Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include
pulmonary hypertension and right
heart failure. Concomitant production of proinflammatory mediators during
hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute
hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory
cytokines via a
protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during
hypoxia in the presence and absence of the PKC inhibitors
calphostin C or
chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator
thymeleatoxin for 60 min. After
hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to
mRNA analysis for
TNF-alpha and IL-1beta via RT-PCR. Our results showed that, in isolated pulmonary arteries,
hypoxia caused a biphasic contraction and increased expression of
TNF-alpha and IL-1beta
mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of
TNF-alpha and IL-1beta
mRNA. These findings suggest that
hypoxia induces the expression of inflammatory
cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application.