Participation ofKCNQ(Kv7) potassium channels in myogenic control of cerebral arterial diameter

Abstract

KCNQ gene expression was previously shown in various rodent blood vessels, where the products of KCNQ4 and KCNQ5, Kv7.4 and Kv7.5 potassium channel subunits, respectively, have an influence on vascular reactivity. The aim of this study was to determine if small cerebral resistance arteries of the rat express KCNQ genes and whether Kv7 channels participate in the regulation of myogenic control of diameter. Quantitative reverse transcription polymerase chain reaction (QPCR) was undertaken using RNA isolated from rat middle cerebral arteries (RMCAs) and immunocytochemistry was performed using Kv7 subunit-specific antibodies and freshly isolated RMCA myocytes. KCNQ4 message was more abundant than KCNQ5 = KCNQ1, but KCNQ2 and KCNQ3 message levels were negligible. Kv7.1, Kv7.4 and Kv7.5 immunoreactivity was present at the sarcolemma of freshly isolated RMCA myocytes. Linopirdine (1 μm) partially depressed, whereas the Kv7 activator S-1 (3 and/or 20 μm) enhanced whole-cell Kv7.4 (in HEK 293 cells), as well as native RMCA myocyte Kv current amplitude. The effects of S-1 were voltage-dependent, with progressive loss of stimulation at potentials of >−15 mV. At the concentrations employed linopirdine and S-1 did not alter currents due to recombinant Kv1.2/Kv1.5 or Kv2.1/Kv9.3 channels (in HEK 293 cells) that are also expressed by RMCA myocytes. In contrast, another widely used Kv7 blocker, XE991 (10 μm), significantly attenuated native Kv current and also reduced Kv1.2/Kv1.5 and Kv2.1/Kv9.3 currents. Pressurized arterial myography was performed using RMCAs exposed to intravascular pressures of 10-100 mmHg. Linopirdine (1 μm) enhanced the myogenic response at ≥20 mmHg, whereas the activation of Kv7 channels with S-1 (20 μm) inhibited myogenic constriction at >20 mmHg and reversed the increased myogenic response produced by suppression of Kv2-containing channels with 30 nm stromatoxin (ScTx1). These data reveal a novel contribution of KCNQ gene products to the regulation of myogenic control of cerebral arterial diameter and suggest that Kv7 channel activating drugs may be appropriate candidates for the development of an effective therapy to ameliorate cerebral vasospasm.

Role of KCNQ Channels in Skeletal Muscle Arteries and Periadventitial Vascular Dysfunction

“…They have been successfully used to identify specific roles of KCNQ channels in the circulatory system. 30,37 Of note, XE991 has been reported to reduce currents carried by heteromeric K v 1.2/K v 1.5 channels in HEK293 cells, 38 which have been suggested to be predominantly expressed in rat cerebral artery smooth muscle cells. 39 In contrast, our real-time PCR analysis of rat Gracilis muscle arteries 39,40 In addition, the anticontractile effect of perivascular fat was also not influenced by blockers targeting other non-K v -type K + channels expressed in vascular smooth muscle cells.…”

Novel Expression and Regulation of Voltage-Dependent Potassium Channels in Placentas From Women With Preeclampsia

“…39 -41 The importance of K V 7 channels to vascular reactivity has also been repeatedly demonstrated. 18,20 Immunohistochemistry data also provide some insight into the potential impact of altered K V 7 channel composition. The distribution of KCNQ3 and KCNE5 protein was not as localized to vascular regions as might be expected.…”

KCNQ Channels and Novel Insights Into Coronary Perfusion

“…Nonetheless, it was surprising that prolonged infusion with XE-991 or linopirdine (K V 7 blockers) to the isolated hearts only resulted in a very modest reduction of coronary flow. Based on previous data 6 and current views, 11 one would have expected a much more profound reduction in blood flow if KCNQ channels had the proposed prominent role in the …”

“…KCNQ1, 3, 4, and 5 gene products are widely expressed in systemic arteries with KCNQ 4 and 5 being predominant. [3][4][5] Current data suggest important roles for K V 7 family in systemic peripheral arteries, namely myogenic response 6 and vasoregulation by vasopressin, 7 β-adrenoceptors, 8 hydrogen sulfide, and perivascular adipose tissue. 5,9 In this current issue, Khanamiri et al 10 have examined the possible role of K V 7 channels in the rat coronary circulation.…”