Amplification effect and mechanism of action of ET-1 in U-46619-induced vasoconstriction in pig skin
American Journal of Physiology. Regulatory Integrative and Comparative Physiology
Pang, Cho Y., Huai Xu, Ning Huang, Christopher R. Forrest, Thé rè se M. Perré ault, and Peter C. Neligan. Amplification effect and mechanism of action of ET-1 in U-46619-induced vasoconstriction in pig skin. Am J Physiol Regulatory Integrative Comp Physiol 280: R713-R720, 2001.-The aim of this study was to investigate if a low concentration of endothelin-1 (ET-1; 8 ϫ 10 Ϫ10 M) may amplify the skin vasoconstrictor effect of other vasoactive substances in the pathogenesis of skin vasospasm. Pig
... in vasospasm. Pig skin flaps (6 ϫ 16 cm) were perfused with Krebs buffer equilibrated with 95% O 2 and 5% CO 2 at 37°C and pH 7.4. Skin perfusion pressure measured by a pressure transducer and skin perfusion assessed by the dermofluorometry technique were used for assessment of skin vasoconstriction. We observed that ET-1 (8 ϫ 10 Ϫ10 M) significantly amplified the concentrationdependent (10 Ϫ7 -10 Ϫ5 M) skin vasoconstrictor effect of norepinephrine. More importantly, we observed for the first time that this low concentration of ET-1 also amplified the concentration-dependent (10 Ϫ8 -10 Ϫ6 M) skin vasoconstrictor effect of the thromboxane A 2 mimetic U-46619, and this amplification effect of ET-1 was completely blocked by the protein kinase C (PKC) inhibitor chelerythrine (5 ϫ 10 Ϫ6 M). Conversely, the PKC activator phorbol 12,13-dibutyrate (10 Ϫ7 M) amplified the vasoconstrictor effect of U-46619. Furthermore, the sensitivity of the skin vasculature to the vasoconstrictor effect of extracellular Ca 2ϩ in U-46619-induced skin vasoconstriction was significantly enhanced in the presence of 8 ϫ 10 Ϫ10 M ET-1. Finally, the cyclooxygenase inhibitor indomethacin (5 ϫ 10 Ϫ6 M) did not affect the amplification effect of ET-1 on U-46619-induced skin vasoconstriction. We conclude that a low concentration of ET-1 can amplify the skin vasoconstrictor effect of U-46619 independent of endogenous cyclooxygenase products, and the mechanism may involve activation of PKC and increase in sensitivity of the contractile apparatus to Ca 2ϩ in smooth muscle cells.