Induction of Functional Bradykinin B 1 -Receptors in Normotensive Rats and Mice Under Chronic Angiotensin-Converting Enzyme Inhibitor Treatment

Background — The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B 1 - and B 2 -receptor expression, which are the molecular entities responsible for the biological effects of kinins. Methods and Results — Rats were subjected to different 6-week treatments using various mixtures of the following agents: ACE inhibitor, angiotensin AT 1 -receptor antagonist, and B 1 - and B 2 -receptor antagonists. Chronic ACE inhibition induced both renal and vascular B 1 -receptor expression, whereas B 2 -receptor expression was not modified. Furthermore, with B 1 -receptor antagonists, it was shown that B 1 -receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor–induced expression of functional B 1 -receptors in all segments. ACE-inhibitor–induced B 1 -receptor induction involved homologous upregulation, because it was prevented by B 1 -receptor antagonist treatment. Finally, using B 2 -receptor knockout mice, we showed that ACE-inhibitor–induced B 1 -receptor expression was B 2 -receptor independent. Conclusions — This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B 1 -receptor induction, which is involved in ACE-inhibitor–induced hypotension. The observed B 1 -receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.