Browsing by Author "Kim, Taeyeob"

Now showing 1 - 1 of 1
  • Thumbnail Image
    ItemOpen Access
    Effects of a Pharmacological Activator of Ca2+-activated K+ Channels (KCa2/3) on Recovery from Acute Myocardial Infarction in Mice
    (2021-08) Kim, Taeyeob; Braun, Andrew; Belke, Darrell; Patel, Vaibhav; Duff, Henry; Rose, Robert
    The goal of this project is to investigate the potential cardio-protective effects of a small molecule activator of endothelial KCa 2.3 and KCa 3.1 channel activity (i.e. SKA-31). Recent studies from our group have demonstrated that acute SKA-31 treatment improved agonist-evoked vasodilation in resistance arteries from multiple vascular beds and species, and this effect remains robust in arteries from Type 2 Diabetic tissues. Prolonged administration of SKA-31 to aged male rats also improved both their cardiac and vascular functions. In my research, I have hypothesized that enhancement of endothelial function by in vivo SKA-31 administration would improve recovery of the heart following an acute injury, such as myocardial infarction (MI). Experimentally, male mice (12-15 weeks of age, C57BL/6 strain) were subjected to surgical ligation of the left-anterior descending coronary artery to establish an acute MI. Sham surgeries involved all the same surgical procedures, except for the coronary ligation. Within 48 h post-surgery, MI and sham surgery mice were treated orally with either vehicle or 10 mg/kg of SKA-31 daily for 6 weeks. Echocardiography, Pressure-Volume (P-V) loop measurements and histological analysis were implemented to assess cardiac performance and structure, respectively, in each of the four treatment groups. Myocardial damage in MI mice was confirmed by histological staining. Echocardiographic assessment of cardiac function 4 weeks post-surgery revealed that Ejection Fraction (EF), Fractional Shortening (FS), end systolic volume (ESV) and end diastolic volume (EDV) were similar in sham animals treated with either vehicle or SKA-31. In contrast, the MI animals treated with vehicle displayed ~50% decreases in EF and FS, and significantly larger values for ESV and EDV, compared with sham-treated mice. In addition, the MI animals displayed elevated EDPVR values of ~0.7 compared to ~0.3 observed in sham animals. This finding indicates that the left ventricular wall is stiffer following infarction and strongly suggests the presence of diastolic dysfunction. However, no significant changes in other diastolic parameters, such as [dP/dt]min and Tau, were detected in MI groups compared to the sham groups. These functional and structural parameters thus confirm the presence of sustained cardiac dysfunction in the MI mice. Treatment of MI mice with SKA-31 did not lead to improvements in EF, FS, ESV or EDV compared with vehicle treated MI animals. The results of my study show that a pharmacological intervention designed to enhance endothelial function did not significantly improve cardiac function in the setting of an acute injury. A potential confounding factor in this study is the possible effect of SKA-31 on the robust cardio-immunological responses in the post-MI heart, due to the expression of KCa3.1 channels within pro-inflammatory immune cells such as monocytes, neutrophils and macrophages.