TY - JOUR
T1 - Angiotensin I-converting enzyme-dependent and neutral endopeptidase- dependent generation and degradation of angiotensin II contrarily modulate noradrenaline release: Implications for vasopeptidase-inhibitor therapy?
AU - Raasch, Walter
AU - Dominiak, Peter
AU - Dendorfer, Andreas
PY - 2005/1/1
Y1 - 2005/1/1
N2 - Objectives: Vasopeptidase inhibitors inhibit neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE). Since angiotensin (ANG) II availability is decreased by ACE inhibition but is increased by NEP inhibition, we evaluated the influence of the vasopeptidase inhibitor omapatrilat on ANG II-dependent noradrenaline (NA) release. Design: The functional relevance of ACE-dependent and NEP-dependent generation and degradation of ANG II on NA overflow was determined in pithed rats by applications of ANG I (0.1 - 100 μg/kg) or ANG II (0.01 - 10 μg/kg) after single injections of ramipril (1 mg/kg), the NEP inhibitor candoxatril (100 mg/kg), or the vasopeptidase inhibitor omapatrilat (30 mg/kg). Results: Blood pressure was equipotently decreased by ramipril and omapatrilat, but not by candoxatril. NA overflow was increased after ANG I infusions in controls (EC50 = 9.0 μg/kg ANG I, Emax = 5680 pg/ml), but almost completely suppressed by ramipril and omapatrilat. Candoxatril decreased EC50 (4.1 μ/kg) and increased Emax (7259 pg/ml). NA overflow after ANG II infusions was enhanced by candoxatril or omapatrilat. Ex vivo ACE activity was extensively inhibited by ramipril or omapatrilat, whereas ex vivo NEP activity was reduced by omapatrilat and candoxatril only. In vitro, omapatrilat inhibited NEP and ACE with similar potencies (IC50 NEP/IC 50 ACE = 0.4). Conclusions: Vasopeptidase inhibitors influence ANG II-related NA release depending on their ability to modulate the availability of ANG II via ACE or NEP. After acute application, the vasopeptidase inhibitor suppresses NA release in response to ANG I due to a predominant reduction of ANG II formation. These results indicate that the ratio of ACE-inhibitory and NEP-inhibitory potencies of vasopeptidase inhibitors may be relevant for sympathetic activation in chronic therapy.
AB - Objectives: Vasopeptidase inhibitors inhibit neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE). Since angiotensin (ANG) II availability is decreased by ACE inhibition but is increased by NEP inhibition, we evaluated the influence of the vasopeptidase inhibitor omapatrilat on ANG II-dependent noradrenaline (NA) release. Design: The functional relevance of ACE-dependent and NEP-dependent generation and degradation of ANG II on NA overflow was determined in pithed rats by applications of ANG I (0.1 - 100 μg/kg) or ANG II (0.01 - 10 μg/kg) after single injections of ramipril (1 mg/kg), the NEP inhibitor candoxatril (100 mg/kg), or the vasopeptidase inhibitor omapatrilat (30 mg/kg). Results: Blood pressure was equipotently decreased by ramipril and omapatrilat, but not by candoxatril. NA overflow was increased after ANG I infusions in controls (EC50 = 9.0 μg/kg ANG I, Emax = 5680 pg/ml), but almost completely suppressed by ramipril and omapatrilat. Candoxatril decreased EC50 (4.1 μ/kg) and increased Emax (7259 pg/ml). NA overflow after ANG II infusions was enhanced by candoxatril or omapatrilat. Ex vivo ACE activity was extensively inhibited by ramipril or omapatrilat, whereas ex vivo NEP activity was reduced by omapatrilat and candoxatril only. In vitro, omapatrilat inhibited NEP and ACE with similar potencies (IC50 NEP/IC 50 ACE = 0.4). Conclusions: Vasopeptidase inhibitors influence ANG II-related NA release depending on their ability to modulate the availability of ANG II via ACE or NEP. After acute application, the vasopeptidase inhibitor suppresses NA release in response to ANG I due to a predominant reduction of ANG II formation. These results indicate that the ratio of ACE-inhibitory and NEP-inhibitory potencies of vasopeptidase inhibitors may be relevant for sympathetic activation in chronic therapy.
UR - http://www.scopus.com/inward/record.url?scp=23344437714&partnerID=8YFLogxK
U2 - 10.1097/01.hjh.0000173395.42794.cd
DO - 10.1097/01.hjh.0000173395.42794.cd
M3 - Journal articles
C2 - 16003188
AN - SCOPUS:23344437714
VL - 23
SP - 1597
EP - 1604
JO - Journal of Hypertension
JF - Journal of Hypertension
SN - 0263-6352
IS - 8
ER -