Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction.
OBJECTIVE
Congestive heart failure with left ventricular (LV) diastolic dysfunction and preserved systolic function, i.e. diastolic heart failure (DHF), is often observed in hypertensive patients. Although angiotensin converting enzyme (ACE) inhibitors are widely used as antihypertensive therapy, there is a continued controversy about long-term effect of ACE inhibition on diastolic function. The current study was designed to elucidate a therapeutic effect of ACE inhibitor, temocapril, administration initiated after LV hypertrophy (LVH) and diastolic dysfunction are evident.


METHODS
Dahl salt sensitive rats fed on 8% NaCl diet from 7 weeks (hypertensive DHF model) were studied at 13 weeks (n=6) or at 19 weeks following chronic administration of a subdepressor dose of temocapril (0.2 mg/kg/day, TEM(+), n=6) or placebo (TEM(-), n=7) from 13 weeks.


RESULTS
Compensatory LVH was associated with prolonged time constant of LV relaxation (Tau) at 13 weeks. In TEM(-), progression of LVH and fibrosis and elevation of LV end diastolic pressure were observed at 19 weeks. Administration of temocapril from 13 weeks prevented the further progression of LVH and fibrosis, attenuated increases in myocardial stiffness constant and Tau, and prevented the development of DHF. These effects were accompanied with the attenuation of decreases in sarcoplasmic reticulum calcium(2+)-ATPase 2a and phosphorylated phospholamban and of hypertrophic signalings' upregulation.


CONCLUSIONS
This study demonstrated that chronic administration of temocapril exerts a therapeutic effect on diastolic dysfunction and prevents the transition to DHF even if initiated after appearance of LVH and diastolic dysfunction.
Sakata
Yasushi
Y
Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, Suita, Japan.
Yamamoto
Kazuhiro
K
Mano
Toshiaki
T
Nishikawa
Nagahiro
N
Yoshida
Junichi
J
Miwa
Takeshi
T
Hori
Masatsugu
M
Masuyama
Tohru
T
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000517:prevention & control*; D006439:Hemodynamics; D006973:Hypertension / Q000188:drug therapy; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020303:Rats, Inbred Dahl; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013841:Thiazepines / Q000627:therapeutic use*; D016277:Ventricular Function, Left; D000099211:Phospholamban
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D012333:RNA, Messenger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013841:Thiazepines; D000099211:Phospholamban; C055603:temocapril hydrochloride