(Circulation. 1998;98:2065-2073.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Cardiac Endothelin-1 Plays a Critical Role in the Functional Deterioration of Left Ventricles During the Transition From Compensatory Hypertrophy to Congestive Heart Failure in Salt-Sensitive Hypertensive Rats
From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Correspondence to Yasuki Kihara, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail kihara{at}kuhp.kyoto-u.ac.jp
Background—To investigate whether endogenous ET-1 participates in an adaptive process of left ventricular hypertrophy (LVH) or a maladaptive process from LVH to congestive heart failure (CHF), we used a Dahl salt-sensitive (DS) rat model, in which systemic hypertension caused compensated concentric LVH at the age of 11 weeks followed by marked LV dilatation and global hypokinesis at the age of 17 weeks.
Methods and Results—By specific sandwich enzyme immunoassay,
serum and myocardial ET-1 levels at the LVH stage were not elevated
compared with age-matched Dahl salt-resistant (DR) rats,
despite the marked increase of LV/body weight ratio (LV/BW). However,
at the CHF stage, serum and LV ET-1 levels increased by 3.8-fold and
5.4-fold, respectively. LV ET-1 contents had close relationships with
the fractional shortening (r=0.763) and the
systolic wall stress (r=0.858) measured by in
vivo transthoracic echocardiography.
Immunohistochemistry demonstrated that the remarkably increased ET-1 in
LV is located mainly in cardiomyocytes. By competitive
reverse transcriptase–polymerase chain reaction, LV prepro-ET-1 mRNA
levels increased by 4.1-fold in CHF rats. We randomized 11-week-old LVH
rats to chronic treatment with the endothelin receptor
antagonist bosentan (Bos, 100 mg ·
kg-1 · d-1, n=14), the
1-receptor antagonist doxazosin (Dox, 1
mg · kg-1 · d-1, n=12), or
vehicle (Cont, n=14). Bos treatment did not alter the LV geometry and
function at 15 weeks; however, it attenuated the decrease of LV
fractional shortening by 51% (P<0.01) without reducing
the LV/BW at 17 weeks. Conversely, Dox, which decreased the blood
pressure to the same extent as Bos, did not affect the progression of
LV dysfunction. Bos (93%; P<0.0001 versus Cont) but
not Dox (42%; P=0.8465 versus Cont) ameliorated the
survival rate at 17 weeks (Cont; 36%).
Conclusions—The accelerated myocardial synthesis of ET-1 contributes directly to LV contractile dysfunction during the transition from LVH to CHF. Unelevated levels of LV ET-1 at the established LVH stage and lack of effects on LV mass by chronic bosentan treatment suggest that myocardial growth is mediated through alternative pathways. These studies indicate that chronic ET antagonism may provide an additional strategy for heart failure therapy in humans.
Key Words: endothelin • heart failure • hypertrophy • remodeling • hypertension
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