Toluene is a cerebral artery constrictor acting via BK channels

Acute intoxication by toluene usually follows intentional inhalation to achieve a "high", which may lead to repeated use due to toluene's reinforcing properties. In both acute and chronic intoxication brain function is primarily affected. Neuronal and glial elements participate in toluene's reinforcing properties and chronic toxicity, yet the targets underlying acute toxicity remain unknown. Many signs of toluene's acute toxicity overlap with those of brain ischemia. Moreover, two studies in humans who abused toluene reveal brain hypoperfusion in middle cerebral artery (MCA) territories. Hypoperfusion, however, may result from either excessive vasoconstriction/increased vasodilation. Using rat and mouse models, we demonstrate that toluene at concentrations reached during recreational inhalation (8000 ppm) significantly decreases (-8%) MCA diameter in vivo in male and female animals. Using GC-MS, we determined toluene blood levels from inhalation (0.09-127 mM) and then show that <1 mM toluene constricts ex vivo-pressurized MCA independently of endothelium. Toluene action is blunted by deletion of KCNMA1, which codes for BK channels, key regulators of MCA diameter, and upon selective channel blockade by 1 μM paxilline. Lastly, when applied onto an isolated membrane patch several minutes after patch-excision from the SM cell, submM toluene reduces mildly yet statistically significantly (P < 0.05) both steady-state activity (-15%) and unitary current amplitude (-20%) of MCA myocyte BK channels. Thus, BK channels themselves and their immediate proteolipid microenvironment suffice for these drug actions. Collectively, data unveil a direct inhibition of MCA myocyte BK currents by intoxicating levels of toluene, which determines, or at least contributes to, MCA constriction by toluene levels reached during inhalation by humans who suffer acute brain intoxication.