Article
Influence of vasopeptidase-inhibitors on the ACE- and NEP-dependent release of noradrenaline
Einfluss von Vasopeptidase-Inhibitoren auf die ACE- und NEP-abhängige Noradrenalinfreisetzung
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Published: | August 10, 2005 |
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Vasopeptidase-inhibitors inhibit NEP and ACE. Since angiotensin II (ANG II) availability is decreased by ACE-, but increased by NEP-inhibition, we evaluated the influence of vasopeptidase-inhibitors on ANG II-dependent noradrenaline (NA)-release.
The functional relevance of ACE- and NEP-dependent generation and degradation of ANG II on NA-overflow was determined in pithed rats by applications of angiotensin I (ANG I, 0.1-100µg/kg) or ANG II (0.01-10µg/kg) after single injections of ramipril (1mg/kg), the NEP-inhibitor candoxatril (100mg/kg), and the vasopeptidase-inhibitors omapatrilat (30mg/kg) or AVE7688 (30mg/kg).
Blood pressure was equipotently decreased by ramipril, omapatrilat and AVE7688, but not by candoxatril. NA-overflow was increased after ANG I-infusions in controls (EC50 9.0µg/kgAng I, Emax 5680pg/ml), but almost suppressed by ramipril, omapatrilat or AVE7688. Candoxatril decreased EC50 (4.1µg/kg) and increased Emax (7259pg/ml). NA-overflow after ANG II-infusions was enhanced by candoxatril or omapatrilat. Ex-vivo ACE activity was extensively inhibited by ramipril, omapatrilat or AVE7688, whereas ex-vivo NEP-activity was reduced by omapatrilat and candoxatril only. In-vitro, omapatrilat inhibited NEP and ACE with similar potencies (IC50 NEP/IC50 ACE=0.4), whereas the NEP inhibitory potency of AVE7688 was less pronounced (IC50 NEP/IC50 ACE=150).
Vasopeptidase-inhibitors influence ANG II-related NA-release dependent on their ability to modulate the availability of ANG II via ACE or NEP. After acute applications, both vasopeptidase-inhibitors suppress NA-release in response to ANG I due to a predominant reduction of ANG II formation. These results indicate, that the ratio of ACE- and NEP-inhibitory potencies of vasopeptidase-inhibitors may be relevant for sympathetic activation in chronic therapy.