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

Background-To investigate whether endogenous ET-1 participates in an a daptive process of left ventricular hypertrophy (LVH) or a maladaptive process from LVH to congestive heart failure (CHF), we used a Dahl sa lt-sensitive (DS) rat model, in which systemic hypertension caused com pensated concentric LVH at the age of 11 weeks followed by marked LV d ilatation and global hypokinesis at the age of 17 weeks. Methods and R esults-By specific sandwich enzyme immunoassay, serum and myocardial E T-1 levels at the LVH stage were not elevated compared with age-matche d Dahl salt-resistant (DR) rats, despite the marked increase of LV/bod y weight ratio (LV/BW). However, at the CHF stage, serum and LV ET-1 l evels increased by 3.8-fold and 5.4-fold, respectively. LV ET-1 conten ts had close relationships with the fractional shortening (r=0.763) an d the systolic wall stress (r=0.858) measured by in vivo transthoracic echocardiography. Immunohistochemistry demonstrated that the remarkab ly increased ET-1 in LV is located mainly in cardiomyocytes. By compet itive reverse transcriptase-polymerase chain reaction, LV prepro-ET-1 mRNA levels increased by 4.1-fold in CHF rats. We randomized 11-week-o ld LVH rats to chronic treatment with the endothelin receptor antagoni st bosentan (Bos, 100 mg.kg(-1).d(-1), n=14), the alpha(1)-receptor an tagonist 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 w eeks; however, it attenuated the decrease of LV fractional shortening by 51% (P<0.01) without reducing the LV/BW at 17 weeks. Conversely, Do x, which decreased the blood pressure to the same extent as Bos, did n ot affect the progression of LV dysfunction. Bos (93%; P<0.0001 versus Cont) but not Dox (42%; P=0.8465 versus Cent) ameliorated the surviva l 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 b osentan treatment suggest that myocardial growth is mediated through a lternative pathways. These studies indicate that chronic ET antagonism may provide an additional strategy for heart failure therapy in human s.