Calcineurin inhibitor attenuates left ventricular hypertrophy, leading to prevention of heart failure in hypertensive rats.
BACKGROUND
There is controversy regarding the contribution of calcineurin activation to the development of pressure-overload left ventricular (LV) hypertrophy and heart failure. The aim of this study was to explore whether the inhibition of calcineurin may prevent the transition to heart failure in hypertensive rats and, if so, to clarify in which developmental stage of LV hypertrophy calcineurin plays a key role.


RESULTS
Dahl salt-sensitive rats placed on an 8% NaCl diet from the age of 7 weeks (hypertensive rats) were randomized to no treatment (n=6) or treatment with the calcineurin inhibitor FK506 (1 mg x kg(-1) x d(-1)) from 8 weeks (FKE, n=7) or from 17 weeks (FKL, n=7). Rats placed on a 0.3% NaCl diet were defined as control rats (n=6). The administration of FK506 from 8 weeks attenuated, although it did not block, LV hypertrophy observed in the untreated rats and prevented the transition to heart failure. The development of LV fibrosis, however, was not attenuated by the administration of FK506 from 8 weeks. The administration of FK506 from 17 weeks brought no benefit for cardiac remodeling or LV function and failed to prevent heart failure.


CONCLUSIONS
Calcineurin inhibition, if started from the initial stage of pressure overload, attenuated the development of LV hypertrophy without any effect on LV fibrosis and prevented the transition to heart failure. The activation of calcineurin is involved in the development of LV hypertrophy but not of LV fibrosis, and this involvement may be crucial at the initial stage.
Sakata
Y
Y
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Yamadaoka, Suita 565-0871, Japan.
Masuyama
T
T
Yamamoto
K
K
Nishikawa
N
N
Yamamoto
H
H
Kondo
H
H
Ono
K
K
Otsu
K
K
Kuzuya
T
T
Miwa
T
T
Takeda
H
H
Miyamoto
E
E
Hori
M
M
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D065095:Calcineurin Inhibitors; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004452:Echocardiography; D005355:Fibrosis / Q000209:etiology / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000235:genetics; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D012965:Sodium Chloride; D016559:Tacrolimus / Q000008:administration & dosage*
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D012965:Sodium Chloride; D009320:Atrial Natriuretic Factor; D016559:Tacrolimus