Pinacidil induces vascular dilation and hyperemia in vivo and does not impact biophysical properties of neurons and astrocytes in vitro
ABSTRACT
Vascular and neural systems are highly interdependent, as evidenced by the wealth of intrinsic modulators shared by the two systems. We tested the hypothesis that pinacidil, a selective agonist for the SUR2B receptor found on smooth muscles, could serve as an independent means of inducing vasodilation and increased local blood volume to emulate functional hyperemia. Application of pinacidil induced vasodilation and increased blood volume in the in vivo neocortex in anesthetized rats and awake mice. Direct application of this agent to the in vitro neocortical slice had no direct impact on biophysical properties of neurons or astrocytes assessed with whole-cell recording. These findings suggest that pinacidil provides an effective and selective means for inducing hyperemia in vivo, and may provide a useful tool in directly testing the impact of hemodynamics on neural activity, as recently predicted by the hemo-neural hypothesis.
DISCUSSION
Pinacidil provides an effective means of inducing vasodilation in vivo. At concentrations less than 400 μM, pinacidil is also selective for cortical vascular smooth muscle, exhibiting no direct effect on intrinsic properties of neurons or astrocytes. As an independent means to induce increased vasodilation and blood volume in a manner analogous to that seen in functional hyperemia, pinacidil provides a viable method for testing the impact of hyperemic events on neural or astrocytic activity. Pinacidil may also be a selective means of emulating other normal hemodynamic phenomena and could have therapeutic applications, such as targeted administration of pinacidil in response to acute vessel obstruction to maintain sufficient perfusion.
The hemodynamic effects induced by pinacidil are similar to natural functional hyperemia. In SI during sensory stimulation in rodents, increases in total oxygenated hemoglobin during sensory stimulation— analogous to our measurement of cortical darkening at 550 nm—peak in a range of 2% to 5%,20–22 and arteries/arterioles dilate 10% to 20%.23 The time course of pinacidil’s effects also parallels the sustained response to continued sensory drive. Arterial diameter in rodent SI and the blood oxygen level–dependent response on functional magnetic resonance imaging in humans and rodents remain high when tactile input is sustained for periods lasting tens of seconds,23,24 as they do under pinacidil application.
Although pinacidil represents an important step forward in our ability to control blood flow while probing the impact of hemodynamics in cortex, it has limitations. The drug is only capable of producing vasodilation; drugs in the same family that block the SUR2B channels to create vasoconstriction (such as diazoxide or glibenclamide) or thromboxane receptor agonists18,25,26 are unfortunately known to be nonspecific, affecting neurons as well as blood vessels. Pinacidil is also not water-soluble, requiring its dissolution in ethanol or DMSO, agents that can have confounding impacts on the system. Applied in vivo, pinacidil also does not appear to wash out fully, or its impact on smooth muscles persists, so that the first trial in each animal is the most consistent and effective one. These limitations stated, this pharmacological approach nevertheless represents a unique means of selective hyperemia induction in vivo.
