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Intermittent hypoxia increases ET‐1 vasoconstrictor sensitivity through increased PKC‐dependent Ca‐sensitization
Author(s) -
Allahdadi Kyan J.,
Walker Benjimen R.,
Kanagy Nancy L.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a790
Subject(s) - constriction , vasoconstriction , protein kinase c , mesenteric arteries , medicine , endocrinology , vascular smooth muscle , hypoxia (environmental) , chemistry , hypoxic pulmonary vasoconstriction , endothelin 1 , anatomy , phosphorylation , receptor , artery , smooth muscle , oxygen , biochemistry , organic chemistry
We previously observed that in mesenteric arteries from intermittent hypoxia‐induced (IH) hypertensive rats endothelin‐1 (ET‐1) constriction is augmented compared to constriction in Sham arteries. Furthermore, in Sham arteries, ET‐1 constriction was accompanied by increases in vessel wall [Ca 2+ ] but in IH arteries, constriction occurred without increases in [Ca 2+ ]. Thus IH appears to augment ET‐1 constriction by increasing vascular smooth muscle Ca‐sensitizing pathways. We hypothesized that IH increased ET‐1 activation of either protein kinase C (PKC) or Rho associated kinase (ROK) to augment Ca‐sensitivity. We observed that ROK inhibition (Y‐27632, 3 μM) attenuated ET‐1 constriction slightly more in IH arteries than in Sham arteries (IH 80±3, Sham 89±4 % control ET‐1 constriction). However, PKC inhibition (GF‐109203x, 3 μM) greatly attenuated ET‐1 mediated constriction in IH arteries but did not affect ET‐1 constriction in Sham arteries (IH 50±3*, Sham 98±4 % control ET‐1 constriction, * P <0.05). This suggests that IH greatly increases ET‐1 activation of PKC‐mediated constriction and slightly increases ET‐1 activation of ROK‐dependent constriction. Western analysis suggested that there is a tendency for PKC‐α expression to be increased in IH mesenteric arteries compared to Sham but the difference was not significant ( P = 0.33). Therefore augmented ET‐1 vasoconstriction in IH arteries is mediated almost exclusively through Ca‐sensitization with a large contribution by PKC activation that appears to be independent of IH‐induced increases PKC‐α expression. (Supported by AHA Established Investigator award and EPA RD‐83186001, NLK)