The Positive Inotropic Effect of Relaxin-2 in Human Atrial Myocardium is Preserved in End-Stage Heart Failure: Role of G_i-Phosphoinositide-3 Kinase Signaling

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• 作者：Thomas Dschietzig MD¹ ; ^{thomas.dschietzig@charite.de} ; Konstantin Alexiou MD² ; Hans-Tilman Kinkel MD¹ ; Gert Baumann MD¹ ; Klaus Matschke MD² ; Karl Stangl MD¹
• 关键词：Heart failure ; myocardium ; Gi protein
• 刊名：Journal of Cardiac Failure
• 出版年：2011
• 出版时间：February 2011
• 年：2011
• 卷：17
• 期：2
• 页码：158-166
• 全文大小：362 K

文摘

Background

Relaxin-2, a candidate drug for acute heart failure, has been tested successfully in the first human trials. We investigated relaxin’s inotropic effects in human myocardium.

Methods and Results

In atrial samples from donor (n = 7) and failing (n = 7) hearts, relaxin-2 evoked remarkable positive inotropic effects: showing a half maximum effective concentration of < 1 nmol/L, the maximum peak developed tension (PDT) rose to approximately 270 % of baseline, without differences between failing and nonfailing myocardium. The effects critically depended on protein kinase A activation and inhibition of the transient potassium outward current; phosphoinositide-3 kinase inhibition and pertussis toxin pretreatment moderately blunted the effects in nonfailing but markedly suppressed them in failing myocardium. Action potential recordings revealed identical effects of inhibition of the transient potassium outward current and relaxin. In ventricular myocardium, however, relaxin did not show any inotropic effects. The expression of the RXFP1 receptor was moderately decreased in failing compared with nonfailing atrial myocardium but not detectable in any ventricular samples.

Conclusions

Relaxin is a positive inotrope in nonfailing and failing human atria, with critical involvement of protein kinase A and inhibition of the transient potassium outward current and an increasing role for G_i protein–phosphoinositide-3 kinase signaling in failing myocardium.