Abstract 57: Pharmacologic Inhibition of BK Channels Affects Cardiac Function

Abstract

Calcium and voltage activated potassium channels (BK) are ubiquitously distributed, and have been shown to play roles in cardioprotection and cardiac function. To date, however, the effect of BK channel activation or inhibition in cardiac cells has only been studied using in vitro or ex vivo models. In this study, for the first time we demonstrate the role of BK channels on cardiac function in vivo using an antagonist, Paxilline. Male Sprague Dawley rats had an initial echocardiogram to establish baseline values of cardiac function. Afterwards, the femoral vein was isolated and rats injected with either DMSO or Paxilline of various concentrations ranging from 2 ng/mL/kg to 500 μg/mL/kg. Echocardiograms were then repeated 30 seconds, 15 minutes, and 24 hours after injection. Some rats at higher drug dosage suffered cardiac arrest within 15 minutes. In a separate experiment, a pressure transducer was inserted into the left ventricle (LV) via cannulation of the carotid artery. LV Developed Pressure (LVDP) and Heart Rate (HR) were continuously recorded as rats were infused with DMSO or Paxilline via the femoral vein. In agreement with BK null mutant mice, we found that rats receiving Paxilline had a significant decrease in HR compared to controls, as BK is known to play a role in SA nodal cells. In rats that lived, the transient decrease in HR averaged ~26.20%. Rats receiving Paxilline also had diminished Ejection Fraction (EF) ranging from 26.53% to 100% fold-decrease compared to controls. The decrease in EF occurred in a dose dependent manner, with rats receiving higher doses (> 13 ng/mL/kg) of Paxilline typically suffering cardiac arrest within 15 minutes. Measurements using pressure transduction of the LV showed results similar to those rats assessed using echocardiography, with a significant decrease in LVDP ranging from 36.9% to 100% decrease. Rats that received lower doses (<4 ng/mL/kg) of Paxilline showed improvement in their cardiac function back to baseline by 24 hours post injection, suggesting that the effects we observed are transient and that BK inhibition is reversible. We have shown that inhibition of BK is detrimental to cardiac function, suggesting that BK channels in cardiac tissue are not only functional but essential to maintain normal cardiac function.