Effects of inhibitors of protein kinase C and phosphodiesterase on the contractile effects of endothelin in dog femoral artery

Endothelin-induced contraction in dog femoral artery strips was relaxed by a protein kinase C inhibitor (MDL 27,032), cyclic nucleotide phosphodiesterase (PDE) inhibitors (enoximone, piroximone, rolipram, 3-isobutyl-1-methylxanthine), an adenylcyclase activator (forskolin), a guanylcyclase activator (nitroprusside), but only slightly relaxed by a calcium channel blocker (nifedipine).

Endothelin-induced contractions were effectively relaxed by MDL 27,032, but were only slightly antagonized by nifedipine. Endothelin lost its contractile effect in the absence of external calcium whereas phorbol 12, 13-dibutyrate produced a contractile effect in the presence or absence of external calcium. Thus, endothelin-induced contraction requires external calcium ions which may enter vascular smooth muscle cells through nifedipine resistant channels. Endothelin-induced contraction also appears to involve activation of protein kinase C. PDE inhibitors, forskolin and nitroprusside all antagonized the contractile effect of endothelin in femoral arteries.

These results indicate that protein kinase C inhibitors and compounds which increase cyclic nucleotide levels can be used to antagonize the vasoconstriction produced by endothelin.