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Critical Role for Transient Receptor Potential Channel TRPM4 in Myogenic Constriction of Cerebral Arteries

From the Department of Pharmacology, University of Vermont College of Medicine, Burlington.

Correspondence to Scott Earley, PhD, Dept of Pharmacology, University of Vermont College of Medicine, 89 Beaumont Ave, Burlington, VT. E-mail Scott.Earley{at}uvm.edu

Local control of cerebral blood flow is regulated in part through myogenic constriction of resistance arteries. Although this response requires Ca²⁺ influx via voltage-dependent Ca²⁺ channels secondary to smooth muscle cell depolarization, the mechanisms responsible for alteration of vascular smooth muscle (VSM) cell membrane potential are not fully understood. A previous study from our laboratory demonstrated a critical role for a member of the transient receptor potential (TRP) superfamily of ion channels, TRPC6, in this response. Several other of the approximately 22 identified TRP proteins are also present in cerebral arteries, but their functions have not been elucidated. Two of these channels, TRPM4 and TRPM5, exhibit biophysical properties that are consistent with a role for control of membrane potential of excitable cells. We hypothesized that TRPM4/TRPM5-dependent currents contribute to myogenic vasoconstriction of cerebral arteries. Cation channels with unitary conductance, ion selectivity and Ca²⁺-dependence similar to those of cloned TRPM4 and TRPM5 were present in freshly isolated VSM cells. We found that TRPM4 mRNA was detected in both whole cerebral arteries and in isolated VSM cells whereas TRPM5 message was absent from cerebral artery myocytes. We also found that pressure-induced smooth muscle cell depolarization was attenuated in isolated cerebral arteries treated with TRPM4 antisense oligodeoxynucleotides to downregulate channel subunit expression. In agreement with these data, myogenic vasoconstriction of intact cerebral arteries administered TRPM4 antisense was attenuated compared with controls, whereas KCl-induced constriction did not differ between groups. We concluded that activation of TRPM4-dependent currents contributed to myogenic vasoconstriction of cerebral arteries.

Key Words: TRP channels • cerebral circulation • cation channels • vasoconstriction

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