Abstract 961: Adrenomedullin Acutely Decreases Myocardial Stiffness - An Endocardial Endothelium Mediated-effect
Background: Adrenomedullin (AM) is a potent, long-lasting vasoactive peptide originally isolated from human pheochromocytoma. However, the mRNA is expressed in a variety of tissues, including the cardiovascular system. AM has hypotensive, diuretic and natriuretic properties but its role in the development of cardiac pathologies is less clear, considering that it produces disparate biological effects in the cardiovascular system. In the current study, we investigated the, yet unknown, acute effects of AM on the diastolic properties of the myocardium.
Methods: Effects of increasing concentrations of AM (10−10 to 10−6M) were evaluated in isolated right papillary muscles from male New Zealand White rabbits (Krebs-Ringer: 1,8mM CaCl2, 35°C) in the presence of intact endocardial endothelium (EE) (n=10) and damaged EE (n=9). Reported parameters include: active tension (AT; mN/mm2), passive tension (PT; mN/mm2) and muscle length (L; L/Lmax). Only significant results (means±SEM, p<0.05) are given, expressed as % change from baseline.
Results: In papillary muscles with intact EE, AM induced a significant concentration-dependent negative inotropic effect, with the highest concentration decreasing the AT by 17.8±5.4%. It also promoted a concentration-dependent increase in resting muscle length (increased diastolic distensibility) up to 1.009± 0,003 L/Lmax at the highest concentration. Correcting muscle length to its initial value resulted in a 25.0±5.9% decrease of PT, indicating decreased muscle stiffness. The effects of AM on diastolic distensibility were abolished after damaging EE.
Conclusion: The present study showed that AM significantly decreased PT, indicating a decrease in myocardial stiffness, an effect that is dependent of the EE. This effect is a potentially powerful physiologic mechanism, as it may allow the heart to reach the same diastolic volume with up to 25% lower filling pressures. Furthermore, as the plasma AM levels are increased in cardiovascular diseases such as heart failure, this is a novel finding with potential pathophysiologic and therapeutic implications in this syndrome, which deserves further investigation.