Key result
Acute administration of the KCa channel activator SKA-31 failed to reverse endothelial dysfunction in situ and modestly elevated mean arterial pressure in vivo compared with vehicle.
Why the study?
Systemic hypertension is linked to endothelial dysfunction, prompting investigation into whether activating endothelial KCa2.x and KCa3.1 channels improves vasodilation and lowers mean arterial pressure.
Does acute treatment with SKA-31 improve endothelium-dependent vasodilation and lower mean arterial pressure in male spontaneously hypertensive rats?
Does acute treatment with SKA-31 improve endothelium-dependent vasodilation and lower mean arterial pressure in male spontaneously hypertensive rats?
Pharmacological targeting of endothelial KCa channels with SKA-31 did not reverse endothelial dysfunction or lower mean arterial pressure in spontaneously hypertensive rats.
Does not support acute KCa activation for endothelial dysfunction; leaves open chronic dosing or alternative targets in preclinical models.
Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a selective activator of KCa2.x and KCa3.1 channels, would improve endothelium-dependent vasodilation and transiently lower mean arterial pressure (MAP) in male, spontaneously hypertensive rats (SHRs). Isolated vascular preparations exhibited impaired vasodilation in response to bradykinin (i.e., endothelial dysfunction) compared with Wistar controls, which was associated with decreased bradykinin receptor expression in mesenteric arteries. In contrast, similar levels of endothelial KCa channel expression were observed, and SKA-31 evoked vasodilation was comparable in vascular preparations from both strains. Addition of a low concentration of SKA-31 (i.e., 0.2-0.3 μM) failed to augment bradykinin-induced vasodilation in arteries from SHRs. However, responses to acetylcholine were enhanced. Surprisingly, acute bolus administration of SKA-31 in vivo (30 mg/kg, i.p. injection) modestly elevated MAP compared with vehicle injection. In summary, pharmacological targeting of endothelial KCa channels in SHRs did not readily reverse endothelial dysfunction in situ, or lower MAP in vivo. SHRs thus appear to be less responsive to endothelial KCa channel activators, which may be related to their vascular pathology.
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Khaddaj‐Mallat et al. (2019) studied Systemic hypertension and endothelial dysfunction. SKA-31 vs. Vehicle injection / Wistar controls was evaluated on Endothelium-dependent vasodilation and mean arterial pressure (MAP). Acute administration of the KCa channel activator SKA-31 failed to reverse endothelial dysfunction in situ and modestly elevated mean arterial pressure in vivo compared with vehicle.
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