Article date: August 2001
By: Thierry Sabourin, Katline Guay, Steeve Houle, Johanne Bouthillier, Dimcho R Bachvarov, Albert Adam, François Marceau in Volume 133, Issue 7, pages 1154-1162
The induction of B1 receptors (B1Rs) and desensitization or down‐regulation of B2 receptors (B2Rs) 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 B1Rs that was up‐regulated upon interleukin‐1β treatment ([3H]‐Lys‐des‐Arg9‐BK binding or mRNA concentration evaluated by RT–PCR; 4 or 3 h, respectively). Treatment with B1R or B2R agonists failed to alter B1R 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 B2Rs in anaesthetized rabbits, dextran sulphate treatment failed to induce B1Rs in conscious animals (RT–PCR in several organs, aortic contractility). By contrast, lipopolysaccharide (LPS, 50 μg kg−1, 5 h) was an effective B1R inducer (kidney, duodenum, aorta) but did not reduce kininogen reserve.
We tested the alternate hypothesis that endogenous kinin participate in LPS induction of B1Rs. Kinin receptor antagonists (icatibant combined to B‐9858, 50 μg kg−1 of each) failed to prevent or reduce the effect of LPS on B1R expression. Dextran sulphate or LPS treatments did not persistently down‐regulate vascular B2Rs (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 B1Rs in a regulated manner (aorta). The activation of the endogenous kallikrein‐kinin system is ineffective to induce B1Rs in vivo in an experimental time frame sufficient for B1R induction by LPS.
The induction of B1 receptors (B1Rs) and desensitization or down‐regulation of B2 receptors (B2Rs) 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 B1Rs that was up‐regulated upon interleukin‐1β treatment ([3H]‐Lys‐des‐Arg9‐BK binding or mRNA concentration evaluated by RT–PCR; 4 or 3 h, respectively). Treatment with B1R or B2R agonists failed to alter B1R 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 B2Rs in anaesthetized rabbits, dextran sulphate treatment failed to induce B1Rs in conscious animals (RT–PCR in several organs, aortic contractility). By contrast, lipopolysaccharide (LPS, 50 μg kg−1, 5 h) was an effective B1R inducer (kidney, duodenum, aorta) but did not reduce kininogen reserve.
We tested the alternate hypothesis that endogenous kinin participate in LPS induction of B1Rs. Kinin receptor antagonists (icatibant combined to B‐9858, 50 μg kg−1 of each) failed to prevent or reduce the effect of LPS on B1R expression. Dextran sulphate or LPS treatments did not persistently down‐regulate vascular B2Rs (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 B1Rs in a regulated manner (aorta). The activation of the endogenous kallikrein‐kinin system is ineffective to induce B1Rs in vivo in an experimental time frame sufficient for B1R induction by LPS.
British Journal of Pharmacology (2001) 133, 1154–1162; doi:10.1038/sj.bjp.0704158
DOI: 10.1038/sj.bjp.0704158
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