Pharmacological modulation of the up-regulated responses to des-Arg9-bradykinin in vivo and in vitro.

Des-Arg9-bradykinin (BK) is a selective agonist of the B1 type receptors for kinins. The biological responses to des-Arg9-BK are known to be selectively up-regulated following some types of tissue injury. Two models using rabbits were previously characterized. Firstly, in vivo, lipopolysaccharide (LPS) induces a state of sensitivity to des-Arg9-BK, which becomes a hypotensive peptide. Pretreatment of rabbits with dexamethasone sodium phosphate (DEX) did not modify the induction of cardiovascular sensitivity by LPS. Secondly, isolated rabbit aortic strips incubated in vitro exhibit a spontaneous, time-dependent increase in their responsiveness to des-Arg9-BK. This up-regulation process is selectively inhibited by DEX and stimulated by LPS applied in vitro. DEX application prevented the stimulant effect of LPS in vitro. A variety of growth factors and interleukins as well as interferon-gamma, serotonin, bradykinin and the metalloprotease inhibitor 2-mercaptoethanol were ineffective in modulating the spontaneous up-regulation of contractile responses to des-Arg9-BK. Of the known substances which do modulate this system, only epidermal growth factor (EGF) enhanced aortic contractions to des-Arg9-BK following an acute (15 min) exposure near the end of the 6-hour incubation period used in these studies. The possible involvement of des-Arg9-BK and related peptides in immunopathology is discussed.