Mechanism of diastolic stiffening of the failing myocardium and its prevention by angiotensin receptor and calcium channel blockers.
OBJECTIVE
To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)].


METHODS
DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls.


RESULTS
Treatment with OLM plus AZE attenuated changes in the expression of collagen isoforms and a decrease in the ratio of elastin to collagen in the left ventricle and prevented the increase in myocardial stiffness and diastolic dysfunction in DS rats in a manner independent of the hypotensive effect of these drugs. Such treatment also inhibited the expression and activation of elastolytic proteases (including cathepsins S and K and metalloproteinases-2, -9, and -12), NADPH oxidase-dependent superoxide production, and inflammatory changes in the failing myocardium. All these effects were mimicked by treatment with apocynin.


CONCLUSIONS
The changes in collagen isoform expression and the decrease in the elastin to collagen ratio in the failing myocardium likely account for the increase in diastolic stiffness in this model of hypertensive heart failure. Administration of angiotensin receptor and calcium channel blockers prevented these changes in a manner independent of the hypotensive effect of these drugs by inhibiting the increase in elastolytic activity induced by activation of NADPH oxidase.
Cheng
Xian Wu
XW
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. xianwu@med.nagoya-u.ac.jp
Okumura
Kenji
K
Kuzuya
Masafumi
M
Jin
Zhehu
Z
Nagata
Kohzo
K
Obata
Koji
K
Inoue
Aiko
A
Hirashiki
Akihiro
A
Takeshita
Kyosuke
K
Unno
Kazumasa
K
Harada
Ken
K
Shi
Guo-Ping
GP
Yokota
Mitsuhiro
M
Murohara
Toyoaki
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D004095:Dihydropyridines / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D001383:Azetidinecarboxylic Acid; C437965:olmesartan; C061679:azelnidipine