The current study was done to test the hypothesis that
protein kinase C (PKC) inhibitors prevent the increase in pulmonary vascular resistance and compliance that occurs in isolated, blood-perfused dog lungs during
hypoxia. Pulmonary vascular resistances and compliances were measured with vascular occlusion techniques.
Hypoxia significantly increased pulmonary arterial resistance, pulmonary venous resistance, and pulmonary capillary pressure and decreased total vascular compliance by decreasing both microvascular and large-vessel compliances. The nonspecific PKC inhibitor
staurosporine (10(-7) M), the specific PKC blocker
calphostin C (10(-7) M), and the specific PKC
isozyme blocker Gö-6976 (10(-7) M) inhibited the effect of
hypoxia on pulmonary vascular resistance and compliance. In addition, the PKC activator
thymeleatoxin (THX; 10(-7) M) increased pulmonary vascular resistance and compliance in a manner similar to that in
hypoxia, and the L-type voltage-dependent Ca(2+) channel blocker
nifedipine (10(-6) M) inhibited the response to both THX and
hypoxia. These results suggest that PKC inhibition blocks the hypoxic pressor response and that the pharmacological activation of PKC by THX mimics the hypoxic pulmonary
vasoconstrictor response. In addition, L-type voltage-dependent Ca(2+) channel blockade may prevent the onset of the
hypoxia- and PKC-induced
vasoconstrictor response in the canine pulmonary vasculature.