Endothelin-1 receptor antagonist and adrenomedullin improve functional recovery after myocardial infarction

Abstract

Background: Endothelin 1 (ET-1) is markedly increased in myocardium during ischemia, and provides a bulk of metabolic, structural and functional disorders. Adrenomedullin (AM) is a vascular wall peptide able for a versatile control of the cardiovascular continuum.

Aim: The in vitro evaluation of the cardiac functional effects of ET-1 receptor antagonist or human recombinant AM administration in rats after myocardial infarction (MI).

Materials and methods: MI has been reproduced classically by ligation of the left coronary artery. BQ-123, a selective antagonist of ET-1 receptor type A was i/p administered immediately after MI during 7 days (0,3 mg/kg, daily). AM also during 7 days after MI was i/p continuously infused (2,0 μg/h) by using an implanted minipump. Both sham-operated rats and rats with MI but without medication received respectively saline solution. The functional indices of working isolated heart perfused by Neely-Morgan method were assessed after 2 and 5 weeks after the last medication.

Results: First and foremost is to note that both remedies significantly reduced rat mortality: 15% (BQ-123) and 18% (AM) vs 34% (MI). At the term of 2 weeks ET-1 receptor antagonist showed a better capacity to improve functional recovery. In indicated series (BQ-123, AM, MI, and control) the main left ventricle parameters followed as: systolic pressure (SP, mm Hg) – 94,5±8,5 (p<0,05 vs MI); 88,7±7,6; 77,2±7,5 and 136,3±7,4; end-diastolic pressure (EDP, mm Hg) - 14,5±0,7 (p<0,05 vs MI); 15,8±0,7 (p<0,05 vs MI); 19,2±1,4 and 10,2±0,6; izovolumetric +dP/dTmax - 8088±520 (p<0,05 vs MI); 7330±480 (p<0,05 vs MI); 6715±440 and 9677±475 and cardiac output (CO, ml/min) – 31,4±2,4 (p<0,05 vs MI); 28,3±2,5 (p<0,05 vs MI); 23,5±2,3 and 40,7±2,8. After 5 weeks functional benefit was more conspicuous, and importantly is that it appeared similar for both medications. Thus, CO increased comparatively to MI by 39–40%, PS elevated by 27–28%, and EDP has fallen averagely by 1/3. Of particular note both remedies ensured after 5 weeks a positive inotropic effect of isolated heart on ET-1 action in concentration of 10–6 M manifested by SP elevation by 6,7% (in control – 11,7%) followed respectively by CO increase almost of 10,6%. In MI series ET-1 action was associated with decrease of both SP by 9,62% and CO by 8,5%.

Conclusion: A 7 days administration of ET-1 receptor antagonist (BQ-123) or adrenomedullin ameliorates heart function recovery after MI: (i) earlier benefit (2nd week) belongs to BQ-123, (ii) but at 5th week effects appear similarly.