Effects of levosimendan on cardiac remodeling and cardiomyocyte apoptosis in hypertensive Dahl/Rapp rats.
OBJECTIVE
Progression of heart failure in hypertensive Dahl rats is associated with cardiac remodeling and increased cardiomyocyte apoptosis. This study was conducted to study whether treatment with a novel inotropic vasodilator compound, levosimendan, could prevent hypertension-induced cardiac remodeling and cardiomyocyte apoptosis.


METHODS
6-week-old salt-sensitive Dahl/Rapp rats received levosimendan (0.3 mg kg(-1) and 3 mg kg(-1) via drinking fluid) and high salt diet (NaCl 7%) for 7 weeks, Dahl/Rapp rats on low-salt diet served as controls. Blood pressure, cardiac functions by echocardiography, cardiomyocyte apoptosis by TUNEL technique, tissue morphology, myocardial expression of calcium cycling proteins, and markers of neurohumoral activation were determined.


RESULTS
Untreated Dahl/Rapp rats on high salt diet developed severe hypertension, cardiac hypertrophy and moderate systolic dysfunction. 38% of Dahl/Rapp rats (9/24) survived the 7-week-follow-up period. Cardiomyocyte apoptosis was increased by 6-fold during high salt diet. Levosimendan improved survival (survival rates in low- and high-dose levosimendan groups 12/12 and 9/12, p<0.001 and p=0.05, respectively), increased cardiac function, and ameliorated cardiac hypertrophy. Levosimendan dose-dependently prevented cardiomyocyte apoptosis. Levosimendan normalized salt-induced increased expression of natriuretic peptide, and decreased urinary noradrenaline excretion. Levosimendan also corrected salt-induced decreases in myocardial SERCA2a protein expression and myocardial SERCA2a/NCX-ratio.


CONCLUSIONS
Improved survival by the novel inotropic vasodilator levosimendan in hypertensive Dahl/Rapp rats is mediated, at least in part, by amelioration of hypertension-induced cardiac remodeling and cardiomyocyte apoptosis.
Louhelainen
M
M
Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
Vahtola
E
E
Kaheinen
P
P
Leskinen
H
H
Merasto
S
S
Kytö
V
V
Finckenberg
P
P
Colucci
W S
WS
Levijoki
J
J
Pollesello
P
P
Haikala
H
H
Mervaala
E M A
EM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006835:Hydrazones / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000235:genetics; D009638:Norepinephrine / Q000652:urine; D053495:Osteopontin / Q000235:genetics; D011724:Pyridazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D000077464:Simendan; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects*
C506948:Atp2a2 protein, rat; D006835:Hydrazones; D011724:Pyridazines; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; C506897:Spp1 protein, rat; D014665:Vasodilator Agents; C472610:atrial natriuretic peptide, rat; C495963:natriuretic peptide precursor type B, rat; D053495:Osteopontin; D020097:Natriuretic Peptide, Brain; D000077464:Simendan; D009320:Atrial Natriuretic Factor; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D009638:Norepinephrine