Abstract
ObjectiveIn vascular biology, endothelial KCa2.3 and KCa3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of KCa2.3 and KCa3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of KCa2.3 and KCa3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension.Approach and ResultMale wild type and KCa3.1−/−/KCa2.3T/T(+DOX) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The KCa3.1−/−/KCa2.3T/T(+DOX) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the KCa2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the KCa2.3 and KCa3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of KCa2.3 and KCa3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype.ConclusionDespite the deficits of the KCa2.3 and KCa3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of KCa2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of KCa2.3/KCa3.1 activators for the treatment of pulmonary hypertension.
Highlights
Pulmonary hypertension is a disabling disease with increased blood pressure in the pulmonary circulation, resulting in shortness of breath, dizziness, edema, right ventricular hypertrophy, heart failure, and premature death
Despite the deficits of the KCa2.3 and KCa3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of KCa2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of KCa2.3/KCa3.1 activators for the treatment of pulmonary hypertension
Endothelium-dependent relaxation involves the release of a variety of diffusible relaxing factors such as nitric oxide (NO) [2,3], prostacyclin [4], CYP450-generated epoxyeicosanoids acids (11,12-EET and 14,15-EET) [5,6,7], and an electrical mechanism known as endothelium-derived hyperpolarization (EDH) [8,9,10] that produces hyperpolarization of the underlying smooth muscle and closure of voltage-gated calcium channels
Summary
Pulmonary hypertension is a disabling disease with increased blood pressure in the pulmonary circulation, resulting in shortness of breath, dizziness, edema, right ventricular hypertrophy, heart failure, and premature death. In line with the roles of the two channels in endothelial function, KCa3.12/2 mice have been reported to have moderately elevated blood pressure [19] and to develop mild left ventricular hypertrophy, as well as a pronounced defect of endothelium-dependent acetylcholine-induced relaxation in both carotid artery and resistance vessels [19,20]. Combined KCa3.1- and KCa2.3 channel deficiency in transgenic doxycycline-treated KCa3.12/2/ KCa2.3T/T(+DOX) mice has been reported to increase blood pressure, reduce hyperpolarization of endothelial cells, and to reduce acetylcholine-induced relaxation in carotid arteries and resistance arteries, the combined deficiency of the two channels has no additive effects on blood pressure [22]. While the roles of the KCa2.3- and the KCa3.1 channels have been at least partially elucidated for systemic blood pressure control [19,21,22,23], the precise role of the channels in the pulmonary circulation is still unclear
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