EFFECTS OF LABETALOL ON THE RELEASE OF PROSTACYCLIN AND ENDOTHELIN-1 BY CULTURED HUMAN UMBILICAL VEIN ENDOTHELIAL-CELLS AND ON THE EXCRETION OF PROSTACYCLIN AND THROMBOXANE METABOLITES IN PREECLAMPTIC PATIENTS

Objective: Labetalol reduces blood pressure primarily by blocking alph a- and beta-receptors, but other mechanisms of action may also be poss ible. We studied the effects of labetalol on the synthesis of vasodila tory prostacyclin (PGI(2)) and vasoconstrictory endothelin-1 (ET-1) by cultured human umbilical vein endothelial cells (HUVECs). We also stu died the effect of oral labetalol treatment on PGI(2) and thromboxane A(2) (TxA(2)) production in preeclamptic patients. Methods: HUVECs wer e incubated in the absence (control) and presence of labetalol (10(-8) -10(-5) mol/L) and the release of PGI(2), as measured by its metabolit e 6-keto-PGF(1 alpha), and that of ET-1, were assessed by radioimmunoa ssays. Because the presence of serum strongly affects endothelial cell function, we studied the effect of labetalol in HUVECs incubated with or without serum. In the in vivo part of the study, urine samples col lected before and during oral labetalol intake were assessed for 2,3-d inor-6-keto-PGF(1 alpha), a metabolite of PGI(2), and for 2,3-dinor-th romboxane-B-2, a metabolite of TxA(2), with high-pressure liquid chrom atography and radioimmunoassay. Results: HUVECs incubated in the prese nce of serum (10%) produced 8 times more 6-keto-PGF(1 alpha) and 5 tim es more ET-1 than HUVECs incubated without serum. Labetalol (10(-8)-10 (-5) mol/L) did not affect the production of PGI(2), although the high est labetalol level (not achievable in vivo, 10(-5) mol/L) was accompa nied by a drop in PGI(2) release in both serum-free (-21%) and serum c onditions (-14%); this was probably a sign of toxic effect. Labetalol caused no consistent change in the release of ET-1 in HUVECs. Oral lab etalol treatment did not affect urinary excretion of PGI(2) and TxA(2) metabolites. Conclusions: No clinically relevant effects of labetalol were found on endothelial cell PGI(2) or ET-1 production. Labetalol a t therapeutic doses and concentrations does not affect the production of vasoactive PGI(2) and TxA(2) in preeclamptic patients.