ENDOTHELIN-INDUCED CONTRACTIONS IN HUMAN PLACENTAL BLOOD-VESSELS ARE ENHANCED IN INTRAUTERINE GROWTH-RETARDATION, AND MODULATED BY AGENTS THAT REGULATE LEVELS OF INTRACELLULAR CALCIUM

Endothelin-1 (ET-1) is a strongly vasoactive polypeptide that may be i nvolved in the regulation of the uteroplacental blood flow. In the pre sent study we have examined the contractile response to ET-1 in human placental arteries in the presence of several agents that interfere wi th storage of intracellular calcium, e.g. caffeine, ryanodine and thap sigargin. We have also compared the contractile response to ET-1 in no rmal pregnancies with that of patients with foetal intrauterine growth retardation (IUGR), a condition with reduced uteroplacental blood flo w. We found that the response to ET-1 in the placental arteries from w omen with normal pregnancies was reduced by 20% in the absence of extr acellular calcium. Caffeine relaxed the basal tone of the vessels and reduced the contractile response to ET-1 by 51%. Nifedipine in additio n to caffeine resulted in a reduction of 70%. Ryanodine also reduced t he tone. Thapsigargin had no effect on the placental arteries at lower concentrations, but gave a progressive and slow contraction at 10(-6) M. The ET-1 induced contraction in placental arteries from IUGR patie nts was 67% more potent than in placental arteries from women with nor mal pregnancies, 129% as compared with 77% of the maximal K+-induced c ontraction. We conclude that the ET-1-induced contractile response in the human placental artery is dependent on influx of extracellular cal cium as well as mobilization of calcium from intracellular stores. An increased sensitivity to ET-1 in placental arteries may contribute to the reduced uteroplacental blood flow in intrauterine growth retardati on.