Absence of ligand‐induced regulation of kinin receptor expression in the rabbit

Abstract

1 The induction of B 1 receptors (B 1 Rs) and desensitization or down-regulation of B 2 receptors (B 2 Rs) as a consequence of the production of endogenous kinins has been termed the autoregulation hypothesis. The latter was investigated using two models based on the rabbit: kinin stimulation of cultured vascular smooth muscle cells (SMCs) and in vivo contact system activation (dextran sulphate intravenous injection, 2 mg kg -BK binding or mRNA concentration evaluated by RT ± PCR; 4 or 3 h, respectively). Treatment with B 1 R or B 2 R agonists failed to alter B 1 R expression under the same conditions. 3 Despite consuming endogenous kininogen (assessed using the kinetics of immunoreactive kinin formation in the plasma exposed to glass beads ex vivo) and producing hypotension mediated by B 2 Rs in anaesthetized rabbits, dextran sulphate treatment failed to induce B 1 Rs in conscious animals (RT ± PCR in several organs, aortic contractility). By contrast, lipopolysaccharide (LPS, 50 mg kg 71 , 5 h) was an eective B 1 R inducer (kidney, duodenum, aorta) but did not reduce kininogen reserve. 4 We tested the alternate hypothesis that endogenous kinin participate in LPS induction of B 1 Rs. Kinin receptor antagonists (icatibant combined to B-9858, 50 mg kg 71 of each) failed to prevent or reduce the eect of LPS on B 1 R expression. Dextran sulphate or LPS treatments did not persistently down-regulate vascular B 2 Rs (jugular vein contractility assessed ex vivo). 5 The kinin receptor autoregulation hypothesis is not applicable to primary cell cultures derived from a tissue known to express B 1 Rs in a regulated manner (aorta). The activation of the endogenous kallikrein-kinin system is ineective to induce B 1 Rs in vivo in an experimental time frame sucient for B 1 R induction by LPS.

The Kallikrein-Kinin System: Current and Future Pharmacological Targets

“…Studies on the human embryonic IMR-90 cell line led to the hypothesis of autoregulation of the B1R; stimulation of either the B1R or B2R in these cells led to the increased expression of the B1R (mRNA, protein) (165,166). However, this model may not be generally applicable, as these permissive cells produce autocrine IL-1β in response to the stimulation of various GPCRs (167) and as kinin receptor stimulation does not up-regulate B1R expression in primary vascular cells (cultured smooth muscle cells) or in vivo, following the activation of the contact system in rabbits using dextran sulfate (168). Evidence of the role of the transcription factor AP-1 in B1R expression has been derived from a construction composed of the 1.8 kb core promoter, exon 1, and 1.5 kb of intron 1, exon 2, intron 2, and a luciferase reporter (169).…”

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

“…Furthermore, kinin receptor antagonists did not modify LPS-induced B 1 receptor induction in the live rabbit (Sabourin et al, 2001). Exogenous kinins acting on either receptor types were unable to translocate NF-B to the nucleus of rabbit aortic smooth muscle cells or to up-regulate the B 1 receptor expression (binding sites, mRNA; Sabourin et al, 2001;Marceau et al, 2002); by contrast, IL-1␤ was active in both respect. Therefore, the autoregulation model, a positive feedback between the kinin receptor stimulation and delayed B 1 receptor expression, is apparently not universally applicable or may be species-specific.…”

“…Activation of the contact system (also known as the kallikrein/kinin system or the intrinsic pathway of coagulation) following intravenous dextran sulfate injection consumed kininogen and generated a prolonged hypotensive state mediated by the B 2 receptor, but failed to induce the B 1 receptor (vascular function, mRNA concentration in several organs) 5 h after treatment. For comparison, bacterial LPS treatment was active in this respect (Sabourin et al, 2001). Furthermore, kinin receptor antagonists did not modify LPS-induced B 1 receptor induction in the live rabbit (Sabourin et al, 2001).…”

“…For comparison, bacterial LPS treatment was active in this respect (Sabourin et al, 2001). Furthermore, kinin receptor antagonists did not modify LPS-induced B 1 receptor induction in the live rabbit (Sabourin et al, 2001). Exogenous kinins acting on either receptor types were unable to translocate NF-B to the nucleus of rabbit aortic smooth muscle cells or to up-regulate the B 1 receptor expression (binding sites, mRNA; Sabourin et al, 2001;Marceau et al, 2002); by contrast, IL-1␤ was active in both respect.…”

A Novel Nonpeptide Antagonist of the Kinin B1Receptor: Effects at the Rabbit Receptor

“…Agonist-induced down-regulation is difficult to observe with recombinant kinin receptors (Houle and Marceau, 2003). A positive feedback mechanism where kinin receptor stimulation determines further B 1 R expression (the "autoregulation hypothesis"; Schanstra et al, 1998;Phagoo et al, 1999) is controversial and may not be widely applicable (Sabourin et al, 2001(Sabourin et al, , 2002b.…”