A role for potassium channels in smooth muscle cells and platelets in the etiology of primary pulmonary hypertension

被引:33
作者
Weir, EK
Reeve, HL
Johnson, G
Michelakis, ED
Nelson, DP
Archer, SL
机构
[1] Vet Affairs Med Ctr, Dept Med, Minneapolis, MN 55417 USA
[2] Univ Minnesota, Minneapolis, MN USA
关键词
D O I
10.1378/chest.114.3_Supplement.200S
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Plasma serotonin levels are markedly elevated in patients with primary pulmonary hypertension (PPH) and platelet levels of serotonin are low, Furthermore, plasma serotonin levels remain elevated after bilateral lung transplantation, in the absence of any pulmonary hypertension. Dexfenfluramine can cause the anorexigen-induced form of PPH that is clinically and histologically indistinguishable from PPH. We find that dexfenfluramine releases serotonin from platelets and inhibits its reuptake, These observations suggest that serotonin might be involved in, or be a marker for, the mechanism responsible for both forms of PPH. Dexfenfluramine causes inhibition of voltage-sensitive potassium (Kv) channels, membrane depolarization, and calcium entry in pulmonary artery smooth muscle cells and vasoconstriction in isolated perfused rat lungs. We have recently found that dexfenfluramine also inhibits Ky channels in megakaryocytes, the stem cell for platelets. In smooth muscle cells, taken from the pulmonary arteries of PPH patients, Ky channels appear to be dysfunctional, The underlying defect in PPH is likely to be an abnormality of one or more Ky channels in both pulmonary artery smooth muscle cells and platelets. Relatively few patients exposed to dexfenfluramine develop PPH. The factors responsible for susceptibility might be a difference in expression of potassium channels and/or a decrease in the endogenous production of nitric oxide.
引用
收藏
页码:200S / 204S
页数:5
相关论文
共 36 条
  • [1] Appetite-suppressant drugs and the risk of primary pulmonary hypertension
    Abenhaim, L
    Moride, Y
    Brenot, F
    Rich, S
    Benichou, J
    Kurz, X
    Higenbottam, T
    Oakley, C
    Wouters, E
    Aubier, M
    Simonneau, G
    Begaud, B
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1996, 335 (09) : 609 - 616
  • [2] THIOL-DEPENDENT AND NON-THIOL-DEPENDENT STIMULATIONS OF INSULIN RELEASE
    AMMON, HPT
    ABDELHAMID, M
    RAO, PG
    ENZ, G
    [J]. DIABETES, 1984, 33 (03) : 251 - 257
  • [3] ARCHER S, IN PRESS AM J RESP C
  • [4] ARCHER SL, 1986, HERZ, V11, P127
  • [5] Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia
    Archer, SL
    Huang, JMC
    Reeve, HL
    Hampl, V
    Tolarova, S
    Michelakis, E
    Weir, EK
    [J]. CIRCULATION RESEARCH, 1996, 78 (03) : 431 - 442
  • [6] ASHMORE R, 1991, AM J PHYSIOL, V260, pH1829
  • [7] BRENOT F, 1993, BRIT HEART J, V70, P537
  • [8] Valvular heart disease associated with dexfenfluramine
    Cannistra, LB
    Davis, SM
    Bauman, AG
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1997, 337 (09) : 636 - 636
  • [9] Valvular heart disease associated with fenfluramine-phentermine
    Connolly, HM
    Crary, JL
    McGoon, MD
    Hensrud, DD
    Edwards, BS
    Edwards, WD
    Schaff, HV
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1997, 337 (09) : 581 - 588
  • [10] DJABALLAH K, 1997, CIRCULATION, V96, P1