Endothelium-dependent vasodilation of small pulmonary arteries (PAs) lowers the resting pulmonary arterial pressure (PAP). Moreover, a loss of endothelium-dependent vasodilation is a major contributor to elevated PAP in pulmonary hypertension (PH). Therefore, therapeutic strategies specifically targeting endothelial vasodilatory mechanisms may have beneficial effects on PAP in PH. In this regard, endothelial Ca2+ signaling mechanisms promote PA dilation and may present potential therapeutic targets for lowering PAP in PH. Under homeostatic conditions, Ca2+ signals activate endothelial nitric oxide synthase (eNOS) and Ca2+-sensitive intermediate and small conductance potassium (IK and SK) channels to dilate PAs. eNOS activity and NO signaling are impaired in PH. However, the activity of IK/SK channels and its effect on PAP in PH have not been investigated. We hypothesized that IK/SK channels can be targeted for lowering PAP in PH. A mouse model of PH (chronic hypoxia + Sugen 5416, hereafter CH+Su, for 3 weeks) showed elevated right ventricular systolic pressure (RVSP, an indirect indicator of PAP) and development of pulmonary arterial lesions. We recently showed that adenosine triphosphate (ATP) dilates PAs through Ca2+-dependent activation of eNOS in normal mice (Daneva et al., PNAS, 2021). PA pressure myography experiments demonstrated that ATP was unable to dilate PAs from CH+Su mice, confirming a loss of eNOS-dependent vasodilation in these mice. However, PA dilation in response to IK/SK channel agonist NS309 (1 μM) was not different between PAs from control and CH+Su mice. Whole-cell patch-clamp studies in freshly isolated endothelial cells showed that IK/SK channel activity is not impaired in the endothelium from CH+Su mice. Finally, intraperitoneal administration of the IK/SK channel activator better suited for in vivo treatment, SKA-31 (30 mg/kg), lowered the RVSP in CH+Su mice. Cardiac functional magnetic resonance imaging studies revealed that acute SKA-31 administration does not alter the heart rate, stroke volume, ejection fraction, and cardiac output. Importantly, the RVSP-lowering effect of SKA-31 was not observed in normal mice. Collectively, our data reveal unaltered IK/SK channel activity in PH and provide proof of principle that IK/SK activation can be used as a strategy for lowering PAP in PH.
