Attenuation of Conduction Slowing during Global Ischemia in Guinea Pig Hearts through Increased Extracellular Calcium

Abstract

Cardiac ischemia is associated with decreased conduction velocity (CV) which can lead to conduction block and reentrant arrhythmias. Previously we have demonstrated that physiologically relevant changes in extracellular [K+] and [Ca2+] can modulate CV. The aim of the current study was to test whether changes in perfusate [K+] or [Ca2+] could alter loss of conduction during global ischemia and reperfusion. Guinea pig Langendorff hearts were perfused with a modified Tyrode's solution containing 153mM Na+, 4.6 or 6.9mM K+, and 1.25 or 2.0mM Ca2+, and loaded with the voltage-sensitive dye di-4-ANEPPS. Hearts were paced at a cycle length of 300ms at baseline and every 2 minutes during no flow ischemia to assess changes in transverse CV (CVT) and the time to conduction block. In separate studies, hearts were perfused with Tyrode's solution containing 146mM Na+, 4.6mM K+, and 1.25mM Ca2+, then subjected to 15 minutes of no flow ischemia before reperfusion with the test solutions for 15 minutes. At baseline (preischemia), there were no significant differences in CVT among the test solutions (153Na+/4.6K+/1.25Ca2+: 19.3±1.7 cm/s, n=6; 153Na+/4.6K+/2.0Ca2+: 16.4±1.9 cm/s, n=7; 153Na+/6.9K+/1.25Ca2+: 20.8±1.1 cm/s, n=6; p=NS). By 4 minutes of ischemia, CVT decreased significantly in the 153Na+/4.6K+/1.25Ca2+ (95% of baseline, p<0.05) and 153Na+/6.9K+/1.25Ca2+ (84% of baseline, p<0.05) solutions. In contrast, increasing [Ca2+] preserved CVT (153Na+/4.6K+/2.0Ca2+: 111% of baseline, p=NS). This preservation of CVT persisted through 12 minutes of ischemia (98% of baseline, p=NS), whereas at the same time point CVT in the 153Na+/4.6K+/1.25Ca2+ solution had decreased by 40% (p<0.01) and all hearts with 153Na+/6.9K+/1.25Ca2+ exhibited conduction block by 8 minutes. Despite the Ca2+-mediated differences in ischemia-induced changes in CV, the median time to conduction block was not significantly different between the 153Na+/4.6K+/1.25Ca2+ (16 minutes) and 153Na+/4.6K+/2.0Ca2+ (12 minutes, p=NS) solutions. However, increasing [K+] significantly shortened the median time to block (153Na+/6.9K+/1.25Ca2+: 7 minutes) relative to either solution containing 4.6mM K+ (p<0.01). Upon reperfusion, there were no significant differences in CVT among the test solutions, with a restoration of preischemia values within 3 minutes for each solution. In conclusion, increased extracellular Ca2+ improved conduction during global no flow ischemia, whereas decreased extracellular K+ prolonged the time to conduction block. Therefore, altering plasma ionic milieu during acute ischemia, in order to preserve cardiac conduction, may be a novel mechanism for preventing reentrant arrhythmias.