The Functional Availability of Arterial Kv7 Channels Is Suppressed Considerably by Large-Conductance Calcium-Activated Potassium Channels in 2- to 3-Month Old but Not in 10- to 15-Day Old Rats

Abstract

BackgroundVoltage-gated potassium (Kv) channels, especially Kv7 channels, are major potassium channels identified in vascular smooth muscle cells with a great, albeit differential functional impact in various vessels. Vascular smooth muscle Kv7 channels always coexist with other K channels, in particular with BK channels. BK channels differ in the extent to which they influence vascular contractility. Whether this difference also causes the variability in the functional impact of Kv7 channels is unknown. Therefore, this study addressed the hypothesis that the functional impact of Kv7 channels depends on BK channels.Experimental ApproachExperiments were performed on young and adult rat gracilis and saphenous arteries using real-time PCR as well as pressure and wire myography.Key ResultsSeveral subfamily members of Kv7 (KCNQ) and BK channels were expressed in saphenous and gracilis arteries: the highest expression was observed for BKα, BKβ1 and KCNQ4. Arterial contractility was assessed with methoxamine-induced contractions and pressure-induced myogenic responses. In vessels of adult rats, inhibition of Kv7 channels or BK channels by XE991 or IBTX, respectively enhanced arterial contractility to a similar degree, whereas activation of Kv7 channels or BK channels by retigabine or NS19504, respectively reduced arterial contractility to a similar degree. Further, IBTX increased both the contractile effect of XE991 and the anticontractile effect of retigabine, whereas NS19504 reduced the effect of retigabine and impaired the effect of XE991. In vessels of young rats, inhibition of Kv7 channels by XE991 enhanced arterial contractility much stronger than inhibition of BK channels by IBTX, whereas activation of Kv7 by retigabine reduced arterial contractility to a greater extent than activation of BK channels by NS19504. Further, IBTX increased the anticontractile effect of retigabine but not the contractile effect of XE991, whereas NS19504 reduced the effect of retigabine and impaired the effect of XE991.ConclusionKv7 and BK channels are expressed in young and adult rat arteries and function as negative feedback modulators in the regulation of contractility of these arteries. Importantly, BK channels govern the extent of functional impact of Kv7 channels. This effect depends on the relationship between the functional activities of BK and Kv7 channels.

Remodeling of Arterial Tone Regulation in Postnatal Development: Focus on Smooth Muscle Cell Potassium Channels

“…In addition to different expression levels, the functional impact of K v 7 channels depends on the activity of other potassium channels. A recent study demonstrated that BK Ca channel activity (which increases with age, see further in detail) suppresses K v 7 channel functional availability in saphenous arteries of adult, but not young, rats [46].…”

“…In rat cerebral arteries, the effects of BK Ca channel blockade became more pronounced with age-the BK Ca channel blocker, iberiotoxin, caused a contraction and an increase in the intracellular calcium concentration in arteries of adult (12-14 weeks old), but not newborn, rats (1-2 days old) [77]. Similarly, iberiotoxin led to an increase in basal tone and sensitivity to the α 1 -adrenoceptor agonist methoxamine in saphenous arteries of adult (2-3 months old), but not of young (10-15 day old), rats [45,46]. The effects of iberiotoxin on the contraction of sheep middle cerebral arteries also increased with age [40].…”

“…The functional role of K v 7 channels strongly declines with maturation. Blockade of these channels with XE991 and linopirdine led to the development of basal tone, increased contractile responses and sensitivity to the α 1 -adrenoreceptor agonist methoxamine and the thromboxane A2 receptor agonist U46619 in saphenous arteries of young rats [45,46]. These effects were considerably less pronounced in arteries of adult rats.…”

“…Third, the expression of BK Ca channels in smooth muscle cells can change as the organism matures. It was demonstrated that the mRNA expression of both the poreforming α1and the regulatory β1-subunits, where the latter has a positive effect on channel activity [84,85], increases with age [45,46]. In addition, the level of labeled charybdotoxin (a ligand of BK Ca channels) binding was considerably lower in the aorta of 4-week-old compared to 12-week-old rats [38].…”

Kv7 channel trafficking by the microtubule network in vascular smooth muscle

“… 23 Importantly, these channels are active at more negative membrane potentials compared to other Kv channels making them perfect candidates for the K + current controlling the resting membrane potential of vascular smooth muscle cells. Over the past 20 years, a key role in vascular (and non‐vascular) smooth muscle has been established, with Kv7.4 and Kv7.5 channels predominating, 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 which are likely to be regulated by the ancillary subunit KCNE4. 5 , 33 , 34 Several reviews have summarized the evidence supporting an important role for Kv7.4 and Kv7.5 channels in vascular smooth muscle.…”