Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts

Abstract

INTRODUCTION This study compared the effects of ATP-regulated potassium channel (KATP) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. METHODS We optically mapped the endocardium of coronary-perfused right (n=11) or left (n=2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n=8) and non-failing human hearts without (NF, n=3) or with (INF, n=2) infarction. We also analyzed the mRNA expression of the KATP targets Kir6.1, Kir6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n=8) and CHF (n=4) hearts. RESULTS In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by −21±3% and −27±13%, p<0.01) and ventricles (by −28±7% and −28±4%, p<0.01). Diazoxide did not change APD (0±5%) in NF atria. Pinacidil significantly decreased APDs in both atria (−46 to - 80%, p<0.01) and ventricles (−65 to −93%, p<0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p<0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4±6.1 Hz and 17.5 ±5.1 Hz, respectively. Glibenclamide (10 μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of KATP targets were correlated to functional observations. CONCLUSION Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular KATP channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts.

KATPChannels in the Cardiovascular System

“…The SUR1 composition of atrial K ATP channels appears therefore to be responsible for the unusually high diazoxide sensitivity in this tissue (TABLE 3). It should be noted that this situation may be unique to rodents since the differential sensitivity to diazoxide in the atria and ventricles of dog and human heart is less prominent (222,922).…”

“…Ϫ/Ϫ mice were instrumental in the identification of a novel subtype of SUR1-based, diazoxide-sensitive, K ATP channels in mouse atria (237), which may also be present in the human atria and ventricle (222). The SUR1-null mice are unexpectedly protected from cardiac ischemia; they exhibit a reduced postischemic infarct size and preservation of left ventricular function upon reperfusion after ischemia (207).…”

Ca²⁺-Activated K⁺ Channels as Therapeutic Targets for Myocardial and Vascular Protection

“…Activation of plasma membrane K + currents could lead to altered action potential and arrhythmia, as seen with KATP modulating compounds. 10 In coronary VSMC, BKCa channel expression is more straightforward. They are expressed on the plasma membrane (Figure 2) where they modulate vascular tone and relaxation (see later).…”

Theoretical considerations for mapping activation in human cardiac fibrillation

“…3 High resolution mapping techniques, especially ones using optical dyes, have proven to be instrumental in determining the spatio-temporal wave organization in animal models and in explanted human hearts. 4,5 Such models have shown that spatiotemporally variable AF may actually result from periodic sources in the form of spiral waves (electrical rotors) 6,7 or focal sources, in which activation spreads from an origin, 8 that are localized yet lie in unpredictable locations and thus are ideally identified using a wide field of view. In patients, optical techniques are not feasible due to the toxicity of dyes and, in the absence of other high resolution and wide field of view mapping studies, it is has not been defined to what extent animal data can be legitimately translated to humans.…”