Intravascular Pressure Augments Cerebral Arterial Constriction by Inducing Voltage‐Insensitive Ca2+ Waves

This study examined whether elevated intravascular pressure stimulates asynchronous Ca 2+ waves and if their generation contributes to myogenic tone development. Rat cerebral arteries were mounted in an arteriograph, pressurized (20–100 mmHg) and examined under a variety of experimental conditions. Diameter and membrane potential (V M ) were monitored using conventional techniques; Ca 2+ wave generation and myosin light chain (MLC 20 )/MYPT1 phosphorylation were assessed by confocal microscopy and western blot analysis, respectively. Elevating intravascular pressure increased the proportion of smooth muscle cells firing Ca 2+ waves as well as event frequency. Ca 2+ wave augmentation occurred primarily at lower intravascular pressures and ryanodine, an agent that depletes the sarcoplasmic reticulum (SR), eliminated these events. Ca 2+ wave generation was voltage‐insensitive as Ca 2+ channel blockade and perturbations in extracellular [K + ] had little effect on measured parameters. Ryanodine‐induced inhibition of Ca 2+ waves attenuated myogenic tone and MLC 20 phosphorylation without altering arterial V M . Thapsigargin also attenuated Ca 2+ waves, pressure‐induced constriction and MLC 20 phosphorylation. The SR‐driven component of the myogenic response was proportionally greater at lower intravascular pressures and subsequent MYPT1 phosphorylation measures revealed that SR Ca 2+ waves facilitate pressure‐induced MLC 20 phosphorylation through mechanisms that include myosin light chain phosphatase inhibition. Our findings show that mechanical stimuli augment Ca 2+ wave generation and that these transient events facilitate tone development particularly at lower intravascular pressures by providing a proportion of the Ca 2+ required to directly control MLC 20 phosphorylation.