Effect of focal cerebral ischemia on BKCa and TRPV4 in rat middle cerebral artery

Large-conductance Ca2+-sensitive K+ channels (BKCa) are prime regulators of vascular smooth muscle cell membrane potential and contraction and may be coupled to transient receptor potential vanillioid-4 (TRPV4) channels. This study examined the expression and function of BKCa and TRPV4 in rat middle-cerebral arteries (MCA) in stroke. Male Sprague-Dawley rats were subject to focal cerebral ischemic stroke by localized bolus injection of endothelin-1 (120 pmol). Controls received saline (0.9%). Five days later, animals were euthanized and the MCAs removed. Immunofluorescence studies showed increased BKCa expression (α- and β1-subunits) in the smooth muscle cells of the arteries from rats with stroke. BKCa was also expressed in the endothelium of MCA from stroke rats, in contrast with arteries from controls. TRPV4 was expressed in both endothelial and smooth muscle cells of the MCA, and expression in both cell types was increased in arteries from stroke rats. Pressurized (80 mmHg) arteries developed myogenic tone, the degree of myogenic tone was not different between arteries from control and stroke rats. The BKCa blocker iberiotoxin (0.1 μM) constricted arteries from stroke rats to greater extent than control MCA. The TRPV4 activator GSK1016790A (GSK) caused concentration-dependent dilation of MCAs from control and stroke rats; there was no effect of stroke on responses to GSK. In both control and stroke rats, MCA dilation induced by GSK was inhibited by the TRPV4 blocker HC-067047 (0.3 μM) but not by iberiotoxin. These studies suggest increased BKCa expression and activity contribute to modulation of MCA tone post-stroke. TRPV4 do not induce dilation of rat MCA through activation of BKCa.