Key Points
- To investigate whether the ACE inhibitor imidapril induces angiogenesis in ischemic tissue through the tissue bradykinin pathway independent of Ang II type 1a receptors.
- Induced hindlimb ischemia in Ang II type 1a receptor knockout (AT1aKO) and wild-type mice, followed by treatment with or without imidapril (0.1 or 1.0 mg/kg per day) for 21 days.
- Evaluated blood flow recovery and capillary density in the presence or absence of an AT2 antagonist (PD123319), B1 antagonist (DesArg9-[Leu8]-bradykinin), B2 antagonist (Hoechst 140), or nitric oxide synthase inhibitor (L-NAME).
- Imidapril significantly enhanced ischemia-induced angiogenesis in AT1aKO mice at both 0.1 and 1.0 mg/kg per day doses compared to untreated controls (P<0.01).
- Angiogenesis was strongly suppressed below baseline levels by AT2 receptor and bradykinin B1 receptor antagonists, whereas B2 receptor antagonism and nitric oxide synthase inhibition moderately attenuated the response.
- Inhibition of the AT2 or B1 receptors markedly reduced vascular endothelial growth factor (VEGF) and VEGF receptor 2 mRNA expression.
Structured PICO
Does imidapril improve angiogenesis in AT1aKO mice with hindlimb ischemia?
PPopulationAng II type 1a receptor knockout (AT1aKO) mice with induced hindlimb ischemia
IInterventionImidapril (1.0 or 0.1 mg/kg per day for 21 days)
CComparatorUntreated AT1aKO mice
OOutcomeAngiogenesis quantified by laser Doppler blood flowmetry and capillary densitysurrogate
Imidapril induces angiogenesis in tissue ischemia via the AT2 receptor and bradykinin/NO-dependent pathways, independent of the AT1 receptor.