Inhibition of K(+) channel activity in human pulmonary artery smooth muscle cells by serum from patients with pulmonary hypertension secondary to congenital heart disease.
Activity of K(+) channels regulates cytosolic free Ca(2+) concentration by controlling membrane potential. A rise in cytosolic free Ca(2+) concentration in pulmonary artery smooth muscle cells (PASMC) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. Whether serum from children with pulmonary hypertension (PH) secondary to congenital cardiopulmonary diseases contains a factor(s) that inhibits K(+) channel function in PASMC was investigated using patch clamp techniques. PASMC isolated from normal subjects were cultured in media containing 5% serum from normotensive (NPH) or PH patients. Cell growth rate and the currents through voltage-gated K(+) channels were determined and compared between the cells treated with serum from NPH and PH patients. In the absence of growth factors, incubation of PASMC in media containing NPH serum for 48 h increased cell numbers by 2.5-fold, whereas incubation of the cells in media containing PH serum increased cell numbers by 4.5-fold (p < 0.001). Amplitude of whole-cell voltage-gated K(+) currents in NPH serum-treated cells (1119 +/- 222 pA at +80 mV, n = 43) was 3.5-fold greater than in PH serum-treated cells (323 +/- 34 pA, n = 43, p < 0.001). Consistently, membrane potential was much more depolarized in PASMC treated with PH serum (-28 +/- 2 mV, n = 29) than cells treated with NPH-serum (-47 +/- 2 mV, n = 28; p < 0.001). These results suggest that a circulating mitogenic agonist, which induces membrane depolarization by inhibiting voltage-gated K(+) channel activity in PASMC, may be produced or up-regulated in pediatric patients with secondary PH.
Limsuwan
A
A
Division of Pulmonary and Critical Care Medicine, University of California School of Medicine, San Diego, California 92103-8382, USA.
Platoshyn
O
O
Yu
Y
Y
Rubin
L J
LJ
Rothman
A
A
Yuan
J X
JX
D001769:Blood; D002455:Cell Division; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D006331:Heart Diseases / Q000150:complications* / Q000151:congenital*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000209:etiology / Q000503:physiopathology; D007223:Infant; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000503:physiopathology*; D026902:Potassium Channel Blockers; D011651:Pulmonary Artery / Q000166:cytology / Q000503:physiopathology*
D026902:Potassium Channel Blockers