SUN-265 - Adaptive Enhancement of Voltage-Gated Potassium (Kv7) Channel Function Regulates Aortic Vascular Tone in Early Type 2 Diabetes

The Kv7 (KCNQ) family of voltage-gated potassium channels plays a key role in regulating vascular smooth muscle excitability and arterial contractility. However, their function in large conduit arteries under metabolic disease conditions such as prediabetes and type 2 diabetes remains poorly understood. This study examined whether progression from prediabetes to early-stage diabetes alters Kv7 channel function and sensitivity in the thoracic aorta.
Thoracic aortae were isolated from age-matched male UC Davis type 2 diabetes mellitus (UCD-T2DM) rats classified as prediabetic or diabetic for three months. Metabolic parameters included body and adipose tissue mass, fasting blood glucose, and glucose tolerance. Endothelium-dependent and -independent vasorelaxation to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were assessed in phenylephrine (PE)-precontracted aortic rings using a Radnoti organ bath system. ACh responses were evaluated following nitric oxide synthase (NOS) inhibition with L-NAME. Kv7 channel function was assessed using retigabine, a Kv7 activator, and PE-induced vasoconstriction was measured before and after pretreatment with L-NAME or XE991, a Kv7 inhibitor.
Diabetic rats exhibited reduced body and adipose tissue mass, elevated fasting glucose, and impaired glucose tolerance compared with prediabetic animals, confirming metabolic progression to early diabetes. Vasorelaxation responses to ACh and SNP were similar in both groups. L-NAME abolished ACh-induced relaxation in prediabetic aortae, whereas residual relaxation persisted in diabetic rings, suggesting recruitment of nitric oxide (NO)–independent vasodilatory mechanisms in early diabetes. Diabetic aortae displayed greater sensitivity to retigabine-induced relaxation, indicating an enhanced functional contribution of Kv7 channels to vasodilation. NOS inhibition significantly attenuated retigabine-mediated relaxation in diabetic but not prediabetic aortae, suggesting an NO-dependent component of Kv7-mediated vasorelaxation in diabetes. PE-induced maximal constriction was significantly reduced in diabetics compared to prediabetics; L-NAME potentiated PE responses in both groups, with significantly greater potentiation in diabetic aortae, consistent with enhanced basal NO-dependent buffering. In addition, XE991 selectively augmented PE-induced contraction in diabetic rings, supporting increased Kv7 channel–dependent restraint of vascular tone.
Together, these findings suggest adaptive regulation of aortic vascular tone in the early stage of diabetes, characterized by enhanced Kv7 channel influence and altered integration with NO signaling. Further studies are needed to define the mechanisms by which Kv7 channels modulate vascular reactivity in this model.

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