Contribution of Rho kinase to TRPM4‐mediated myogenic tone in cerebral parenchymal arterioles (841.5)

Abstract

Cerebral parenchymal arterioles (PAs) play a critical role in assuring appropriate blood flow and perfusion pressure within the brain. PAs are unique in contrast to cerebral pial arteries, as defined by their critical roles in neurovascular coupling and distinct sensitivities to mechanical and chemical stimulants. Elevation in intraluminal pressure, a physiologic vasomotor stimulant, causes smooth muscle membrane depolarization and contraction (myogenic tone) in cerebral arteries. However, the mechanisms by which this myogenic tone is regulated in the cerebral microcirculation remain unclear. Prior research in our laboratory indicates that myogenic tone of PAs is mediated primarily through stimulation of mechano‐sensitive P2Y purinergic receptors. The objective of the present study was to determine the roles of TRPM4 channels and Rho kinase signaling in PA myogenic tone. We show that suppression of TRPM4 channel expression in vivo using antisense oligonucleotides reduced (by ~40%) both myogenic and P2Y‐receptor agonist‐induced tone in PAs. Further, we found that the Rho kinase inhibitor H1152 reversibly and nearly completely inhibited myogenic tone in these brain arterioles (IC50:0.2 µM). H1152 (1 µM) also attenuated P2Y4 and P2Y6 receptor‐mediated vasoconstriction by 85% and 87%, respectively. Finally, H1152 (1 μM) reduced constitutive and UTPγS (0.5 μM)‐activated TRPM4 currents in parenchymal myocytes by 61% and 75%, respectively. These results indicate an important role for Rho kinase in regulation of TRPM4 channel activity and myogenic tone in the cerebral microcirculation.Grant Funding Source: Supported by NIH HL095488