The effect of endothelin-1 (ET-1) and protein kinase C (PKC) inhibitor- chelerithrin on DNA synthesis in vascular smooth muscle cells (VSMC) from young SHR and WKY rats.

ET-1 is a vasoactive peptide produced by endothelial cells. ET-1 has a vasoconstrictive and mitogenic effect upon VSMC, and it may play a role in the pathogenesis of hypertension and atherosclerosis. Its mitogenic activity is mediated by PKC. : To determine the responsiveness of VSMCʹs from young SHR and WKY rats to the mitogenic effect of ET-1 and the effect of PKC inhibitor- Chelerithrin (Chel). VSMCʹs from aortas of young SHR and WKY rats (1-3 weeks old) were grown in microplates for 24 and 48 hours. Then, they were incubated in the presence of different concentrations of ET-1 (0.1- 100 nM) for 24 hours. VSMCʹs were incubated for different times (1-4 hours) with ET-1 in the presence of different concentrations of chelerithrin (0-10 nM). The rate of DNA synthesis was examined by incorporation of labeled thymidine to DNA of VSMCʹs. Increasing concentrations of ET-1 dose dependently increased thymidine incorporation to DNA. There was no difference in thymidine incorporation between SHR and WKY VSMCʹs incubated for 24 and 48 hours. No difference was found between VSMSʹs from SHR and WKY rats incubated with ET-1 for 1,2,3, and 4 hours in SHR and WKY rats. Incubation for 1 hour caused maximal mitogenic effect. Chel caused a dose dependent inhibition of the stimulatory effect of ET-1 in VSMCʹs from SHR and WKY rats. VSMCʹs from SHR were significantly more susceptible to the inhibitory effect of Chel in comparison with VSMCʹs from WKY rats. ET-1 exerts a similar mitogenic effect on VSMCʹs from aortas from SHR and WKy rats. Stimulation with ET-1 for 1 hour is sufficient to cause an almost maximal stimulatory effect. PKC inhibitor-Chel. causes a dose-dependent inhibition of the stimulatory effect of ET-1 in both strains, although VSMCʹs from SHR are more susceptible to inhibition.