Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit - Importance of kinins and influence on angiotensin II type 1 receptor signaling pathway
Jl. Rouleau et al., Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit - Importance of kinins and influence on angiotensin II type 1 receptor signaling pathway, CIRCULATION, 104(8), 2001, pp. 939-944
Citations number
25
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background-The role of kinins in the cardioprotective effects of ACE inhibi
tors remains controversial.
Methods and Results-Right ventricular pressure overload in rabbits was prod
uced by pulmonary artery banding for 21 days. Rabbits were untreated, or th
ey received the ACE inhibitor ramipril with or without bradykinin B-1 and B
-2 receptor blockers or the angiotensin (Ang) II type I (AT(1)) receptor bl
ocker losartan. Pulmonary artery banding caused right ventricular hypertrop
hy, depressed papillary muscle contractility, and loss of Ang II contractil
e effects because of a signaling defect downstream of AT(1) receptors. Para
doxically, AT(1) receptor density and G protein alpha subunits alphaq and a
lpha i1/2 increased. Inotropic responsiveness to the alpha -receptor agonis
t phenylephrine was normal. Ramipril preserved cardiac contractility, but t
his effect was attenuated by simultaneous use of kinin receptor blockers. R
amipril also maintained responsiveness to Ang II and prevented AT(1) recept
or and G protein upregulation. The simultaneous use of a kinin receptor blo
cker attenuated but did not prevent upregulation in the AT(1) receptor and
G protein. Losartan had no effect on baseline contractility, but it maintai
ned cardiac inotropic responsiveness to Ang II, prevented upregulation of A
T(1) receptors, but did not modify G protein upregulation.
Conclusions-Pressure overload of the right ventricle decreases contractilit
y, uncouples AT(1) receptors to downstream signaling pathways, and changes
the expression of components of the AT(1) receptor signaling pathway. Ramip
ril attenuates these effects via kinins. Interventions that prevent local i
ncreases in Ang II or block AT(1) receptors also prevent decreased responsi
veness of the AT(1) receptor in this model.