J Physiol 588.19 (2010) pp 3635–3636 3635

PERSPECT IVES

Under pressure – Kv channels andmyogenic control of cerebralblood flow

Shaun L. Sandowand Timothy V. MurphyDepartments of Pharmacology (SLS) andPhysiology (TVM), School of MedicalSciences, University of New South Wales,Sydney, NSW, 2052, Australia

Email: shaun.sandow@unsw.edu.autim.murphy@unsw.edu.au

The myogenic response was described byBayliss in The Journal of Physiology over100 years ago (Bayliss, 1902). Independentlyof neural and humoral influences, andwithin a physiological pressure range, thisresponse involves the ability of resistancearteries to constrict in response to increasedintravascular pressure, without significantchanges in blood flow (Hill et al. 2006;Brayden et al. 2008). The process is thoughtintegral to the tight autoregulation of bloodflow in the cerebral and other circulationsand for maintaining the balance betweenvasoconstrictor and vasodilator activity, andthereby for the control of vascular tone,blood pressure and normal cardiovascularfunction. Indeed, alterations in myogeniccontrol mechanisms are involved in theetiology of vascular disease, such as diabetes,hypertension and stroke (Brayden et al.2008; Greenwood & Ohya, 2009; Khavandiet al. 2009).

The fundamental mechanism thatunderlies myogenic control involvespressure-induced depolarization of thesmooth muscle cell membrane and calciumentry through voltage-sensitive channels,and a negative hyperpolarization feedbackinvolving K+ channel activation. SeveralK+ channel types have been implicated inthis latter mechanism, most prominentlyBKCa activated by localized smooth musclecell calcium release associated with calcium‘sparks’ (Hill et al. 2006; Brayden et al. 2008;Greenwood & Ohya, 2009). Whilst thebasic characteristics of myogenic controlmechanisms are similar between vascularbeds, species and disease, like many aspectsof vascular function, the involvement ofspecific ion channels and their auxiliary

proteins (that influence channel activity)exhibit significant heterogeneity withinand between vascular beds, species anddisease (Brayden et al. 2008; Greenwood& Ohya, 2009; Khavandi et al. 2009).Such heterogeneity includes the channelsand their subtypes that underlie smoothmuscle calcium and potassium fluxesinvolved in maintaining tone, such asvoltage-dependent calcium, transientreceptor potential, and calcium-activatedand 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 familyhas five members, Kv7.1–7.5, with Kv7.1,7.4 and 7.5 being reported to be expressedin vascular smooth muscle, where theyprobably play a role in modulatingvessel tone (Greenwood & Ohya,2009).

In a recent study in The Journalof Physiology, Greenwood, Cole andcolleagues (Zhong et al. 2010) examinethe involvement KCNQ gene products innegative feedback regulation of myogeniccontrol in rat middle cerebral artery. Datashow that myogenic control in these cerebralvessels involves members of the Kv7 channelfamily. Using qRT-PCR and immuno-histochemistry, Kv7.1, 7.4 and 7.5 sub-unit mRNA and protein were shown to beexpressed in cerebral artery smooth muscle,with negligible Kv7.2 and 7.3 expression.Patch clamp data from freshly isolatedcerebral artery smooth muscle cells, usingapparently selective pharmacological blockand activation of Kv7, support a role forKv7.1, 7.4 and 7.5 in these cells. Thisrole was verified in segments of cerebralartery pressurized at 10–100 mmHg usingthe same pharmacological interventionsas for the isolated smooth muscle celldata. The specificity of the pharmacologicalagents was verified using HEK cells trans-fected with homotetrameric Kv7.4, asa positive control, and heterotetramericKv1.2/Kv1.5 and Kv2.1/Kv9.3; the latterKv channels being present in rat cerebralartery smooth muscle (see references inZhong et al. 2010), but which are potentialtargets for non-selective Kv7 drug action.Via respective current depression andenhancement, these latter data show thatlinopirdine and S-1 are reasonably selectivefor 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 ofan individual family or subtype. From thisviewpoint, it of interest that the magnitudeof the inhibitory effect of the Kv7 activatorS-1, on both myogenic tone and constrictioninduced by Kv2 inhibition in isolatedcerebral arteries, correlated strongly withthe degree of intra-luminal pressure and, byimplication, smooth muscle cell membranepotential. Furthermore, it is of note that thehyperpolarizing current induced by S-1 inisolated smooth muscle cells was also greatlyenhanced across a range of membranepotentials (−45 to −20 mV) likely to beexperienced by the cells in pressurizedcerebral arteries (−65 to −35 mV; Knot& Nelson, 1998). Collectively, these dataprovide concise and convincing evidenceof a role for Kv7 in rat middle cerebralartery function, and specifically for theircontribution in regulating pressure-inducedmyogenic tone in this vessel.

Zhong et al. 2010 make a significantcontribution to understanding themechanisms that underlie the controlof vascular tone, with a specific focuson cerebral blood flow. Thus, Kv7activation may theoretically correctimpaired depolarization and excess vesselconstriction associated with vasculardisease. Whilst Kv7 represents significantpotential targets for therapeutic inter-vention, characterization of the roleand potential heterogeneity in Kv7 sub-units, potential splice variants, and theirassociation with auxiliary subunits indifferent vascular beds and states is an areathat requires further attention.

In summary, Zhong et al. 2010 clarifyan integral role for Kv7 in the myogenicresponse of the rat cerebral artery. Datasuggest that pharmacological modulation ofKv7 may represent a novel target to controlcompromised cerebral artery diameter. Itwill be of interest to see if Kv7 arepresent in human cerebral vessels, andwhether their modulation can regulate tone.In such a scenario, Kv7 modulation may beuseful in the treatment of conditions wherecerebral blood flow is compromised, such asin cerebral vasospasm associated with sub-arachnoid haemorrhage and stroke.

C© 2010 The Authors. Journal compilation C© 2010 The Physiological Society DOI: 10.1113/jphysiol.2010.197996

3636 Perspectives J Physiol 588.19

References

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Greenwood I & Ohya S (2009). Br J Pharmacol156, 1196–1203.

Hill MA, Davis MJ, Meininger GA, Potocnik SJ& Murphy TV (2006). Clin HemorheolMicrocirc 34, 67–79.

Khavandi K, Greenstein AS, Sonoyama K,Withers S, Price A, Malik RA & Heagerty AM(2009). Nephrol Dial Transplant 24, 361–369.

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Zhong XZ, Harhun MI, Olesen SP, Ohya S,Moffatt JD, Cole WC & Greenwood IA (2010).J Physiol 588, 3277–3293.

C© 2010 The Authors. Journal compilation C© 2010 The Physiological Society