KCNQ channels have been 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 that they represent novel targets to rescue periadventitial vascular dysfunction. Two models, spontaneously hypertensive rats and New Zealand obese mice, were studied using quantitative polymerase chain reaction, the patch-clamp technique, membrane potential measurements, myography of isolated vessels, and blood pressure telemetry. In rat Gracilis muscle arteries, anticontractile effects of perivascular fat were inhibited by the KCNQ channel blockers XE991 and linopirdine but not by other selective K + channel inhibitors. Accordingly, XE991 and linopirdine blocked noninactivating K + currents in freshly isolated Gracilis artery smooth muscle cells. mRNAs of several KCNQ channel subtypes were detected in those arteries, with KCNQ4 channels being dominant. In spontaneously hypertensive rats, the anticontractile effect of perivascular fat in Gracilis muscle arteries was largely reduced compared with 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 anticontractile effects of perivascular fat in spontaneously hypertensive rats. Moreover, KCNQ channel openers reduced arterial blood pressure in both models of hypertension independent of ganglionic blockade. Thus, our data suggest that KCNQ channels play a pivotal role in periadventitial vasoregulation of peripheral skeletal muscle arteries, and KCNQ channel opening may be an effective mechanism to improve impaired periadventitial vasoregulation and associated hypertension.

The regulation of the activity of calcium-activated potassium (BK_Ca) channels by intracellular proton ions (pH_i) was investigated using the patch-clamp technique in smooth muscle cells freshly isolated from rat tail small arteries. Single-channel conductance and voltage dependence of activation were not different at pH_i 7.0, 7.4 and 7.8. However, the membrane potential at which channel open probability reached 0.5 was 74 ± 5 mV (n = 6) (mean ± SE) at pH_i 7.4 and 54 ± 2 mV (n = 4) at pH_i 7.8 under conditions of pCa 5.9, and 30 ± 5 mV (n = 5) at pH_i 7.4 and 62 ± 4 mV (n = 5) at pH_i 7.0 under conditions of pCa 5.4. Furthermore, at a membrane potential of 0 mV, the pD₂ for intracellular calcium ions was 5.19 ± 0.04 (n = 26) (mean ± SD) at pH_i 7.8, 5.02 ± 0.05 (n = 28) at pH_i 7.4, and 4.82 ± 0.05 (n = 30) at pH_i 7.0. In addition, an alteration of pH_i resulted in a profound change in the amplitude of BK_Ca currents in intact cells; it reversibly attenuated the current-voltage relationship decreasing the current by 55 ± 3% (n = 7) (p < 0.001) at 70 mV after lowering the extracellular NH₄Cl concentration to decrease the calculated pH_i from 7.2 to 6.8. Thus, alterations of pH_i in the range from 7.0 to 7.8 did not affect single-channel conductance and voltage dependence of activation but markedly altered single BK_Ca channel activity as well as intact cell BK_Ca current amplitude, where an increase of the intracellular proton concentration inhibited this channel.