title: 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.
abstract: 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.
  
  
  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 alpha1-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.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Iwanaga
authors.forename: Y
authors.initials: Y
authors.lastname: Kihara
authors.forename: K
authors.initials: K
authors.lastname: Hasegawa
authors.forename: K
authors.initials: K
authors.lastname: Inagaki
authors.forename: T
authors.initials: T
authors.lastname: Yoneda
authors.forename: S
authors.initials: S
authors.lastname: Kaburagi
authors.forename: M
authors.initials: M
authors.lastname: Araki
authors.forename: S
authors.initials: S
authors.lastname: Sasayama
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000150:complications* / Q000503:physiopathology; D004452:Echocardiography; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D016232:Endothelins / Q000235:genetics; D006333:Heart Failure / Q000209:etiology*; D007150:Immunohistochemistry; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D016019:Survival Analysis; D013599:Systole / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000209:etiology*
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger