Pharmacological Targeting of Endothelial KCa Channels In Vivo Augments Vasodilatory Responses in Rat Femoral and Coronary Arteries in Health and Disease

Abstract

As the primary interface between the blood and organs, the vascular endothelium functions as a key regulator of tissue blood flow by sensing chemical and mechanical stimuli and producing vasoactive signals to dynamically control intraluminal diameter in local arterioles and upstream arteries. Flow-mediated dilation (FMD) is an important physiological mechanism to modify local tissue perfusion in response to dynamic metabolic conditions, and reduced FMD responses are indicative of endothelial dysfunction, the latter being a major risk factor for cardiovascular disease. We have previously reported that pharmacological enhancement of endothelial KCa2.3 and KCa3.1 channel activity by SKA-31 augmented vasodilatory responses in small resistance arteries and intact hearts isolated from healthy and Type 2 Diabetic (T2D) rats (RC Mishra et al, 2014, 2021). In the present study, we have investigated the ability of SKA-31 to enhance endothelium-dependent vasodilation in vivo in femoral and coronary arteries of healthy and T2D male rats. Methods: FMD responses associated with reactive hyperemia were measured in a side branch of the femoral artery by high sensitivity Doppler ultrasound following release of an inflated pressure cuff placed on the distal hind limb of male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26-32 weeks of age). Rats were injected i.p. with either 10 mg/kg SKA-31 or drug vehicle ~ 3 hours prior to cuff inflation. M-mode echocardiographic imaging was used to visualize intraluminal diameter changes in the left main coronary artery in the same four treatment groups in response to an increase in inhalational isoflurane from 2% to 5%. Results: Femoral artery blood flow increased ~2-fold during reactive hyperemia in vehicle treated SD rats, as quantified by velocity-time integral, and did not increase further with SKA-31 treatment. In contrast, the FMD response in vehicle treated T2D GK rats was substantially blunted vs. SD rats, and SKA-31 administration restored this response to the level observed in healthy controls, which was still observable 15-24 hours later. In vehicle treated SD rats, exposure to 5% isoflurane increased left main coronary arterial diameter by 50-60%, which reversed to baseline following return to the original 2% isoflurane condition. SKA-31 treatment of SD rats increased basal arterial diameter by ~30%, but did not significantly modify the observed increase in arterial diameter evoked by 5% isoflurane inhalation, compared with vehicle treatment. In vehicle treated T2D GK rats, exposure to 5% isoflurane did not increase coronary artery diameter over a 10 min period, which is suggestive of endothelial dysfunction. However, SKA-31 treatment significantly increased basal coronary arterial diameter by 40-50%, and promoted a rapid and robust increase in diameter following exposure to 5% isoflurane (80-90% increase above that observed in vehicle treated T2D rats), which reversed to baseline upon return to 2% isoflurane inhalation. No enhancement of isoflurane evoked coronary vasodilation was observable in T2D GK rats 15-24 hrs post-SKA-31 treatment. In summary, these data provide the first direct demonstration that low dose administration of a KCa channel activator can enhance vasodilatory responses in vivo. This study was supported by research funding to APB from the Canadian Institutes of Health Research (MOP-142467) and NSERC (RGPIN 2017-04116). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.