Central Role of TRPM4 Channels in Cerebral Blood Flow Regulation

Abstract

Background and Purpose-The transient receptor potential channel TRPM4 is critically linked to the myogenic constrictor response of cerebral arteries that occurs when intravascular pressure increases. This myogenic behavior is thought to be fundamentally involved in the mechanisms of blood flow autoregulation. In this study, we tested the hypothesis that TRPM4 channels in cerebrovascular myocytes contribute to cerebral blood flow autoregulation in vivo. Methods-In vivo suppression of cerebrovascular TRPM4 expression was achieved by infusing antisense oligodeoxynucleotides into the cerebral spinal fluid of 400-to 550-g Sprague-Dawley rats at 80 g ⅐ day Ϫ1 for 7 days using an osmotic pump that discharged into the lateral cerebral ventricle. Absolute cerebral blood flow measurements were obtained over a range of mean arterial pressures using fluorescent microsphere methods. Results-Oligonucleotides infused into the cerebrospinal fluid were detected in the smooth muscle cells of pial arteries.Semi-quantitative RT-PCR indicated that the message for TRPM4 was decreased in the cerebral arteries of antisense-treated rats. Myogenic constriction was decreased by 70% to 85% in cerebral arteries isolated from TRPM4 antisense-compared with control sense-treated rats. Cerebral blood flow was significantly greater in TRPM4 antisenseversus sense-treated rats at resting and elevated mean arterial pressures, indicating that autoregulatory vasoconstrictor activity was compromised in TRPM4 antisense-treated animals. Conclusions-In vivo suppression of TRPM4 decreases cerebral artery myogenic constrictions and impairs autoregulation, thus implicating TRPM4 channels and myogenic constriction as major contributors to cerebral blood flow regulation in the living animal.

Pharmacological inhibition of TRPM4 hyperpolarizes vascular smooth muscle

“…It is also impossible to examine the acute effects and reversibility of channel inhibition using these methods. Antisense-mediated downregulation experiments suggest that TRPM4 is an important mediator of pressure-dependent (6) and protein kinase C-dependent (5) vasoconstriction and autoregulation of cerebral blood flow in vivo (18). To better understand the significance of this channel, we sought a pharmacological inhibitor that was without significant off-target effects.…”

“…Furthermore, Ca 2ϩ -activated Cl Ϫ channels are not present in cerebral artery smooth muscle (23), and swelling-activated mechanosensitive currents in these cells are dependent on cation channel activity (25). In contrast, significant evidence suggests that TRPC3, TRPC6, and TRPM4 cation currents contribute to agonist and pressureinduced membrane potential depolarization and constriction of cerebral arteries (6,18,19,24). In the presence of 9-phenanthrol, smooth muscle membrane potential in pressurized cerebral arteries is significantly hyperpolarized and myogenic tone is nearly abolished.…”

“…Antisense-mediated gene silencing has been used to demonstrate that expression of TRPM4 (5,6,18) and TRPC6 (24) channels is required for pressure-induced smooth muscle cell depolarization and myogenic vasoconstriction of cerebral arteries. TRPC3 channels mediate receptor-dependent responses in these vessels (19).…”

On Potential Interactions between Non-selective Cation Channel TRPM4 and Sulfonylurea Receptor SUR1

“…blood flow, the generation of heart rhythm, and the immune response (33)(34)(35)(36)(37)(38)(39). TRPM4-mediated currents are up-regulated in cardiomyocytes from spontaneous hypertensive rats (40), and gain-of-function mutations in TRPM4 have been associated with familial heart disease (41,42).…”

Imbalance and dysfunction of transient receptor potential channels contribute to the pathogenesis of hypertension

“…Activation of TRPM4-dependent currents contributed to myogenic vasoconstriction of cerebral arteries [45]. In vivo suppression of TRPM4 decreases cerebral artery myogenic constrictions and impairs auto-regulation, thus implicating TRPM4 channels and myogenic constriction as major contributors to cerebral blood flow regulation in the living animal [46]. Narayanan et al [47] demonstrated that TRPP2 was expressed in SMCs of resistance-size cerebral arteries and contributed to the myogenic response.…”