Lys-(Des-Arg9,Leu8)-Bradykinin

The effect of bradykinin on the neuroeffector junction of the isolated rat vas deferens was studied in tissues stimulated transmurally at a frequency of 0.15 Hz. Bradykinin caused two distinct and independent actions: it potentiated the magnitude of the muscular response to the electrically driven twitches and, in addition, contracted the smooth muscle generating an increased muscular tone. The former action is referred to as the neurogenic or presynaptic effect, whereas the latter effect is called the musculotropic or postjunctional action. The neurogenic effect was abolished by tetrodotoxin or tissue denervation either by cold storage or chemical sympathectomy after 6-hydroxydopamine administration. However, these procedures did not significantly modify the musculotropic potency of bradykinin. Both actions of the peptide are receptor-mediated, as minor structural modifications in the amino acid sequence caused significant changes in biological potency. In addition, the peptide analog, [Thi5,8-D-Phe7]-bradykinin, behaved as an agonist at the presynaptic site but as an antagonist at the muscular site. The most potent peptide analog to produce the neurogenic effect was Met-Lys-bradykinin followed by Lys-bradykinin and [Tyr8]-bradykinin. In contrast, the potency of these peptide analogs acting at the postsynaptic site was about the same. des Arg9 bradykinin and des Arg9-[Leu8]-bradykinin were inactive at the pre- and postjunctional site. The neurogenic action of bradykinin was not mimicked by angiotensin II, neurotensin, substance P or vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)

Object:The authors previously discovered that genes for the bradykinin-1 (B1) receptor and the transient receptor potential vanilloid subtype 1 (TRPV1) were overexpressed in animals exhibiting thermal hyperalgesia (TH) following spinal cord injury (SCI). They now report the effect of TRPV1 (AMG9810) and B1 (Lys-[Des-Arg9,Leu8]-bradykinin) antagonists on TH in animals following SCI.Methods:The rats were subjected to contusion SCI and then divided into groups in which TH did or did not develop. The animals from both groups were given either AMG9810, Lys-(Des-Arg9,Leu8)-bradykinin, or the drug-specific vehicle (control groups). Animals were tested for TH preinjury and at regular intervals after SCI by using the hindlimb withdrawal latency test.Conclusions:The administration of AMG9810 likely improves TH as a result of a generalized analgesic effect, whereas the effect of Lys-(Des-Arg9,Leu8)-bradykinin appears more specific to the reversal of TH. This information has potential usefulness in the development of treatment strategies for post-SCI neuropathic pain.

Bradykinin is well known to have a biphasic action to contract and relax gastrointestinal tissue. However, no studies have investigated the potential action of bradykinin to affect the peristaltic reflex. In the present study, serosally applied bradykinin (1-1000 nM) and the bradykinin B2 receptor agonist, kallidin (1-1000 nM), had inhibitory actions and increased the pressure threshold for peristalsis (maximum changes seen at 1000 nM were approximately 60 Pa), as did morphine (IC50=22.3+/-4.8 nM; maximum increase in the pressure threshold was approximately 130 Pa). Conversely, the B1 kinin receptor agonist, [des-Arg9]-bradykinin (1-1000 nM), had no effect (P>0.05). Two potent B2 receptor antagonists, FR173657 (1 and 100 nM) and icatibant (10 nM), significantly antagonized the inhibitory action of serosally applied bradykinin on peristalsis (P0.05). In comparison, 5-hydroxytryptamine (1-1000 nM) facilitated peristalsis (EC50=37.7+/-23.0 nM; maximum reduction of the pressure threshold for peristalsis was approximately 76 Pa), as did FR173657 at 100 nM (reducing the pressure threshold for peristalsis by approximately 15 Pa; P0.05). The results indicate that bradykinin B2 receptors mediate an inhibition of peristalsis in the guinea pig isolated ileum.