Kinins, receptors, kininases and inhibitors--where did they lead us?
Based on studies presented here and other published experiments performed with surviving tissue preparations, with transfected cells and with cells that constitutively express the human angiotensin I converting enzyme ACE and B2 receptors, we concluded the following: ACE inhibitors and other endogenous peptides that react with the active site of ACE potentiate the effect of bradykinin and its ACE resistant peptide congeners on the B2 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 reduce the phosphorylation of the B2 receptor. The primary actions of bradykinin on the receptor are not affected by protein kinase C or phosphatase inhibitors, but the potentiation of bradykinin or the resensitization of the receptor by ACE inhibitors are abolished by the same inhibitors. The results with protein kinase C and phosphatase inhibitors indicate that another intermediate protein may be involved in the processes of signaling induced by ACE inhibitors, and that ACE inhibitors affect the signal transduction pathway triggered by bradykinin on the B2 receptor.
Erdös
E G
EG
University of Illinois College of Medicine, Department of Pharmacology, Chicago 60612, USA.
Marcic
B M
BM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D007705:Kinins / Q000378:metabolism / Q000502:physiology*; D001121:Lysine Carboxypeptidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D007705:Kinins; D011956:Receptors, Cell Surface; D007703:Peptidyl-Dipeptidase A; D001121:Lysine Carboxypeptidase; D001920:Bradykinin