ENDOTHELIN-1 POTENTIATES ADP-INDUCED PLATELET-AGGREGATION IN CHRONIC-RENAL-FAILURE

The effect of preincubation of heparinized whole blood with endothelin -1 (ET-1) on the ADP (adenosine diphosphate) and epinephrine-induced p latelet aggregation was examined in 20 healthy donors compared with 20 patients with chronic renal failure (CRF). ET-1 significantly stimula ted ADP-induced aggregation in CRF: EC (effective concentration)(25) = 2.3 +/- 0.20 with ET-1 vs. 2.7 +/- 0.22 mu mol/L without ET-1; EC(50) : 3.8 +/- 0.18 with ET-1 vs. 4.4 +/- 0.24 mu mol/L without ET-1; and E C(75): 5.7 +/- 0.22 with ET-1 vs. 6.4 +/- 0.21 mu mol/L without ET-1. In healthy donors only the EC(25) was significantly increased: EC(25) = 2.5 +/- 0.13 with ET-1 vs. 2.8 +/- 0.20 mu mol/L without ET-1. No si gnificant influence of ET-1 in epinephrine-induced aggregation was obs erved in CRF or in healthy donors. The basal values of determined ET-1 were significantly elevated in CRF: 6.99 +/- 0.29 pmol/mL vs. 5.65 +/ - 0.33 pmol/mL in healthy donors. The high endogenous level of ET-1 in CRF patients together with an observed higher endogenous plasma level of cAMP (58 +/- 5.2 nmol/L compared to 29 +/- 2.0 nmol/L in healthy d onors) may explain the enhanced pharmacological interaction of ET-1 an d ADP in CRF patients. The data suggest that positive agonist interact ion between ET-1 and ADP may result from effects on the concentrations of cAMP within the platelet rather than from direct interaction on th e membrane receptors or the transmembrane coupling mechanisms. Our res ults demonstrate an in vitro effect of high-dose ET-1 on platelet func tion in whole blood, which is enhanced in patients with CRF.