Extracellular HCO3- is sensed by mouse cerebral arteries: Regulation of tone by receptor protein tyrosine phosphatase γ

We investigate sensing and signaling mechanisms for H+, HCO3- and CO2 in basilar arteries using out-of-equilibriumsolutions. Selectively varying pHo, [HCO3-](o), or pCO(2), we find: (a) lowering pHo attenuates vasoconstriction and vascular smooth muscle cell (VSMC) Ca2+-responses whereas raising pHo augments vasoconstriction independently of VSMC [Ca2+](i), (b) lowering [HCO3-](o) increases arterial agonist-sensitivity of tone development without affecting VSMC [Ca2+](i) but c) no evidence that CO2 has direct net vasomotor effects. Receptor protein tyrosine phosphatase (RPTP) g is transcribed in endothelial cells, and direct vasomotor effects of HCO3o- are absent in arteries from RPTP gamma-knockout mice. At pHo 7.4, selective changes in [HCO3-](o) or pCO(2) have little effect on pHi. At pHo 7.1, decreased [HCO3-](o) or increased pCO(2) causes intracellular acidification, which attenuates vasoconstriction. Under equilibrated conditions, anticontractile effects of CO2/HCO3- are endothelium-dependent and absent in arteries from RPTP gamma-knockout mice. With CO2/HCO3- present, contractile responses to agonist-stimulation are potentiated in arteries from RPTP gamma-knockout compared to wild-type mice, and this difference is larger for respiratory than metabolic acidosis. In conclusion, decreased pHo and pHi inhibit vasoconstriction, whereas decreased [HCO3-](o) promotes vasoconstriction through RPTP gamma-dependent changes in VSMC Ca2+-sensitivity. HCO3o-serves dual roles, providing substrate for pHi-regulating membrane transporters and modulating arterial responses to acid-base disturbances.