Bradykinin increases catecholamine release via B₂ receptors

The mechanism by which bradykinin induces catecholamine release from neural tissues was investigated in two experimental models of rat origin. The rat phaeochromocytoma cell line PC12 was used to identify the subtype of bradykinin receptors involved in the stimulation of noradrenaline secretion and to compare the effects of three different B₂-antagonists. An increase of catecholamine release induced by bradykinin in vivo could be confirmed by measuring plasma levels in pithed spontaneously hypertensive rats (SHR) during electric preganglionic stimulation of the spinal cord. In this whole animal model, the effects of inhibition of both uptake₁ and α₂-adrenoceptors on plasma levels of noradrenaline and adrenaline were studied as well as the potentiation of exogenous bradykinin by inhibition of angiotensin I-converting enzyme and neutral endopeptidase. The receptor subtypes involved (i.e. B₁ or B₂) were characterized by application either of HOE 140 or desArg⁹-[Leu⁸]-bradykinin respectively. In PC12 cells bradykinin provoked a prominent increase of noradrenaline release at low concentrations (concentration required for 50% of the maximum response 1 nM), whereas the B₁-agonist desArg⁹-bradykinin was only effective at concentrations higher than 30 μM. The effects of both kinins could be blocked by the B₂-specific antagonist HOE 890307 which, like HOE 140, exerted no agonistic effect of its own. As has been shown in other neural cells, the B₂-specific antagonist [Thi^5,8, D- Phe⁷]-bradykinin only acted as a low-affinity agonist without any antagonistic effects. In experiments where the intention was to induce B₁-receptor expression either by angiotensin I-converting enzyme inhibition or lipopolysaccharide application, no alteration of the secretory response of PC12 cells to bradykinin or desArg⁹-bradykinin could be shown. In pithed SHR, infusion of bradykinin (up to 1200 ng/min/kg) did not enhance stimulation-dependent release of noradrenaline or adrenaline After pretreatment of the rats with ramipril bradykinin became effective and its effects were further potentiated by the concomitant application of phosphoramidon. B₂-antagonism by HOE 140 abolished the bradykinin-induced release of noradrenaline and reduced the effect on plasma adrenaline. The B₁-specific antagonist desArg⁹-[Leu⁸]-bradykinin was unable to diminish the stimulatory effects of bradykinin and instead brought about an increase of plasma adrenaline levels. In conclusion, bradykinin stimulates release of catecholamines from PC12 cells, peripheral sympathetic neurons and chromaffine cells by activation of ganglionic or presynaptic B₂-receptors. The adrenal medulla and PC12 eels appear to be highly susceptible not only to stimulation by bradykinin, but also to non-specific stimulatory effects of certain kinin-antagonists.