BRADYKININ INCREASES CATECHOLAMINE RELEASE VIA B-2 RECEPTORS

The mechanism by which bradykinin induces catecholamine release from n eural tissues was investigated in two experimental models of rat origi n. The rat phaeochromocytoma cell line PC12 was used to identify the s ubtype of bradykinin receptors involved in the stimulation of noradren aline secretion and to compare the effects of three different B-2-anta gonists. An increase of catecholamine release induced by bradykinin in vivo could be confirmed by measuring plasma levels in pithed spontane ously hypertensive rats (SPIR) during electric preganglionic stimulati on of the spinal cord. In this whole animal model, the effects of inhi bition of both uptake, and alpha(2)-adrenoceptors on plasma levels of noradrenaline and adrenaline were studied as well as the potentiation of exogenous bradykinin by inhibition of angiotensin I-converting enzy me and neutral endopeptidase. The receptor subtypes involved (i.e. B-1 or B-2) were characterized by application either of HOE 140 or desArg (9)-[Leu(8)]-bradykinin respectively. In PC12 cells bradykinin provoke d a prominent increase of noradrenaline release at low concentrations (concentration required for 50% of the maximum response 1 nM), whereas the B-1-agonist desArg(9)-bradykinin was only effective at concentrat ions higher than 30 mu M. The effects of both kinins could be blocked by the B-2-specific antagonist HOE 890307 which, like HOE 140, exerted no agonistic effect of its own. As has been shown in 3 other neural c ells, the B-2-specific antagonist [Thi(5,8), D-Phe(7)]-bradykinin only acted as a low-affinity agonist without any antagonistic effects. In experiments where the intention was to induce B-1-receptor expression either by angiotensin I-converting enzyme inhibition or lipopolysaccha ride application, no alteration of the secretory response of PC12 cell s to bradykinin or desArg(9)-bradykinin could be shown. In pithed SHR, infusion of bradykinin (up to 1200 ng/min/kg) did not enhance stimula tion-dependent release of noradrenaline or adrenaline. After pretreatm ent of the rats with ramipril bradykinin became effective and its effe cts were further potentiated by the concomitant application of phospho ramidon. B-2-antagonism by HOE 140 abolished the bradykinin-induced re lease of noradrenaline and reduced the effect on plasma adrenaline. Th e B-1-specific antagonist desArg(9)-[Leu(8)]-bradykinin was unable to diminish the stimulatory effects of bradykinin and instead brought abo ut an increase of plasma adrenaline levels. In conclusion, bradykinin stimulates release of catecholamines from PC12 cells, peripheral sympa thetic neurons and chromaffine cells by activation of ganglionic or pr esynaptic B-2-receptors. The adrenal medulla and PC12 cells appear to be highly suscepti ble not only to stimulation by bradykinin, but also to non-specific stimulatory effects of certain kinin-antagonists.