Therapy with the nonpeptide endothelin receptor antagonist 97-139 in a murine model of congestive heart failure - Reduction of cardiac mass and myofiber hypertrophy

Endothelin-l (ET-1) is a potent vasoconstrictor, This peptide exerts numero us effects on the heart, including regulation of cardiomyocyte growth durin g hypertrophy. The effects of the structurally novel, nonpeptide, ET-1-sele ctive, competitive antagonist (ETA) 97-139 were investigated in mice with c ongestive heart failure (CHF) and myocardial hypertrophy. Morphological and microscopical analyses were conducted on day 56 after viral inoculation fo llowing 28 day treatment with 99-139, Eight week-old DBA2 mice were intrape ritoneally inoculated with encephalomyocarditis virus at a dose of 500 pfu / mouse. The 30 mice were divided into two groups-an ETA treated group and an untreated group. Heart weight (HW) in the infected group was significant ly (p < 0.05) increased compared to that in the uninfected group. HW and th e HUT / body weight (BW) ratio were significantly (p < 0.05) reduced in the ETA treated group compared with the untreated group (HW; 127.7 +/- 6.2mg v s 144.3 +/- 4.2 mg, HW/BW; 4.9 +/- 0.9x10(-3) vs 5.4+/-0.5x10(-3)). Myofibe r diameter in the ETA treated group was significantly reduced compared with the untreated group (12.1 +/- 1.5 mu m vs 14.3 +/- 1.9 mu m). These result s suggest the ET-I receptor antagonist 97-139 has an effect on the reductio n of cardiac mass and myofiber hypertrophy, and that 97-139 may be a useful agent for CHF due to viral myocarditis.