Inhibitors of angiotensin I-converting enzyme (ACE) are very efficacious in
the potentiation of the actions of bradykinin (BK) and are able to provoke
a B-2 receptor-mediated vasodilation even after desensitization of this re
ceptor. Because this activity cannot be easily explained only by an inhibit
ion of kinin degradation, direct interactions of ACE inhibitors with the B-
2 receptor or its signal transduction have been hypothesized. To clarify th
e significance of degradation-independent potentiation, we studied the vaso
dilatory effects of BK and 2 degradation-resistant B-2 receptor agonists in
the isolated rat heart, a model in which ACE and aminopeptidase P (APP) co
ntribute equally to the degradation of BK. Coronary vasodilation to BK and
to a peptidic (B6014) and a nonpeptidic (FR190997) degradation-resistant B-
2 agonist was assessed in the presence or absence of the ACE inhibitor rami
prilat, the APP inhibitor mercaptoethanol, or both, Ramiprilat or mercaptoe
thanol induced leftward shifts in the BK dose-response curve (EC50=3.4 nmol
/L) by a actor of 4.6 or 4.9, respectively. Combined inhibition of ACE and
APP reduced the EC50 of BK to 0.18 nmol/L (ie, by a factor of 19) but poten
tiated the activity of B6014 (EC50=1.9 nmol/L) only weakly without altering
that of FR190997 (EC50=0.34 nmol/L). Desensitization of B-2 receptors was
induced by the administration of BK (0.2 mu mol/L) or FR190997 (0.1 mu mol/
L) for 30 minutes; the vascular reactivity to ramiprilat or increasing dose
s of BK was tested thereafter. After desensitization with BK, but not FR190
997, an additional application of ramiprilat provoked a B-2 receptor-mediat
ed vasodilation. High BK concentrations were still effective at the desensi
tized receptor. The process of desensitization was not altered by ramiprila
t, These results show that in this model, all potentiating actions of ACE i
nhibitors on kinin-induced vasodilation are exclusively related to the redu
ction in BK breakdown and are equivalently provoked by APP inhibition. The
desensitization of B-2 receptors is overcome by increasing BK concentration
s, either directly or through the inhibition of ACE. These observations do
not suggest any direct interactions of ACE inhibitors with the B-2 receptor
or its signal transduction but point to a very high activity of BK degrada
tion in the vicinity of the B-2 receptor in combination with a stimulation-
dependent reduction in receptor affinity.