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Received for publication April 29, 2005.
Revised May 24, 2005.
Accepted for publication May 24, 2005.
The B1 receptor for kinins is selectively stimulated by bradykinin-related fragments lacking the C-terminal arginine, des-arginine9-bradykinin (des-Arg9-BK) and Lys-des-Arg9-BK. The latter peptide is the optimal agonist at the human and rabbit receptor. The B1 receptor is inducible as a function of inflammatory conditions in the vasculature. We studied the effect of endogenously expressed peptidases on the potency of ligands of this receptor in an established bioassay, the rabbit aorta contractility. The potency measured for agonists (EC50) or antagonists (pA2 scale) in this assay was compared to the affinity of each agent determined using [3H]Lys-des-Arg9-BK binding competition in cultured aortic smooth muscle cells and to the competition Ki for the hydrolysis of the aminopeptidase chromogenic substrate L-Ala-p-nitroanilide by smooth muscle cell membranes. The contractile potency of the agonist Lys-des-Arg9-BK is decreased by in situ metabolism and aminopeptidase N mediates most of the distortion (inhibited by amastatin, but not efficiently by puromycin). At the other end of the spectrum, the fully protected agonist Sar-[D-Phe8]des-Arg9-BK is not significantly potentiated by peptidase inhibitors. A similar distortion of apparent potency was observed for some peptide antagonists used in the contractility assay, B-10350 and Lys-[Leu8]des-Arg9-BK being intensely potentiated by amastatin treatment and effective L-Ala-p-nitroanilide competitors. N-protected peptide antagonists or a nonpeptide antagonist of the B1 receptor were not potentiated by amastatin. The co-expression of aminopeptidase N and the kinin B1 receptor in rabbit arterial tissue is of interest for the inactivation of the high affinity agonist Lys-des-Arg9-BK and for the design of hydrosoluble antagonist drugs.
Key words:
B1 receptor for kinin, aminopeptidase N, angiotensin converting enzyme, bradykinin related peptides, rabbit aorta, smooth muscle cells
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