Endothelin-1 (ET-1), the most potent vasoconstrictor peptide in nature, is involved in systemic and pulmonary hypertension and in closure of the ductus arteriosus in neonates. Heparin, a heterogeneous glycosaminoglycan, suppresses the production of ET-1 in human unbilical vein cultured endothelial cells(HUVEC). We have shown that the most negatively charged fractions of heparin have the highest ET-1-suppressive activity. This effect of heparin is independent of size, down to 2,400 daltons (octasaccharide).

The purpose of this study is to evaluate the suppression of ET-1 by heparin disaccharides which differ in number and position of sulfate groups. These disaccharides were incubated with HUVEC for 48 hr at 37° C. [ET-1] in the media was measured by radioimmunoassay and divided by cell number. Results are expressed as percent of control without heparin. Significance was determined by ANOVA, followed by the Bonferonni multiple comparison test. The disaccharides consist of a uronic acid (U) moiety and a glucosamine (G) moiety with sulfates at the following positions: SØ = no sulfate, S2 = sulfate on position 2, S6 = sulfate on position 6. Results are presented in the table.

Table 1 No caption available.
Full size table

These data show that all the disaccharides significantly suppress ET-1 production by HUVEC. Since these disaccharides are devoid of anticoagulant activity, they may be clinically useful in regulating persistent pulmonary hypertension of the newborn and systemic hypertension.