Role of endothelial nitric oxide and smooth muscle potassium channels in cerebral arteriolar dilation in response to acidosis

Background and Purpose - Potassium channels or nitric oxide or both are major mediators of acidosis-induced dilation in the cerebral circulation. However, these contributions depend on a variety of factors such as species and vessel location. The present study was designed to clarify whether potassium channels and endothelial nitric oxide are involved in acidosis-induced dilation of isolated rat cerebral arterioles. Methods - Cerebral arterioles were cannulated and monitored with an inverted microscope. Acidosis (pH 6.8 to 7.4) produced by adding hydrogen ions mediated dilation of the cerebral arterioles in a concentration-dependent manner. The role of nitric oxide and potassium channels in response to acidosis was examined with several specific inhibitors and endothelial damage. Results - The dilation was significantly inhibited by potassium chloride (30 mmol/L) and glibenclamide (3 μmol/L; ATP-sensitive potassium channel inhibitor). We found that 30 μmol/L BaCl₂ (concentration-dependent potassium channel inhibitor) also affected the dilation; however, an additional treatment of 3 μmol/L glibenclamide did not produce further inhibition. Tetraethylammonium ion (1 mmol/L; calcium-activated potassium channel inhibitor) and 4-aminopyridine (100 μmol/L; voltage-dependent potassium channel inhibitor) as well as ouabain (10 μmol/L; Na-K ATPase inhibitor) and N-methylsulphonyl-6-(2-proparglyloxyphenyl) hexanamide (1 μmol/L; cytochrome P450 epoxygenase inhibitor) did not alter acidotic dilation. N^ω-Monomethyl-L-arginine (10 μmol/L) and N^ω-nitro-L-arginine (10 μmol/L) as nitric oxide synthase inhibitor blunted the dilation. Furthermore, the dilation was significantly attenuated after the endothelial impairment. Additional treatment with glibenclamide (3 μmol/L) further reduced the dilation in response to acidosis. Conclusions - Endothelial nitric oxide and smooth muscle ATP-sensitive potassium channels contribute to acidosis-induced dilation of rat cerebral arterioles. Endothelial damage caused by pathological conditions such as subarachnoid hemorrhage or traumatic brain injury may contribute to reduced blood flow despite injury-induced cerebral acidosis.