Peptide fragments of bradykinin show unexpected biological activity not
mediated by B1 or B2 receptors
Abstract
Background and purpose: Bradykinin [BK-(1-9)] is an
endogenous nonapeptide involved in multiple physiological and
pathological processes. A long-held belief is that peptide fragments of
BK-(1-9) are biologically inactive. Here, we have tested the biological
activities of BK-(1-9) and two major peptide fragments in human and
animal systems. Experimental Approach: Levels of BK peptides in
male Wistar rat plasma were quantified by mass spectrometric methods.
Nitric oxide was quantified in human, mouse and rat cells, and loaded
with DAF-FM. We used aortic rings from adult male Wistar rats to test
vascular reactivity. Changes in blood pressure and heart rate were
measured in conscious adult male Wistar rats. Key results:
Plasma levels of BK-(1-7) and BK-(1-5) in rats were increased following
infusion of BK-(1-9). All tested peptides induced NO production in all
cell types tested. However, unlike BK-(1-9), NO production elicited by
BK-(1-7) or BK-(1-5) was not inhibited by B1 or
B2 receptor antagonists. BK-(1-7) or BK-(1-5) also
induced concentration-dependent vasorelaxation of aortic rings, without
involving B1 or B2 receptors. In vivo,
either intravenous or intra-arterial administration of BK-(1-7) or
BK-(1-5) induced similar hypotension response. Conclusions and
implications: BK-(1-7) and BK-(1-5) are endogenous peptides present in
plasma. They are formed, at least partially, through the BK-(1-9)
proteolysis. BK-related peptide fragments show biological activity, not
mediated by B1 or B2 receptors. These
BK-fragments could constitute new, active components of the
kallikrein-kinin system.