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Effects of adrenomedullin on human myocyte contractile function and beta-adrenergic response
Rupak Mukherjee1, M Marlina Multani, Jeffrey A Sample
1Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Insights
Adrenomedullin, a peptide known for vasodilation, was found to reduce contractility in human heart cells. It also negatively interacted with the beta-adrenergic system, impacting heart muscle function.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
Background:
- Adrenomedullin (ADM) is a peptide hormone known to induce systemic vasodilation.
- Elevated plasma ADM levels are associated with cardiovascular diseases like heart failure.
- While ADM receptors are present in the myocardium, its direct impact on human myocyte contractility was previously uncharacterized.
Purpose of the Study:
- To investigate the direct effects of adrenomedullin on the contractility of isolated human left ventricular myocytes.
- To explore the potential interaction between adrenomedullin and the beta-adrenergic receptor system in human cardiac myocytes.
Main Methods:
- Human left ventricular myocytes were isolated from myocardial biopsies of patients undergoing coronary artery bypass surgery.
- Myocyte shortening velocity was measured using videomicroscopy at baseline and after exposure to varying concentrations of adrenomedullin.
- The effect of adrenomedullin on beta-adrenergic receptor-mediated contractility was assessed using isoproterenol.
Main Results:
- Adrenomedullin significantly reduced myocyte shortening velocity in a dose-dependent manner.
- The presence of adrenomedullin blunted the increase in myocyte shortening velocity induced by isoproterenol, indicating an interaction with the beta-adrenergic system.
- These findings were observed in myocytes with normal left ventricular ejection fractions.
Conclusions:
- Adrenomedullin exerts a negative inotropic effect on isolated human left ventricular myocytes.
- Adrenomedullin negatively interacts with the beta-adrenergic receptor system, potentially modulating cardiac response to adrenergic stimulation.
- This study reveals a dual role for adrenomedullin, causing systemic vasodilation while also reducing myocardial contractility.
Background:
Adrenomedullin has been demonstrated to cause systemic vasodilation, and increased plasma adrenomedullin levels have been observed in cardiovascular disease states such as heart failure. While adrenomedullin receptors have been localized to the myocardium, the effects of adrenomedullin on human myocyte contractility remained unknown.
Methods And Results:
Left ventricular myocytes were isolated from myocardial biopsies of patients (n = 16) undergoing elective coronary artery bypass surgery with normal left ventricular ejection fractions (51 +/- 1%). A total of 233 left ventricular myocytes were studied by videomicroscopy. Myocyte shortening velocity (microm/s) was measured at baseline and following the addition of either 3 nM, 30 nM, or 60 nM of adrenomedullin. The change in myocyte shortening velocity with increasing concentrations of adrenomedullin was computed. At all concentrations, adrenomedullin reduced myocyte shortening velocity from baseline values (P < 0.05). Next, the potential interaction of adrenomedullin with the beta-adrenergic receptor system was examined using 25 nM isoproterenol. The beta-adrenergic receptor-mediated increase in the myocyte shortening velocity was blunted with adrenomedullin (29 +/- 7 vs 63 +/- 13 microm/s, P < 0.05).
Conclusions:
These unique findings demonstrate that adrenomedullin reduced contractility in isolated human left ventricular myocytes and exhibited a negative interaction with the beta-adrenergic receptor system. Past studies have shown that adrenomedullin induces nitric oxide synthesis and that nitric oxide can uncouple myocyte metabolism. Thus, while adrenomedullin causes systemic vasodilation, this peptide can also exert a negative contractile effect in human left ventricular myocytes.