Vascular smooth muscle BK channels limit ouabain-induced vasocontraction: Dual role of the Na/K-ATPase as a hub for Src-kinase and the Na/Ca-exchanger.

Large-conductance, calcium-activated potassium channels (BK channels) and the Na/K-ATPase are expressed universally in vascular smooth muscle. The Na/K-ATPase may act via changes in the intracellular Ca2+ concentration mediated by the Na/Ca exchanger (NCX) and via Src kinase. Both pathways are known to regulate BK channels. Whether BK channels functionally interact in vascular smooth muscle cells with the Na/K-ATPase remains to be elucidated. Thus, this study addressed the hypothesis that BK channels limit ouabain-induced vasocontraction. Rat mesenteric arteries were studied using isometric myography, FURA-2 fluorimetry and proximity ligation assay. The BK channel blocker iberiotoxin potentiated methoxamine-induced contractions. The cardiotonic steroid, ouabain (10-5 M), induced a contractile effect of IBTX at basal tension prior to methoxamine administration and enhanced the pro-contractile effect of IBTX on methoxamine-induced contractions. These facilitating effects of ouabain were prevented by the inhibition of either NCX or Src kinase. Furthermore, inhibition of NCX or Src kinase reduced the BK channel-mediated negative feedback regulation of arterial contraction. The effects of NCX and Src kinase inhibition were independent of each other. Co-localization of the Na/K-ATPase and the BK channel was evident. Our data suggest that BK channels limit ouabain-induced vasocontraction by a dual mechanism involving the NCX and Src kinase signaling. The data propose that the NCX and the Src kinase pathways, mediating the ouabain-induced activation of the BK channel, act in an independent manner.

Clinical and imaging manifestations of intracerebral hemorrhage in brain tumors and metastatic lesions: a comprehensive overview.

PURPOSE: This observational study aims to provide a detailed clinical and imaging characterization/workup of acute intracerebral hemorrhage (ICH) due to either an underlying metastasis (mICH) or brain tumor (tICH) lesion. METHODS: We conducted a retrospective, single-center study, evaluating patients presenting with occult ICH on initial CT imaging, classified as tICH or mICH on follow-up MRI imaging according to the H-Atomic classification. Demographic, clinical and radiological data were reviewed. RESULTS: We included 116 patients (tICH: 20/116, 17.24%; mICH: 96/116, 82.76%). The most common malignancies causing ICH were lung cancer (27.59%), malignant melanoma (18.10%) and glioblastoma (10.34%). The three most common stroke-like symptoms observed were focal deficit (62/116, 53.45%), dizziness (42/116, 36.21%) and cognitive impairment (27/116, 23.28%). Highest mICH prevalence was seen in the occipital lobe (mICH: 28.13%, tICH: 0.00%; p = 0.004) with tICH more in the corpus callosum (tICH: 10.00%, mICH: 0.00%; p = 0.029). Anticoagulation therapy was only frequent in mICH patients (tICH: 0.00%, mICH: 5.21%; p = 0.586). Hemorrhage (tICH: 12682 mm3, mICH: 5708 mm3, p = 0.020) and edema volumes (tICH: 49389 mm3, mICH: 20972 mm3, p = 0.035) were significantly larger within tICH patients. CONCLUSION: More than half of the patients with neoplastic ICH exhibited stroke-like symptoms. Lung cancer was most common in mICH, glioblastoma in tICH. While clinical presentations were similar, significant differences in tumor location and treatments were discernible.

External validation of the diagnostic value of perihematomal edema characteristics in neoplastic and non-neoplastic intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Neoplastic intracerebral hemorrhage (ICH) may be incorrectly identified as non-neoplastic ICH on imaging. Relative perihematomal edema (relPHE) on computed tomography (CT) has been proposed as a marker to discriminate neoplastic from non-neoplastic ICH but has not been externally validated. The purpose of this study was to evaluate the discriminatory power of relPHE in an independent cohort. METHODS: A total of 291 patients with acute ICH on CT and follow-up magnetic resonance imaging (MRI) were included in this single-center retrospective study. ICH subjects were dichotomized into non-neoplastic or neoplastic ICH based on the diagnosis on the follow-up MRI. ICH and PHE volumes and density values were derived from semi-manually segmented CT scans. Calculated PHE characteristics for discriminating neoplastic ICH were evaluated using receiver-operating characteristic (ROC) curves. ROC curve-associated cut-offs were calculated and compared between the initial and the validation cohort. RESULTS: A total of 116 patients (39.86%) with neoplastic ICH and 175 (60.14%) with non-neoplastic ICH were included. Median PHE volumes, relPHE, and relPHE adjusted for hematoma density were significantly higher in subjects with neoplastic ICH (all p values <0.001). ROC curves for relPHE had an area under the curve (AUC) of 0.72 (95% confidence interval [CI] 0.66-0.78) and an AUC of 0.81 (95% CI 0.76-0.87) for adjusted relPHE. The cut-offs were identical in the two cohorts, with >0.70 for relPHE and >0.01 for adjusted relPHE. CONCLUSIONS: Relative perihematomal edema and adjusted relPHE accurately discriminated neoplastic from non-neoplastic ICH on CT imaging in an external patient cohort. These results confirmed the findings of the initial study and may improve clinical decision making.