Kinin B1 and B2 receptors in pig vessels: characterization of two monoreceptor systems

Abstract

The coronary artery and renal vein of the adult pig are sensitive and reliable monoreceptor systems for studying kinin receptors. The pig coronary artery with intact endothelium is highly sensitive to bradykinin (BK, pEC50 8.6), while being insensitive to the B1 receptor agonist, LysdesArg9BK. The tissue responds to BK with concentration-dependent relaxation, which is prevented by B2 receptor antagonists, particularly DArg[Hyp3, Thi5, DTic7, Oic8]BK (HOE 140, pKB 9.3), (E)-3-(6-acetoamido-3-pyridyl)-N-(N-{2, 4-dichloro-3-[(2-methyl-8-quinolinyl)oxy-methyl]phenyl}-N- methylaminocarbonyl-methyl)acrylamide (FR 173657), a new non peptide compound (pKB 9.3), while B1 receptor antagonists (e.g. Lys[Leu8]desArg9BK) are inactive. The order of potency of kinin-related peptides in this vessel is: LysBK > or = BK > [Hyp3]BK > [Aib7]BK, a sequence typical of a B2 receptor system. Antagonists such as HOE 140 and FR 173657, at high concentrations reduce the maximum effect of BK and thus behave as noncompetitive antagonists. The kinin B1 receptor was studied in the pig renal vein without endothelium and incubated for several hours in order to allow for the de novo formation of this functional site. After 7-8 h in vitro incubation, the vessel shows high sensitivity to LysdesArg9BK (pEC50 8.3) and is insensitive to BK. The pig renal vein responds to B1 receptor agonists with concentration-dependent contraction which maintains a stable plateau and is prevented by selective B1 receptor antagonists such as Lys[Leu8]desArg9BK (pKB 6.7). The most active antagonist has been found to be desArg9HOE 140 (pA2 7.6) which acts as competitive antagonist in this preparation. Some B2 antagonists (e.g. HOE 140) show weak (pKB 6.1) anti-B1 receptor activity while the non-peptide compound FR 173657 is inactive on the B1 receptor and therefore acts as a potent and selective kinin B2 receptor antagonist in the pig. The data obtained in this study allow us to compare the porcine B2 and B1 receptors with those of other species including man, and underline some interesting features that are unique to the porcine functional sites.

Bradykinin stimulates ceramide production by activating specific BK-B1receptor in rat small artery

“…BK has been shown to induce relaxation of many types of arteries, for example, in coronary arteries (2,14,30,32,33), pancreaticoduodenal artery (28), and rat mesenteric arteries (3,5,37). Contraction has also been observed, for example, in rat tail arteries (45) and in human umbilical and rabbit jugular veins (19, 30); this contraction is sometimes transient and followed and/or preceded by relaxation (30,32,33).…”

“…BK receptors are generally divided into two major subtypes, BK-B 1 and BK-B 2 (18,30,32,33). BK acts primarily by binding to the BK-B 2 receptor, which is responsible for most of the following effects of BK: arterial vasodilatation, plasma extravasation, venoconstriction, activation of sensory fibers (pain), release of prostaglandins, and relaxing factors from the endothelium (19,30,32,33).…”

“…BK acts primarily by binding to the BK-B 2 receptor, which is responsible for most of the following effects of BK: arterial vasodilatation, plasma extravasation, venoconstriction, activation of sensory fibers (pain), release of prostaglandins, and relaxing factors from the endothelium (19,30,32,33). BK binds to the BK-B 1 receptor; however, the receptor has a much higher affinity for the metabolite des-[Arg 9 ]-BK.…”

“…In general, it is the BK-B 2 receptor that is responsible for the contraction-inducing effect of BK on vessels such as the human umbilical vein (33), the rabbit jugular vein (33), and rat tail arteries (38) or for the BK-induced relaxation of pig coronary arteries (14,32) and pancreatic arteries (28). More importantly, the relaxation that is induced by BK in rat mesenteric arteries is also mediated by the BK-B 2 receptor (33,37 signals; however, it is known that ceramide and other sphingolipid metabolites are implicated in generating these signals including in smooth muscle cells (19,26,27).…”

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…The only natural kinin sequence with a subnanomolar affinity for the human and rabbit B 1 receptors is Lys-des-Arg 9 -BK, a fact of particular significance that may suggest that the B 1 receptor belongs to the "tissue" kallikrein-kinin system, jointly with tissue kallikrein that generates Lys-BK from low molecular weight kininogen (L-kininogen). If one considers a more distantly related mammalian species, the pig, functional data (porcine renal vein contractility) show that the B 1 receptor is also preferentially stimulated by Lys-desArg 9 -BK, 16-fold more potent than des-Arg 9 -BK (Rizzi et al, 1997). Thus, an order of agonist potency widely valid for mammalian kinin receptors could be: B 1 , Lys-desArg 9 -BK Ͼ Lys-BK Ϸ des-Arg 9 -BK Ͼ Ͼ BK; B 2 , BK Ϸ Lys-BK Ͼ Ͼ des-Arg 9 -BK and Lys-des-Arg 9 -BK.…”