Induction of functional bradykinin B₁-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 B₁- and B₂-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 AT₁-receptor antagonist, and B₁ and B₂-receptor antagonists. Chronic ACE inhibition induced both renal and vascular B₁-receptor expression, whereas B₂-receptor expression was not modified. Furthermore, with B₁-receptor antagonists, it was shown that B₁-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 B₁-receptors in all segments. ACE-inhibitor-induced B₁-receptor induction involved homologous upregulation, because it was prevented by B₁-receptor antagonist treatment. Finally, using B₂-receptor knockout mice, we showed that ACE-inhibitor-induced B₁-receptor expression was B₂-receptor independent. Conclusions - This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B₁-receptor induction, which is involved in ACE- inhibitor-induced hypotension. The observed B₁-receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.