Atrial myocardium is the predominant inotropic target of adrenomedullin in the human heart

Bisping, Egbert; Tenderich, Gero; Barckhausen, Paul; Stumme, Burkhard; Bruns, Sebastian; Lewinski, Dirk von; Pieske, Burkert

doi:10.1152/ajpheart.01276.2006

Cited by 19 publications

(13 citation statements)

References 35 publications

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“…Admr, receptor of the potent vasodilator adrenomedullin, and its chaperone protein Ramp2 were both highly expressed in the right atrium, whereas the related CALCRL receptor, together with its chaperone protein Ramp1, were expressed throughout the heart. This result is consistent with data showing that adrenomedullin exerts Ca 2ϩ -dependent-positive inotropic effects in human atria and, to a lesser extent, in ventricular myocardium (Bisping et al, 2007). Only the chemokine Ccr10rr receptor and two orphan receptors, Pgr1 and GPR162, constituted the signature of the left atrium.…”

Section: Discussionsupporting

confidence: 92%

Identification of Potential Pharmacological Targets by Analysis of the Comprehensive G Protein-Coupled Receptor Repertoire in the Four Cardiac Chambers

Moore-Morris¹,

Varrault²,

Mangoni³

et al. 2009

Molecular Pharmacology

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Cardiac function is regulated by many hormones and neurotransmitters that exert their physiological effects through the activation of G protein-coupled receptors (GPCRs). Identification of new GPCRs that might display a specific pattern of expression within the heart and differentially regulate specific cardiac functions represents an important issue for the development of new drugs. Indeed, highly targeted receptors represent only a small percentage of known GPCRs. Here, we quantified the expression of 395 endoGPCRs (all GPCRs excluding taste and odorant receptors) in male mouse right and left atria and ventricles by using high-throughput real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and focused on the 135 most highly expressed transcripts. No cardiac functional data are available for almost half of these receptors; therefore, linking GPCR expression patterns to cardiac function has allowed us to provide new insights into the possible function of some of these receptors. Indeed, ventricles and atria are both contractile; however, the latter, and especially the right atrium, are central to the generation and regulation of cardiac rhythm. Accordingly, the right atrium exhibited the most specific signature, whereas the majority of GPCRs found in ventricles were evenly expressed in both the right and left chambers. RT-PCR data were confirmed at the protein level for six selected transcripts. Furthermore, we provide new data showing that, as suggested by our repertoire, the metabotropic glutamate receptor 1b is expressed and is functional in ventricular cardiac myocytes. This is the first report describing GPCRs in the four cardiac chambers and may assist in the identification of therapeutic targets.The four cardiac chambers display morphological and functional differences. They can be distinguished on the basis of contractile properties, rhythm generation, and response to neurohumoral stimulation (Brown et al., 1991;Barth et al., 2005;Narolska et al., 2005). Contractile activity of the heart ensures that blood flow is adapted to the needs of the organism. Left ventricular performance depends on the chamber's capacity to fill up (diastolic property) and to empty (systolic property), and these properties are altered in pathological conditions, the final consequence being heart failure. To trigger the contractile activity, cardiac automaticity is generated by a set of specialized pacemaker cells forming the sinoatrial node (SAN) (Mangoni and Nargeot, 2008). Compared with myocytes of the working myocardium, pacemaker SAN cells are devoted to the generation of an electrical oscillation rather than having a contractile activity. At the molecular level, heart chamber heterogeneity is reflected by the expression patterns of different sets of genes such as transcription factors (Tabibiazar et al., 2003) and ion channels (Marionneau et al., 2005). The heart expresses GPCRs (Regard et al.,

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Section: Discussionsupporting

confidence: 92%

Identification of Potential Pharmacological Targets by Analysis of the Comprehensive G Protein-Coupled Receptor Repertoire in the Four Cardiac Chambers

Moore-Morris¹,

Varrault²,

Mangoni³

et al. 2009

Molecular Pharmacology

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“…AM is a vasorelaxant peptide with favorable hemodynamic effects in vivo. Prior studies suggest that AM exerts potent inotropic effect in the atria as well as in the ventricle (2,45). We found that atrial stretch led to a significant decrease in both AM and AM receptor mRNA levels, suggesting a substantial downregulation of local AM system.…”

Section: Discussionsupporting

confidence: 51%

Key roles of endothelin-1 and p38 MAPK in the regulation of atrial stretch response

