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• W2059348791 abstract "The myogenic response was described by Bayliss in The Journal of Physiology over 100 years ago (Bayliss, 1902). Independently of neural and humoral influences, and within a physiological pressure range, this response involves the ability of resistance arteries to constrict in response to increased intravascular pressure, without significant changes in blood flow (Hill et al. 2006; Brayden et al. 2008). The process is thought integral to the tight autoregulation of blood flow in the cerebral and other circulations and for maintaining the balance between vasoconstrictor and vasodilator activity, and thereby for the control of vascular tone, blood pressure and normal cardiovascular function. Indeed, alterations in myogenic control mechanisms are involved in the etiology of vascular disease, such as diabetes, hypertension and stroke (Brayden et al. 2008; Greenwood & Ohya, 2009; Khavandi et al. 2009).The fundamental mechanism that underlies myogenic control involves pressure-induced depolarization of the smooth muscle cell membrane and calcium entry through voltage-sensitive channels, and a negative hyperpolarization feedback involving K+ channel activation. Several K+ channel types have been implicated in this latter mechanism, most prominently BKCa activated by localized smooth muscle cell calcium release associated with calcium ‘sparks’ (Hill et al. 2006; Brayden et al. 2008; Greenwood & Ohya, 2009). Whilst the basic characteristics of myogenic control mechanisms are similar between vascular beds, species and disease, like many aspects of vascular function, the involvement of specific ion channels and their auxiliary proteins (that influence channel activity) exhibit significant heterogeneity within and between vascular beds, species and disease (Brayden et al. 2008; Greenwood & Ohya, 2009; Khavandi et al. 2009). Such heterogeneity includes the channels and their subtypes that underlie smooth muscle calcium and potassium fluxes involved in maintaining tone, such as voltage-dependent calcium, transient receptor potential, and calcium-activated and voltage-gated potassium channels (Kv; Hill et al. 2006; Brayden et al. 2008; Greenwood & Ohya, 2009; Khavandi et al. 2009). The Kv7.x or KCNQ gene family has five members, Kv7.1–7.5, with Kv7.1, 7.4 and 7.5 being reported to be expressed in vascular smooth muscle, where they probably play a role in modulating vessel tone (Greenwood & Ohya, 2009).In a recent study in The Journal of Physiology, Greenwood, Cole and colleagues (Zhong et al. 2010) examine the involvement KCNQ gene products in negative feedback regulation of myogenic control in rat middle cerebral artery. Data show that myogenic control in these cerebral vessels involves members of the Kv7 channel family. Using qRT-PCR and immunohistochemistry, Kv7.1, 7.4 and 7.5 subunit mRNA and protein were shown to be expressed in cerebral artery smooth muscle, with negligible Kv7.2 and 7.3 expression. Patch clamp data from freshly isolated cerebral artery smooth muscle cells, using apparently selective pharmacological block and activation of Kv7, support a role for Kv7.1, 7.4 and 7.5 in these cells. This role was verified in segments of cerebral artery pressurized at 10–100 mmHg using the same pharmacological interventions as for the isolated smooth muscle cell data. The specificity of the pharmacological agents was verified using HEK cells transfected with homotetrameric Kv7.4, as a positive control, and heterotetrameric Kv1.2/Kv1.5 and Kv2.1/Kv9.3; the latter Kv channels being present in rat cerebral artery smooth muscle (see references in Zhong et al. 2010), but which are potential targets for non-selective Kv7 drug action. Via respective current depression and enhancement, these latter data show that linopirdine and S-1 are reasonably selective for Kv7 currents, whilst XE991 is less so, having effects at other heterotetrameric Kv channels.With many of the K+ channel families identified in vascular smooth muscle cells, a question arises as to the specific role of an individual family or subtype. From this viewpoint, it of interest that the magnitude of the inhibitory effect of the Kv7 activator S-1, on both myogenic tone and constriction induced by Kv2 inhibition in isolated cerebral arteries, correlated strongly with the degree of intra-luminal pressure and, by implication, smooth muscle cell membrane potential. Furthermore, it is of note that the hyperpolarizing current induced by S-1 in isolated smooth muscle cells was also greatly enhanced across a range of membrane potentials (−45 to −20 mV) likely to be experienced by the cells in pressurized cerebral arteries (−65 to −35 mV; Knot & Nelson, 1998). Collectively, these data provide concise and convincing evidence of a role for Kv7 in rat middle cerebral artery function, and specifically for their contribution in regulating pressure-induced myogenic tone in this vessel.Zhong et al. 2010 make a significant contribution to understanding the mechanisms that underlie the control of vascular tone, with a specific focus on cerebral blood flow. Thus, Kv7 activation may theoretically correct impaired depolarization and excess vessel constriction associated with vascular disease. Whilst Kv7 represents significant potential targets for therapeutic intervention, characterization of the role and potential heterogeneity in Kv7 subunits, potential splice variants, and their association with auxiliary subunits in different vascular beds and states is an area that requires further attention.In summary, Zhong et al. 2010 clarify an integral role for Kv7 in the myogenic response of the rat cerebral artery. Data suggest that pharmacological modulation of Kv7 may represent a novel target to control compromised cerebral artery diameter. It will be of interest to see if Kv7 are present in human cerebral vessels, and whether their modulation can regulate tone. In such a scenario, Kv7 modulation may be useful in the treatment of conditions where cerebral blood flow is compromised, such as in cerebral vasospasm associated with subarachnoid haemorrhage and stroke." @default.
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• W2059348791 date "2010-09-30" @default.
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• W2059348791 title "Under pressure - Kvchannels and myogenic control of cerebral blood flow" @default.
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• W2059348791 doi "https://doi.org/10.1113/jphysiol.2010.197996" @default.
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