Modulatory effect of bradykinin on noradrenaline release in isolated atria from normal and B 2 knockout transgenic mice

Abstract

The modulatory effect of bradykinin on electrically-induced noradrenaline release was assessed in isolated atria from normal and B 2 knockout transgenic mice preincubated with [ 3H]noradrenaline. Concentrations of 1, 3 and 10 nM of bradykinin did not significantly alter the outflow of radioactivity whereas higher concentrations of bradykinin (30 and 100 nM) enhanced it. The facilitatory effect of 30 nM bradykinin was inhibited by a selective bradykinin B 2 receptor antagonist, Hoe 140 ( d-Arg-[Hyp 3,Thi 5, d-Tic 7,Oic 8]bradykinin, 30 nM), and by a protein kinase C inhibitor, bisindolylmaleimide (1 μM). The co-administration of bradykinin (1 to 100 nM) with either [Leu 8]des-Arg 9-bradykinin (100 nM), AcLys[ d βNal 7,Ile 8]des-Arg 9-bradykinin (30 nM) (bradykinin B 1 receptor antagonists) or diclofenac (1 μM) (a cyclooxygenase inhibitor), shifted the facilitatory effect of bradykinin to lower concentrations. The facilitatory effect of bradykinin also was enhanced by enalaprilat (1 μM) and mergetpa (1 μM), inhibitors of angiotensin-converting enzyme (kininase II) and kininase I, respectively. In contrast, selective bradykinin B 1 receptor agonists, des-Arg 9-bradykinin (1 to 100 nM) and Sar[ d-Phe 8]des-Arg 9-bradykinin (1 to 100 nM), did not significantly affect the stimulation-induced outflow of radioactivity. Neither bradykinin (100 nM) nor des-Arg 9-bradykinin (100 nM) had any modulatory effect in B 2 knockout transgenic mice. These findings suggest that the facilitatory effect of bradykinin on noradrenaline release in the mouse atria is mediated exclusively by presynaptic bradykinin B 2 receptors which are linked to protein kinase C. The greater release of noradrenaline with bradykinin under inhibition of prostaglandins production and kininases I and II activity might be of importance in pharmacotherapies.