type nor erg-mediated K⁺ current was altered by its presence. In whole-cell potential recordings, addition of PFD reduced the firing frequency, and this effect was accompanied by the depression in the amplitude of sag voltage elicited by hyperpolarizing current stimulus. Overall, this study highlights evidence that PFD is capable of perturbing specific ionic currents, revealing a potential additional impact on functional activities of different excitable cells.

Pressure wave reflection is associated with cardiovascular risk. The conceptual distance to a theoretical major reflection site, termed effective reflection distance (ERD), has been associated with aging and augmentation index (AIx) clinically. However, it remains unclear whether and how ERD varies and associates with AIx when the hemodynamic condition is acutely perturbed in a patient. The objective of this study was to address this issue in rigorously controlled animal experiments. In 13 anesthetized dogs, we measured arterial pressure, aortic flow and femoral arterial flow, while altering the hemodynamic condition over wide ranges by administering zatebradine (bradycardic agent), nitroprusside (vasodilator), noradrenaline (vasoconstrictor), dobutamine (inotrope), and dextran (volume-expander). Using the measured data, we determined ERD based on an arterial model comprising a tube with a complex frequency-dependent load (ERD_TL), which has been considered a physiologically valid model. We also determined ERD based on wave separation (ERD_WSA) and pressure-based analyses (ERD_AW). ERD_TL was shortened significantly in response to nitroprusside or dobutamine infusion, and was significantly and negatively associated with AIx in multiple regression analysis using pooled data. ERD_WSA or ERD_AW did not necessarily correlate with ERD_TL in terms of responses to drug administration or association with AIx. In conclusion, under diverse hemodynamic conditions, ERD_TL changes sensitively and shows physiologically reasonable association with AIx. This result substantiates the importance of paying close attention to medications during clinical analysis of wave reflection. Caution is required when using ERD_WSA or ERD_AW as an alternative to ERD_TL.