Cellular and molecular mechanisms of tissue protection by lipophilic calcium channel blockers.
Long-acting third-generation dihydropyridine calcium channel blockers (CCBs) improve endothelial dysfunction and prevent cardiovascular events in humans, but their cellular and molecular mechanisms of tissue protection are not elucidated in detail. We assessed organ (renal) protection by the highly lipophilic CCB lercanidipine in a double-transgenic rat (dTGR) model with overexpression of human renin and angiotensinogen genes. We randomly treated dTGR with lercanidipine (2.5 mg/kg/day; n=20) or vehicle (n=20) for 3 wk. Furthermore, we explored the influence of lercanidipine on protein kinase C (PKC) signaling in vivo and in vitro using endothelial and vascular smooth muscle cell cultures. Cumulative mortality was 60% in untreated dTGR, whereas none of the lercanidipine-treated animals died (P<0.001). We found significantly less albuminuria and improved renal function in lercanidipine-treated dTGR (both P<0.05). Lercanidipine treatment also significantly (P<0.05) reduced blood levels of the endogenous NOS inhibitor asymmetric dimethylarginine. On histological examination, we observed significantly less tissue inflammation and fibrosis in lercanidipine-treated animals (both P<0.05). Lercanidipine significantly inhibited angiotensin (ANG) I-mediated PKC-alpha and -delta activation in vivo and in vitro, partly due to reduced intracellular calcium flux. As a result, lercanidipine improved endothelial cell permeability in vitro. Lercanidipine prevents tissue injury and improves survival in a model of progressive organ damage. These effects may result, at least in part, from inhibition of tissue inflammation as well as improved NO bioavailability. Modulation of PKC activity may be an important underlying intracellular mechanism.
Menne
Jan
J
Department of Internal Medicine, Medical School Hannover, Carl-Neuberg-Strasse 1, Hannover 30625, Germany. janmenne@gmx.de
Park
Joon-Keun
JK
Agrawal
Rahul
R
Lindschau
Carsten
C
Kielstein
Jan T
JT
Kirsch
Torsten
T
Marx
Axel
A
Muller
Dominik
D
Bahlmann
Ferdinand H
FH
Meier
Matthias
M
Bode-Böger
Stefanie M
SM
Haller
Hermann
H
Fliser
Danilo
D
D000418:Albumins / Q000378:metabolism; D000581:Amidohydrolases / Q000378:metabolism; D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics / Q000378:metabolism
D000418:Albumins; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C487735:dimethylarginine; D000808:Angiotensinogen; D000804:Angiotensin II; D001120:Arginine; D012083:Renin; D000581:Amidohydrolases; C059999:dimethylargininase; C060343:lercanidipine