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

Abstract

To investigate the role of angiotensin converting enzyme (ACE) inhibition in bradykinin-mediated modulation of noradrenaline release in human and rat atrium. Human and rat atrial slices were incubated with [3H]-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. In the absence of ACE inhibition 0.01-1 micromol/l bradykinin failed to alter the release of noradrenaline in human atrium. In contrast, 0.001-0.1 micromol/l bradykinin enhanced the release of noradrenaline in rat atrium. In the presence of 3 micromol/l of the ACE inhibitor captopril, however, bradykinin significantly enhanced the release of noradrenaline in human atrium. The bradykinin B1-receptor agonist (Des-Arg9)-bradykinin (0.01-1 micromol/l) had no effect on the release of noradrenaline in human atrium both in the absence and in the presence of 3 micromol/l captopril. Captopril (3 micromol/l) potentiated the facilitatory effect of bradykinin in rat atrium. The selective bradykinin B2-receptor antagonist D-Arg[Hyp3,Thi5, D-Tic7,Oic8]-bradykinin (Hoe 140, 0.3 micromol/l) and the cyclo-oxygenase inhibitor indomethacin (10 micromol/l) reduced the facilitatory effect of bradykinin significantly in the presence of captopril in rat and human atrium. Prostaglandin F2alpha (0.1 micromol/l), prostaglandin E2 (0.3 micromol/l) and the thromboxane A2 receptor agonist U-46 619 (0.1 micromol/l) enhanced the release of noradrenaline in human atria, whereas 0.1 micromol/l prostaglandin I2 had no effect. These data suggest that bradykinin facilitates the release of noradrenaline in human and rat atrium by activation of bradykinin receptors of the B2-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.