Objectives: 

KCNQ channels have been recently identified in arterial smooth muscle. However, their role in vasoregulation and chronic vascular diseases remains elusive. We tested the hypothesis that KCNQ channels contribute to periadventitial vasoregulation in peripheral skeletal muscle arteries by perivascular adipose tissue and represent novel targets to rescue periadventitial vascular dysfunction.

Materials: 

Two models, spontaneously hypertensive (SHR) rats and New Zealand obese (NZO) mice, were studied using qPCR, the patch-clamp technique, membrane-potential measurements, myography of isolated vessels and blood pressure telemetry.

Results: 

In rat Gracilis muscle arteries, anti-contractile effects of perivascular fat were inhibited by the KCNQ channel blockers XE991 and linopirdine, but not by other K+ channel inhibitors. Accordingly, XE991 and linopirdine blocked non-inactivating K+ currents in freshly isolated Gracilis artery smooth muscle cells and mRNA of several KCNQ channel subtypes were detected in those arteries, with KCNQ4 channels being dominant. In SHR, the anti-contractile effect of perivascular fat in Gracilis muscle arteries was largely reduced compared to Wistar rats. However, the vasodilator effects of KCNQ channel openers and mRNA expression of KCNQ channels were normal. Furthermore, KCNQ channel openers restored the diminished anti-contractile effects of perivascular fat in SHR. Moreover, KCNQ channel openers reduced arterial blood pressure in both models of hypertension independently of ganglionic blockade.

Conclusions: 

Thus, our data suggest that KCNQ channels play a pivotal role in periadventitial vasoregulation of peripheral skeletal muscle arteries. KCNQ channel opening is an effective mechanism to improve impaired periadventitial vasoregulation and associated hypertension.