K_ATP channel inhibition blunts electromechanical decline during hypoxia in left ventricular working rabbit hearts

Abstract

Sarcolemmal ATP-sensitive potassium channel (K channel) activation in isolated cells is generally understood, although the relationship between myocardial oxygenation and K activation in excised working rabbit hearts remains unknown. We optically mapped action potentials (APs) in excised rabbit hearts to test the hypothesis that hypoxic changes would be more severe in left ventricular (LV) working hearts (LWHs) than Langendorff (LANG) perfused hearts. We further hypothesized that K inhibition would prevent those changes. Optical APs were mapped when measuring LV developed pressure (LVDP), coronary flow rate and oxygen consumption in LANG and LWHs. Hearts were paced to increase workload and perfusate was deoxygenated to study the effects of myocardial hypoxia. A subset of hearts was perfused with 1 μm tolbutamide (TOLB) to identify the level of AP duration (APD) shortening attributed to K channel activation. During sinus rhythm, APD was shorter in LWHs compared to LANG hearts. APD in both LWHs and LANG hearts dropped steadily during deoxygenation. With TOLB, APDs in LWHs were longer at all workloads and APD reductions during deoxygenation were blunted in both LWHs and LANG hearts. At 50% perfusate oxygenation, APD and LVDP were significantly higher in LWHs perfused with TOLB (199 ± 16 ms; 92 ± 5.3 mmHg) than in LWHs without TOLB (109 ± 14 ms, P = 0.005; 65 ± 6.5 mmHg, P = 0.01). Our results indicate that K channels are activated to a greater extent in perfused hearts when the LV performs pressure-volume work. The results of the present study demonstrate the critical role of K channels in modulating myocardial function over a wide range of physiological conditions.

Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart

“…Collectively, previous studies have suggested that the crystalloid-perfused heart is at or near the brink of functional hypoxia, implying that the metabolic reserve capacity of the perfused heart is limited. Consistent with this notion, crystalloid-perfused hearts are highly sensitive to changes in perfusate oxygenation: a small reduction in arterial PO 2 decreases Mb oxygen saturation (33), shortens the action potential duration (APD) (20), and increases in mitochondrial NADH (43). Naturally, any changes in metabolic rate, such as increased heart rate (HR) or increased contractility, could induce mitochondrial hypoxia in the crystalloid-perfused heart.…”

“…Rabbits were then subjected to inhalation of 5% isoflurane. After cessation of pain reflexes, the heart was quickly excised via thoracotomy and Langendorff perfused at 60 mmHg and 37°C on a biventricular working heart system (Hugo Sachs Elektronik) using the KH solution described above (20,43). Hearts were stained while perfused with KH using 60 nmol of the voltage-sensitive dye di-4-ANEPPS dissolved in 30 l of DMSO and then diluted in 3 ml perfusate and injected into the aorta.…”

“…Motion tracking and excitation ratiometry optical mapping. Epicardial action potential signals were optically mapped using motion tracking with excitation ratiometry, as previously described (20,49). Excitation LEDs (450 and 505 nm, Phillips Luxeon) were coupled to the inputs of two randomized quad fiber optic bundles (Schott), and the singular outputs were aimed at the LV epicardium of perfused rabbit hearts.…”

Effects of antiarrhythmics on the electrical restitution in perfused guinea‐pig heart are critically determined by the applied cardiac pacing protocol

“…Fast cardiac activation rates during dynamic pacing may potentially induce ischaemic changes owing to the increased myocardial oxygen demands, and therefore provoke APD 90 shortening via K ATP channel activation in ventricular cells (Garrott et al, 2017). ERP-to-APD 90 ratio (post-repolarization refractoriness) (Downar, Janse, & Durrer, 1977;Shaw & Rudy, 1997).…”

Cardiac regulatory mechanisms: new concepts and challenges

“…), and that K ATP channel inhibition protects against electromechanical decline of the heart during hypoxia (Garrott et al . ).…”