Regulation of calcium-activated potassium channels by blood breakdown products

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DESCRIPTION (provided by applicant): Many of us will be eventually afflicted with vascular disorders, such as hypertension and brain hemorrhage. Cerebral hemorrhage is often followed by delayed cerebral vasospasm, which itself represents a significant morbidity and mortality factor. Cerebral vasospasm is characterized by a long-lasting abnormal contraction of vascular smooth muscle cells. Previous studies have suggested that blood breakdown products, such as heme, CO, bilirubin and bilirubin oxidation end products (BOXes), may be involved but the underlying mechanism has remained elusive. Among the many proteins involved in regulation of vascular smooth muscles, large-conductance calcium- and voltage-activated (Slo1 BK) potassium channels play a critical role in vascular relaxation. The importance of Slo1 channels in regulation of vascular tone suggests that many disorders of vascular relaxation, including cerebral vasospasm, may involve dysregulation of Slo1 channels. Because bilirubin and bilirubin oxidation end products are implicated in vasospasm and Slo1 channels play a critical role in regulation of vascular tone, we hypothesize that heme catabolic products may contribute to cerebral vasospasm by modulating Slo1 channels. To test this hypothesis, effects of heme catabolic products (CO, bilirubin and bilirubin oxidation end products) on the Slo1 channel function are electrophysiologically and quantitatively investigated using macroscopic and single-channel ionic current and macroscopic gating current measurements. These biophysical measurements are complemented with physiological isometric force measurements using aortic blood vessels from wild-type and Slo1 knockout mice. The results expected from the research program proposed will establish a new paradigm of CO sensing by Slo1 and will highlight Slo1 channels as an important causal link between cerebral hemorrhage and cerebral vasospasm. These novel conceptual frameworks in turn suggest new therapeutic strategies for disorders of vascular relaxation including delayed cerebral vasospasm.