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.
BACKGROUND
The role of kinins in the cardioprotective effects of ACE inhibitors remains controversial.


RESULTS
Right ventricular pressure overload in rabbits was produced by pulmonary artery banding for 21 days. Rabbits were untreated, or they 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 blocker losartan. Pulmonary artery banding caused right ventricular hypertrophy, depressed papillary muscle contractility, and loss of Ang II contractile effects because of a signaling defect downstream of AT(1) receptors. Paradoxically, AT(1) receptor density and G protein alpha subunits alphaq and alphai1/2 increased. Inotropic responsiveness to the alpha-receptor agonist phenylephrine was normal. Ramipril preserved cardiac contractility, but this effect was attenuated by simultaneous use of kinin receptor blockers. Ramipril also maintained responsiveness to Ang II and prevented AT(1) receptor and G protein upregulation. The simultaneous use of a kinin receptor blocker attenuated but did not prevent upregulation in the AT(1) receptor and G protein. Losartan had no effect on baseline contractility, but it maintained cardiac inotropic responsiveness to Ang II, prevented upregulation of AT(1) receptors, but did not modify G protein upregulation.


CONCLUSIONS
Pressure overload of the right ventricle decreases contractility, uncouples AT(1) receptors to downstream signaling pathways, and changes the expression of components of the AT(1) receptor signaling pathway. Ramipril attenuates these effects via kinins. Interventions that prevent local increases in Ang II or block AT(1) receptors also prevent decreased responsiveness of the AT(1) receptor in this model.
Rouleau
J L
JL
Department of Medicine, Montreal Heart Institute, Canada. jean.rouleau@uhn.on.ca
Kapuku
G
G
Pelletier
S
S
Gosselin
H
H
Adam
A
A
Gagnon
C
C
Lambert
C
C
Meloche
S
S
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D065168:Bradykinin Receptor Antagonists; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019204:GTP-Binding Proteins / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007705:Kinins / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D021122:Protein Subunits; D011651:Pulmonary Artery / Q000503:physiopathology; D011817:Rabbits; D017257:Ramipril / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy* / Q000503:physiopathology
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D007705:Kinins; D021122:Protein Subunits; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D019204:GTP-Binding Proteins; D019808:Losartan; D017257:Ramipril