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In vivo suppression of TRPM4 compromises autoregulation of cerebral blood flow

The transient receptor potential channel TRPM4 is a key component of the cerebral artery myogenic response and as such should play a central role in cerebral blood flow (CBF) autoregulation. In this study, we tested the hypothesis that in vivo suppression of cerebrovascular TRPM4 channel expression compromises the maintenance of constant CBF in the face of rising mean arterial pressure (MAP). In vivo suppression of cerebrovascular TRPM4 expression was achieved by infusing sense (S) or antisense (AS) oligodeoxynucleotides (ODNs) into the cerebral spinal fluid of 350g Sprague‐Dawley rats at 280μg·day−1 for 7 days using an osmotic pump that discharged into the lateral cerebral ventricle. ODNs tagged with a fluorescent label could be visualized in confocal images of cerebral arterial smooth muscle cells isolated from arteries of treated rats indicating that the ODNs were delivered to the target tissue. Semi quantitative RT‐PCR indicated that the message for TRPM4 was decreased in the arteries following AS‐treatment. Our hypothesis was directly tested by measuring CBF in TRPM4 S‐ and AS‐treated rats using the fluorescent microsphere method. CBF was not different between S and AS‐treated rats at a MAP of 110±5 mmHg (69±4 vs. 90±19 mL·100g−1·min−1 S vs. AS, n=5). Venous infusion of noradrenaline (35μg·min−1) increased MAP to 185±10mmHg causing CBF to be increased significantly more in AS vs. S‐treated animals (295±42 vs. 190±27 mL·100g−1·min−1, n=5). Thus, in vivo suppression of TRPM4 compromised CBF autoregulation at high MAP. This suggests that TRPM4 and myogenic constriction are important for protecting the brain from overperfusion when MAP is elevated.