Angiotensin converting enzyme inhibition unmasks the sympathofacilitatory effect of bradykinin in human right atrium

Objective To investigate the role of angiotensin converting enzyme (ACE) inhibition in bradykinin-mediated modulation of noradrenaline release in human and rat atrium, Methods Human and rat atrial slices were incubated with [H-3]-noradrenaline, superfused with Krebs-Henseleit solution and stimulated electrically at 5 Hz. The stimulation-induced outflow of radioactivity was taken as an index of endogenous noradrenaline release, Results In the absence of ACE inhibition 0.01-1 mu mol/l bradykinin failed to alter the release of noradrenaline in human atrium, In contrast, 0.001-0.1 mu mol/l bradykinin enhanced the release of noradrenaline in rat atrium. In the presence of 3 mu mol/l of the ACE inhibitor captopril, however, bradykinin significantly enhanced the release of noradrenaline in human atrium. The bradykinin B-1-receptor agonist (Des-Arg(9))-bradykinin (0.01-1 mu mol/l) had no effect on the release of noradrenaline in human atrium both in the absence and in the presence of 3 mu mol/l captopril, Captopril (3 mu mol/l) potentiated the facilitatory effect of bradykinin in rat atrium, The selective bradykinin B-2-receptor antagonist D-Arg[Hyp(3),Thi(5), D-Tic(7),Oic(8)]-bradykinin (Hoe 140, 0.3 mu mol/l) and the cyclo-oxygenase inhibitor indomethacin (10 mu mol/l) reduced the facilitatory effect of bradykinin significantly in the presence of captopril in rat and human atrium. Prostaglandin F-2 alpha (0.1 mu mol/l), prostaglandin E-2 (0.3 mu mol/l) and the thromboxane A(2) receptor agonist U-46 619 (0.1 pmol/l) enhanced the release of noradrenaline in human atria, whereas 0.1 mu mol/l prostaglandin I-2 had no effect. Conclusion These data suggest that bradykinin facilitates the release of noradrenaline in human and rat atrium by activation of bradykinin receptors of the B-2-subtype and subsequent release of facilitatory prostaglandins, The facilitatory effect of bradykinin in human atrium can only be demonstrated when its enzymatic degradation is prevented by ACE inhibition.