EFFECTS OF ENDOTHELINS, BAY-K-8644 AND OTHER OXYTOCICS IN NONPREGNANT AND LATE PREGNANT RAT ISOLATED UTERUS

Endothelins 1, 2 and 3 (ET-1, ET-2 and ET-3; 1-30 nM) caused long-lasting concentration-dependent tonic contractions of uterine strips from non-pregnant rats. The potency of ET-1 (EC50 7 nM) was similar to that of angiotensin II (AII) and greater than that of ET-2 or ET-3 (EC50s greater-than-or-equal-to 10 nM), bradykinin, Bay K 8644, oxytocin (OT), 5-hydroxytryptamine, prostaglandin F2-alpha (PGF2-alpha) or acetylcholine. Strips from 21-day pregnant rats were 2- to 3-fold more sensitive to ET-1, AII, OT and PGF2-alpha and 200-fold more sensitive to Bay K 8644 than non-pregnant preparations. The development of tonic responses to ET-1 (30 nM) and of phasic-rhythmic ones to Bay K 8644 (300 nM) was fully prevented in strips from non-pregnant rats bathed in Ca2+-free medium, but stepwise reintroduction of Ca2+ (0.03-3 mM) to the solution allowed the manifestation of contractions in response to both agonists. Responses to ET-1 required less Ca2+ than those to Bay K 8644. Strips challenged with ET-1 while in Ca2+-free medium developed greater contractions upon reintroduction of Ca2+ than preparations stimulated with the peptide in normal medium. The reverse occurred with Bay K 8644-induced contractions. Nicardipine (10 nM) abolished the responses of strips from non-pregnant rats to Bay K 8644 (300 nM), but only attenuated ET-1-induced (30 nM) contraction. A subthreshold concentration of ET-1 (0.3 nM) augmented the responses to PGF2-alpha or 5-HT and to AII in preparations taken from non-pregnant and pregnant rats. Thus, ET-1 is one of the most powerful known constrictors of the rat isolated uterus. Its action is enhanced during late pregnancy and is mediated by a mechanism distinct from that of Bay K 8644. It is suggested that ETs may play significant roles in the control of uterine contractility.