Kerkelä

Ilves

Pikkarainen

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Mechanisms regulating stretch response in the left ventricle are investigated in detail but not well understood in atrial myocardium. Hypertrophic growth of atrial myocardium contributes to the pathogenesis of atrial fibrillation. In this study, we sought to elucidate mechanisms of stretch-induced activation of key signaling pathways and hypertrophy-associated genes in rat atria. Stretching of isolated atria induced a rapid increase in phosphorylation of p38 MAPK and ERK and induced a p38 MAPK-dependent increase in DNA binding activity of transcription factors Elk-1 and GATA-4. Inhibition of the ERK pathway had no effect on the cardiac transcription factors studied. Stretch-induced increase in atrial contractile function was substantially enhanced by inhibition of p38 MAPK. p38 MAPK also regulated stretch-induced increase in c-fos, ␤-myosin heavy chain, B-type natriuretic peptide mRNA levels, and atrial natriuretic peptide secretion in isolated atria. Various autocrine/paracrine factors are known to mediate the stretch response in the left ventricle. Stretching of isolated atria resulted in a robust increase in endothelin-1 (ET-1) mRNA levels, while apelin and adrenomedullin signaling cascades were downregulated. Administration of mixed ET A/B receptor antagonist bosentan attenuated the stretch-induced activation of GATA-4 in isolated atria, whereas ANG II receptor type-1 antagonist CV-11974 had no effect. Moreover, analysis of RNA from intact atrial and ventricular myocardium revealed significantly higher mRNA levels of ETA receptor and ET converting enzyme-1 in atrial compared with ventricular myocardium. In conclusion, our findings identify the local ET-1 system and p38 MAPK as key regulators of load-induced hypertrophic response in isolated rat atria.

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“…However, the response of atrial myocardium to various agents could be different from that of the ventricular myocardium. Endothelin [16], calcitonin gene-related peptide [17], and adrenomedulin (ADM) [18] all show pronounced inotropic effects on the atrial myocardium but smaller or even no (angiotensin II) effect on the ventricular myocardium. Flagg et al [19] found a previously unidentified K ATP channel heterogeneity: SUR1 is an essential component of the K ATP channels in atrial but not ventricular cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Opens the K<sub>ATP </sub>Channel on Rat Atrial and Ventricular Myocytes

Zhong¹,

Li²,

Liu³

et al. 2009

Cardiology

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Objective: Hydrogen sulfide (H₂S), an endogenous gaseous transmitter, was found to protect the heart from various forms of injury, but the underlying mechanism is not known. H₂S can open the K_ATP channel on vascular smooth muscle cells, and the objective of this study was to determine whether H₂S can open the K_ATP channel on myocardiocytes. Methods: The whole-cell patch-clamp technique was used to record I_K,ATP and action potentials of atrial and ventricular myocytes isolated from the hearts of male Wistar rats. Sodium hydrogen sulfide (NaHS) was used as a donor of H₂S to observe the effect of exogenous H₂S on I_K,ATP. DL-propargylglycine (PPG), an inhibitor of the synthesis of H₂S, was used at a concentration of 200 µM to observe the effect of endogenous H₂S on I_K,ATP. Results: NaHS at concentrations (in µM) of 9.375, 18.75, 37.5, 75 and 150 increased I_K,ATP by 12.8% (p > 0.05), 28.4% (p < 0.05), 38.8% (p < 0.01), 51.2% (p < 0.01) and 58.6% (p< 0.01) on ventricular myocytes, respectively, and by 6.8% (p > 0.05), 10.4% (p > 0.05), 18.9% (p < 0.01), 24.8% (p < 0.01) and 37.2% (p < 0.01) on atrial myocytes, respectively. The H₂S-induced decrease in the duration of action potentials (APD₉₀) of ventricular myocytes was concentration-dependent, although only NaHS at a concentration of 150 µM decreased the APD₉₀ significantly (15%, p < 0.05). The H₂S-induced decrease in APD₉₀ on atrial myocytes was concentration dependent, but the statistical difference was not significant. Inhibition of I_K,ATP by PPG was time dependent and the level of inhibition was: ventricular myocytes, 7% (p > 0.05), 10% (p < 0.05), 15.3% (p < 0.01), 24.0% (p < 0.01) and 28.9% (p < 0.01); atrial myocytes, 15.8% (p > 0.05), 21.3% (p > 0.05), 26.5% (p < 0.01), 34.0% (p < 0.01) and 43.2% (p < 0.01) measured at 5, 10, 15, 20 and 25 min, respectively. The increase in the APD₉₀, by PPG was time dependent for ventricular myocytes [increased by 12.8% (p < 0.05) at 25 min]. The same was true for atrial myocytes, although only the value at 25 min was significant (15%, p < 0.05). Conclusions: H₂S decreased the APD₉₀,and both the endogenous and exogenous H₂S-induced increase in I_K,ATP on both atrial and ventricular myocytes was concentration dependent. These results may help to explain, at least in part, how H₂S protects heart cells from various forms of injury.

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Atrial myocardium is the predominant inotropic target of adrenomedullin in the human heart

Cited by 19 publications

References 35 publications

Identification of Potential Pharmacological Targets by Analysis of the Comprehensive G Protein-Coupled Receptor Repertoire in the Four Cardiac Chambers

Identification of Potential Pharmacological Targets by Analysis of the Comprehensive G Protein-Coupled Receptor Repertoire in the Four Cardiac Chambers

Key roles of endothelin-1 and p38 MAPK in the regulation of atrial stretch response

Hydrogen Sulfide Opens the K<sub>ATP </sub>Channel on Rat Atrial and Ventricular Myocytes

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