Absence of ligand-induced regulation of kinin receptor expression in the rabbit.

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(-1), 5 h). Rabbit aortic SMCs express a baseline population of B(1)Rs that was up-regulated upon interleukin-1beta treatment ([(3)H]-Lys-des-Arg(9)-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. 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 microg kg(-1), 5 h) was an effective B(1)R inducer (kidney, duodenum, aorta) but did not reduce kininogen reserve. 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 microg kg(-1) of each) failed to prevent or reduce the effect 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). 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 ineffective to induce B(1)Rs in vivo in an experimental time frame sufficient for B(1)R induction by LPS.