Kinins, receptors, kininases and inhibitors - Where did they lead us?

Based on studies presented here and other published experiments performed w ith surviving tissue preparations, with transfected cells and with cells th at constitutively express the human angiotensin I converting enzyme ACE and B-2 receptors, we concluded the following: ACE inhibitors and other endoge nous peptides that react with the active site of ACE potentiate the effect of bradykinin and its ACE resistant peptide congeners on the B-2 receptor. They also resensitize receptors which had been desensitized by the agonist. ACE and bradykinin receptors have to be sterically close, possibly forming a heterodimer, for the ACE inhibitors to induce an allosteric modification on the receptor. When ACE inhibitors augment bradykinin effects, they redu ce the phosphorylation of the B-2 receptor. The primary actions of bradykin in on the receptor are not affected by protein kinase C or phosphatase inhi bitors, but the potentiation of bradykinin or the resensitization of the re ceptor by ACE inhibitors are abolished by the same inhibitors. The results with protein kinase C and phosphatase inhibitors indicate that another inte rmediate protein may be involved in the processes of signaling induced by A CE inhibitors, and that ACE inhibitors affect the signal transduction pathw ay triggered by bradykinin on the B-2 receptor.