No abstract

1The aim of the present study was to characterize pharmacologically endothelin receptors that are present in human umbilical vessels. 2 Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC5o 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). IRL1620 is inactive in both vessels. The order of potency of agonists is suggestive of a typical ETA receptor in the artery (ET-1 = ET-2 > > ET-3) and a mixture of ETA and ETB receptors in the vein (ET-1 = ET-2> ET-3). 3 The selective ETA receptor antagonist, BQ123, competitively inhibits the effect of ET-1 in the human umbilical artery (pA2 6.9), while in the vein, only a mixture of BQ123 and BQ788 (a selective ETB antagonist) weakly displaces to the right the cumulative concentration-response curve to ET-1. Contractions induced by ET-3 in the vein are inhibited by BQ788 (pA2 7.6), but not by BQ123.4 Inhibition of Ca21 channels by nifedipine (0.1 ,uM) is accompanied by a significant decrease of the maximal response to ET-1 by 40% in the artery and by 30% in the vein. The response of the vein to ET-3 is almost abolished by nifedipine. 5 The results indicate that: (i) endothelins contract the human isolated umbilical artery via stimulation of an ETA receptor type; (ii) the contraction induced by ET-1 in the vein is mediated by both ETA and ETB receptors, while ET-3 stimulates the ETB receptor; (iii) the contribution of Ca21 channels to the contraction mediated by the ETB receptor appears to be more important than to that mediated by the ETA receptor.

No abstract

The pharmacodynamic features of the new nonpeptide kinin B2 receptor antagonist FR 173657 were evaluated on pig, rabbit, guinea pig, and human native kinin B2 receptors. FR 173657 exerted high antagonistic activity in all preparations examined. In particular, it acts as a competitive antagonist in the rabbit jugular vein (pA2 8.9) and in the human umbilical vein (pA2 8.2) but as a noncompetitive antagonist in the pig coronary artery (pKB 9.2) and in the guinea pig ileum (pKB 9.2) stimulated with the selective B2 receptor agonist bradykinin (BK). In contrast, FR 173657 failed to antagonize the biological effects of the selective B1 receptor agonist LysdesArg9BK in the pig renal vein, rabbit aorta, and human umbilical vein, three kinin B1 receptor systems. Moreover, this compound was inactive against the effects induced by noradrenaline, 5-hydroxytryptamine, endothelin-1, angiotensin II, substance P, acetylcholine, and histamine in the B2 receptor preparations. Taken together, these results demonstrate that FR 173657 is the first potent nonpeptide B2 receptor antagonist with high affinity, selectivity, and specificity for kinin B2 receptors of different species, including man.