Agonistic and antagonistic properties of the bradykinin B2 receptor antagonist, Hoe 140, in isolated blood vessels from different species.
1. Hoe 140, a recently described bradykinin B2 antagonist, and NPC 567 from an earlier generation of bradykinin B2 antagonists, were tested in rabbit and sheep isolated blood vessels. 2. In rabbit jugular vein, a bradykinin B2 preparation, NPC 567 was an antagonist (apparent pA2: 8.67 +/- 0.16) with marked residual agonistic activity (log[EC50]: -7.29 +/- 0.13). Hoe 140 was a potent non-competitive antagonist devoid of agonistic properties (slope of the Schild plot: 2.02; estimated pA2: 9.04). 3. In rabbit aorta, a bradykinin B1 preparation, NPC 567 was a competitive antagonist (pA2: 6.32 +/- 0.13) but Hoe 140 was ineffective. The two antagonists did not show any agonistic properties in this tissue. 4. In sheep femoral artery without endothelium, bradykinin and Hoe 140 induced contractions with identical efficacy and similar potency (log[EC50]: -8.05 +/- 0.12, -7.73 +/- 0.10; maximal contraction in % of KCl [60 mM]: 59.5 +/- 15.1, 62.0 +/- 13.1; for bradykinin and Hoe 140, respectively). In contrast NPC 567 was an extremely weak agonist. The contractile responses to bradykinin and Hoe 140 were inhibited by NPC 567 (apparent pKB: 6.89 +/- 0.22 and 6.58 +/- 0.08 versus bradykinin and Hoe 140, respectively) but not by a B1 bradykinin antagonist, suggesting that the receptor involved was a bradykinin B2 receptor. 5. In sheep femoral artery with endothelium, bradykinin induced a biphasic response: an endothelium-dependent relaxation and a contraction which were both inhibited by NPC 567 (apparent pKB: 7.10 +/- 0.15) and Hoe 140 (pA2: 8.38 +/- 0.12). As bradykinin B2 receptor antagonists, Hoe 140 and NPC 567 were less potent in the sheep femoral artery than in the rabbit jugular vein. Neither Hoe 140 nor NPC 567 were agonists for the endothelial receptor.6. This study demonstrates that Hoe 140, a new bradykinin B2 receptor antagonist, is more selective and more potent than NPC 567; however, it may possess, depending on the tissue studied, marked residual agonistic properties. Furthermore, bradykinin B2 receptors are subject to important species specificity. Finally, two different bradykinin B2 receptor subtypes may coexist in the sheep femoral artery with endothelium.
Félétou
M
M
Institut de Recherches Servier, Suresnes, France.
Germain
M
M
Thurieau
C
C
Fauchère
J L
JL
Canet
E
E
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011817:Rabbits; D012756:Sheep; D013045:Species Specificity
D065168:Bradykinin Receptor Antagonists; C065679:icatibant; C053010:NPC 567; D001920:Bradykinin