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EXPERIMENTAL STUDY

Long-term administration of amlodipine prevents decompensation to diastolic heart failure in hypertensive rats

Nagahiro Nishikawa, MD^*, Tohru Masuyama, MD, PhD, FACC^*,*, Kazuhiro Yamamoto, MD, PhD, FACC^*, Yasushi Sakata, MD^*, Toshiaki Mano, MD, PhD^*, Takeshi Miwa, PhD, Motoaki Sugawara, PhD and Masatsugu Hori, MD, PhD, FACC^*

^* Department of Internal Medicine and Therapeutics (A8), Suita, Japan
Genome Information Research Center, Osaka University, Suita, Japan
Department of Cardiovascular Sciences, Tokyo Women’s Medical University, Tokyo, Japan

Manuscript received April 26, 2001; revised manuscript received July 10, 2001, accepted July 26, 2001.

^* Reprint requests and correspondence: Dr. Tohru Masuyama, Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan
masuyama{at}medone.med.osaka-u.ac.jp

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.

Abbreviations and Acronyms   BP = blood pressure   CHF = congestive heart failure   Dahl-SS = Dahl-Iwai salt-sensitive rats   DHF = diastolic heart failure   ECM = extracellular matrix   HDA = high-dose amlodipine   LDA = low-dose amlodipine   LV = left ventricular   mRNA = messenger ribonucleic acid   MSC = myocardial stiffness constant   PRAISE II = Prospective Randomized AmlodIpine Survival Evaluation II   tau = time constant of isovolumic left ventricular pressure fall

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