Adrenomedullin-epinephrine cotreatment enhances cardiac output and left ventricular function by energetically neutral mechanisms

Abstract

Adrenomedullin (AM) used therapeutically reduces mortality in the acute phase of experimental myocardial infarction. However, AM is potentially deleterious in acute heart failure as it is vasodilative and inotropically neutral. AM and epinephrine (EPI) are cosecreted from chromaffin cells, indicating a physiological interaction. We assessed the hemodynamic and energetic profile of AM-EPI cotreatment, exploring whether drug interaction improves cardiac function. Left ventricular (LV) mechanoenergetics were evaluated in 14 open-chest pigs using pressure-volume analysis and the pressure-volume area-myocardial O2 consumption (PVA-MV˙o2) framework. AM (15 ng·kg−1·min−1, n = 8) or saline (controls, n = 6) was infused for 120 min. Subsequently, a concurrent infusion of EPI (50 ng·kg−1·min−1) was added in both groups (AM-EPI vs. EPI). AM increased cardiac output (CO) and coronary blood flow by 20 ± 10% and 39 ± 14% (means ± SD, P < 0.05 vs. baseline), whereas controls were unaffected. AM-EPI increased CO and coronary blood flow by 55 ± 17% and 75 ± 16% ( P < 0.05, AM-EPI interaction) compared with 13 ± 12% ( P < 0.05 vs. baseline) and 18 ± 31% ( P = not significant) with EPI. LV systolic capacitance decreased by −37 ± 22% and peak positive derivative of LV pressure (dP/d tmax) increased by 32 ± 7% with AM-EPI ( P < 0.05, AM-EPI interaction), whereas no significant effects were observed with EPI. Mean arterial pressure was maintained by AM-EPI and tended to decrease with EPI (+2 ± 13% vs. −11 ± 10%, P = not significant). PVA-MV˙o2 relationships were unaffected by all treatments. In conclusion, AM-EPI cotreatment has an inodilator profile with CO and LV function augmented beyond individual drug effects and is not associated with relative increases in energetic cost. This can possibly take the inodilator treatment strategy beyond hemodynamic goals and exploit the cardioprotective effects of AM in acute heart failure.