Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats.
OBJECTIVES; We assessed the effects of long-term amlodipine administration in a diastolic heart failure (DHF) rat model with preserved systolic function as well as the relationship between changes in left ventricular (LV) myocardial stiffening and alterations in extracellular matrix.


BACKGROUND
Although the effect of long-term administration of amlodipine has been shown to be disappointing in patients with systolic failure, the effect is unknown in those with DHF.


METHODS
Dahl salt-sensitive rats fed a high-salt diet for seven weeks were divided into three groups: eight untreated rats (DHF group), eight rats given high-dose amlodipine (10 mg/kg/day; HDA group) and seven rats given low-dose amlodipine (1 mg/kg/day; LDA group).


RESULTS
High-dose administration of amlodipine decreased systolic blood pressure and controlled excessive hypertrophy, without a decrease in the collagen content, and prevented the elevation of LV end-diastolic pressure at 19 weeks. Low-dose administration of amlodipine with subdeppressive effects did not control either hypertrophy or fibrosis; however, it prevented myocardial stiffening and, hence, the elevation of LV end-diastolic pressure. The ratio of type I to type III collagen messenger ribonucleic acid levels was significantly lower in both the HDA and LDA groups than in the DHF group.


CONCLUSIONS
Long-term administration of amlodipine prevented the transition to DHF both at the depressor and subdepressor doses. Amlodipine did not decrease the collagen content, but attenuated myocardial stiffness, with inhibition of the phenotype shift from type III to type I collagen. Thus, amlodipine may exert beneficial effects through amelioration of collagen remodeling in the treatment of DHF.
Nishikawa
N
N
Department of Internal Medicine and Therapeutics (A8), Suita, Japan.
Masuyama
T
T
Yamamoto
K
K
Sakata
Y
Y
Mano
T
T
Miwa
T
T
Sugawara
M
M
Hori
M
M
D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D003094:Collagen / Q000032:analysis / Q000235:genetics; D003971:Diastole / Q000187:drug effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D017548:Echocardiography, Transesophageal; D006333:Heart Failure / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy*; D007150:Immunohistochemistry; D016018:Least-Squares Analysis; D016014:Linear Models; D008297:Male; D009206:Myocardium / Q000737:chemistry; D010641:Phenotype; D011897:Random Allocation; D051381:Rats; D020303:Rats, Inbred Dahl; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D017311:Amlodipine; D003094:Collagen