ABSTRACT
Potentiation of hormone actions can occur by different mechanisms, including inhibition of degrading enzymes, interaction with the hormone receptor leading to stabilization of bioactive conformation or leading to receptor homo- and hetero-oligomerization, receptor phosphorylation and dephosphorylation or can occur by directly influencing the signal transduction and ion channels. In this review the potentiation of bradykinin actions in different systems by certain compounds will be reviewed. Despite many long years of experimental research and investigation the mechanisms of potentiating action remain not fully understood. One of the most contradictory findings are the distinct differences between the inhibition of the angiotensin I-converting enzyme and the potentiation of the bradykinin induced smooth muscle reaction. Contradictory findings and hypothesized mechanisms in the literature are discussed in this review and in some cases compared to own results. Investigation of potentiating actions was extended from hypotension, smooth muscle reaction and cellular actions to activation of immunocompetent cells. In our opinion the potentiation of bradykinin action can occur by different mechanisms, depending on the system and the applied potentiating factor used.
ABSTRACT
Synthetic analogues of the bradykinin potentiating nonapeptide BPP9alpha indicate significantly different structural requirements for potentiation of the bradykinin (BK)-induced smooth muscle contraction (GPI) and the inhibition of isolated somatic angiotensin I-converting enzyme (ACE). The results disprove the ACE inhibition as the only single mechanism and also the direct interaction of potentiating peptides with the bradykinin receptors in transfected COS-7 cells as molecular mechanism of potentiation. Our results indicate a stimulation of inositol phosphates (IPn) formation independently from the B2 receptor. Furthermore, the results with La3+ support the role of extracellular Ca2+ and its influx through corresponding channels. The missing effect of calyculin on the GPI disproves the role of phosphatases in the potentiating action. These experimental studies should not only contribute to a better understanding of the potentiating mechanisms but also incorporate a shift in the research towards the immune system, in particular towards the immunocompetent polymorphonuclear leukocytes. The chemotaxis of these cells can be potentiated most likely by exclusive inhibition of the enzymatic degradation of bradykinin. Thus the obtained results give evidence that the potentiation of the bradykinin action can occur by different mechanisms, depending on the system and on the applied potentiating factor.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Bradykinin/pharmacology , Muscle Contraction/drug effects , Teprotide/analogs & derivatives , Amino Acid Sequence , Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/chemistry , Animals , COS Cells , Calcium/metabolism , Chlorocebus aethiops , Drug Synergism , Guinea Pigs , Humans , Inositol Phosphates/biosynthesis , Molecular Sequence Data , Muscle, Smooth/drug effects , Peptides/chemical synthesis , Peptides/chemistry , Peptides/pharmacology , Peptidyl-Dipeptidase A/drug effects , Phosphoprotein Phosphatases/antagonists & inhibitors , Receptor, Bradykinin B2/agonists , Receptor, Bradykinin B2/genetics , Signal Transduction/drug effects , Teprotide/chemistryABSTRACT
The longitudinal muscle of isolated rat ileum is a sensitive bioassay suitable for testing compounds with antagonistic effects on the B(1) receptor. Bradykinin analogues with replacement of proline by alkyl-substituted phenylalanine at position 7 are effective on this receptor as entire molecules and have a stronger antagonistic effect than on the B(2) receptor. A corresponding desArg(9)-compound has a specific effect on the B(1) receptor and a very high antagonistic potency. [LNMPhe(2)]bradykinin as a compound without any replacement at position 7 or 8 shows antagonistic activity as well.
