Intermittent hypoxia increases ET‐1 vasoconstrictor sensitivity through increased PKC‐dependent Ca‐sensitization

Abstract

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 [Ca2+] but in IH arteries, constriction occurred without increases in [Ca2+]. 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)