Pharmacological characterisation of the first non-peptide bradykinin B-2 receptor agonist FR 190997: an in vitro study on human, rabbit and pig vascular B-2 receptors

FR 190997, a new kinin B-2 receptor agonist of non-peptide nature, has been studied in three isolated vessels: the human umbilical vein (hUV), the rab bit jugular vein (rbJV), and the pig coronary artery (pCA). Bradykinin (BK) contracts the hUV and rbJV through smooth muscle BZ receptors, while it re laxes the pCA through endothelial receptors of the B-2 type. Contractions o f the hUV and rbJV in response to FR 190997 show slow onset and are not rep roducible compared to the rapid and reproducible effect of BK. They reach o nly 70% and 30% of the BK-induced maximal contractions in the hUV and rbJV, respectively. The effects of FR 190997 are antagonised by HOE 140 and this antagonist shows similar pK(B) values against BK and FR 190997, indicating that the non-peptide agent interacts with the kinin B-2 receptor. FR 19099 7 is inactive as relaxant of the pCA; in this tissue, it acts as a pure and competitive antagonist, with a pK(B) value of 7.6, while HOE 140 acts as a n insurmountable antagonist (pK(B) 9.3). When tested as an antagonist, FR 190997 inhibits also the contractile effects of BK in the hUV (pK(B) 7.8 ) and in the rbJV (pK(B) 7.6). ER 190997 is selective for the B-2 receptor since it does not interact with the B-1, and is specific since it does not affect the contraction evoked by 5-hydroxytryptamine, endotelin-1, and nora drenaline in the hUV, or the relaxation induced by substance P in the pCA. FR 190997 shows therefore different pharmacological profiles in various pre parations, acting as a partial agonist in the hUV and especially in the rbJ V and as a pure antagonist in the pCA. This new compound could be of intere st in understanding how non-peptide agonists may activate receptors for pep tides.