Protective effect of omapatrilat, a vasopeptidase inhibitor, on the metabolism of bradykinin in normal and failing human hearts.
Because part of the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors results from their protective effects on cardiac bradykinin (BK) metabolism, the purpose of this study was to define the metabolism of BK in normal and failing human hearts and to compare the effect of omapatrilat, a vasopeptidase inhibitor (VPI), which simultaneously inhibits both neutral endopeptidase (NEP) and ACE, with that of an ACE inhibitor. Exogenous BK at a nanomolar concentration was incubated alone, in the presence of an ACE inhibitor (ramiprilat, 36 nM), or in the presence of a VPI (omapatrilat, 61 nM) with left ventricular membranes prepared from normal donor hearts (n = 7), and hearts from patients with an ischemic (n = 11) or dilated (n = 12) cardiomyopathy (DCM). The half-lives calculated for BK alone (199 +/- 60, 224 +/- 108, and 283 +/- 122 s; P = NS) exhibited similar values for normal, ischemic, and DCM heart tissues, respectively. Ramiprilat significantly increased the half-life of BK (P <.01), but the effect was similar for the three kinds of tissues (297 +/- 104, 267 +/- 157, and 407 +/- 146 s, respectively; P = NS). The potentiating effect of the VPI omapatrilat on the kinetic parameter of BK (478 +/- 210, 544 +/- 249, and 811 +/- 349 s, respectively) was greater than that of the ACE inhibitor (P <.01). Moreover, omapatrilat had a more important potentiating effect with DCM than normal heart membranes (P <.05). These results show that not only ACE but also and mainly NEP play an important role in the degradation of BK in human heart membranes. Omapatrilat, a VPI, has a greater protective effect on BK metabolism than that of a pure ACE inhibitor. Thus, inhibition of both ACE and NEP with omapatrilat could be more cardioprotective than ACE inhibition alone.
Blais
C
C
Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada.
Fortin
D
D
Rouleau
J L
JL
Molinaro
G
G
Adam
A
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000378:metabolism*; D002317:Cardiovascular Agents / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008297:Male; D008566:Membranes / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D002317:Cardiovascular Agents; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; C052549:ramiprilat; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D017257:Ramipril; D001920:Bradykinin