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

Abstract

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.