The Relationships Between Plasma Adrenomedullin and Endothelin-1 Concentrations and Doppler Echocardiographic Indices of Left Ventricular Function During Static Exercise in Healthy Men

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Abstract

Our previous study showed a significant relationships between static exercise-induced changes in plasma adrenomedullin (ADM) and those in endothelin-1 (ET-1), noradrenaline (NA) and pre-ejection period/left ventricular ejection time ratio (PEP/LVET) in older healthy men. It is hypothesized that ADM, ET-1, NA and adrenaline (A) may function as endogenous regulators of cardiac function by modulating myocardial contractility during static exercise. The present study was undertaken to assess the relationships between exercise-induced changes in plasma ADM, ET-1, NA, A concentrations and those in ascending aortic blood flow peak velocity (PV) and mean acceleration (MA) measured by Doppler echocardiography in 24 healthy older men during two 3-min bouts of handgrip at 30% of maximal voluntary contraction, performed alternately with each hand without any break between the bouts. Plasma ADM, ET-1, NA and A as well as heart rate (HR), blood pressure (BP), PV and MA were determined. During handgrip, plasma ADM, ET-1, NA and A as well as HR, BP increased, whereas PV and MA decreased. The increases in plasma ADM correlated positively with those in ET-1, NA and diastolic BP, and correlated negatively with changes in PV (r= −0.68) and MA (r= −0.62). The increases in plasma ET-1 correlated positively with those in NA and BPs and correlated negatively with changes in PV (r= −0.67) and MA (r= −0.60). The results of this study suggest that in healthy older men the exercise-induced changes in plasma ADM, ET 1 and catecholamines are related to alterations in left ventricular contractile state and may co-operatively counteract age-related deterioration of cardiac performance in men.

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Most cited references 28

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Endothelin as a regulator of cardiovascular function in health and disease.

Heather Webb, Bryan W Haynes (1998)

The endothelins are a family of endothelium-derived peptides that possess characteristically sustained vasoconstrictor properties. Endothelin-1 appears to be the predominant member of the family generated by vascular endothelial cells. In addition to its direct vascular effects, endothelin-1 has inotropic and mitogenic properties, influences homeostasis of salt and water, alters central and peripheral sympathetic activity and stimulates the renin-angiotensin-aldosterone system. Studies with endothelin receptor antagonists have indicated that endothelin-1 probably has complex opposing vascular effects mediated through vascular smooth muscle and endothelial ET(A) and ET(B)receptors. Endogenous generation of endothelin-1 appears to contribute to maintenance of basal vascular tone and blood pressure through activation of vascular smooth muscle ET(A)receptors. At the same time, endogenous endothelin-1 acts through endothelial ET(B) receptors to stimulate formation of nitric oxide tonically and to oppose vasoconstriction. In view of the multiple cardiovascular actions of endothelin-1, there has been much interest in its contribution to the pathophysiology of hypertension. Results of most studies suggest that generation of, or sensitivity to, endothelin-1 is no greater in hypertensive than it is in normotensive subjects. Nonetheless, the deleterious vascular effects of endogenous endothelin-1 may be accentuated by reduced generation of nitric oxide caused by hypertensive endothelial dysfunction. It also appears likely that endothelin participates in the adverse cardiac and vascular remodelling of hypertension, as well as in hypertensive renal damage. Irrespective of whether vascular endothelin activity is increased in hypertension, anti-endothelin agents do produce vasodilatation and lower blood pressure in hypertensive humans. There is more persuasive evidence for increased endothelin-1 activity in secondary forms of hypertension, including pre-eclampsia and renal hypertension. Endothelin-1 also appears to play an important role in pulmonary hypertension, both primary and secondary to diseases such as chronic heart failure. The hypotensive effects of endothelin converting enzyme inhibitors and endothelin receptor antagonists should be useful in the treatment of hypertension and related diseases. Development of such agents will increase knowledge of the physiological and pathological roles of the endothelins, and should generate drugs with novel benefits.

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Regulation of adrenomedullin production in rat endothelial cells.

Y Isumi, H Shoji, S Sugo … (1998)

Adrenomedullin (AM) is a potent vasorelaxant peptide recently identified in extracts of pheochromocytoma. We have found that AM is actively secreted from endothelial cell (EC) and vascular smooth muscle cell (VSMC). To elucidate the function of AM secreted from EC, the effects of 43 substances on secretion of AM from cultured rat EC were examined in this study. We first confirmed that synthesized AM was not stored but constitutively secreted from EC, indicating that the amount secreted could be used as an index of AM synthesis in EC. EC secreted AM at a rate 5.8 times higher than VSMC, and AM gene transcription in EC significantly contributed to the total aortic AM messenger RNA. Tumor necrosis factor, interleukin-1, and lipopolysaccharide augmented AM secretion from EC, showing cooperative effects, which suggests that AM secreted from EC participates in the induction of hypotension in septic shock. Transforming growth factor beta1 and FCS suppressed AM secretion but stimulated endothelin-1 (ET-1) secretion. Thrombin potently stimulated AM secretion from EC but suppressed it from VSMC. Thyroid hormone and phorbol ester increased AM and ET-1 secretion but to a lesser extent. Interferon-gamma inhibited AM secretion from EC, whereas oxidized LDL stimulated it. Regulation of AM production in EC is found to be similar to that of VSMC with several exceptions, but AM and ET-1 production in EC are deduced to be controlled independently and by different mechanisms. AM stimulates cAMP production in EC, though receptors expressed on cultured rat EC are not specific to AM but to calcitonin gene-related peptide. Based on these findings, AM production in EC is thought to be regulated by a variety of substances coming from blood and neighboring cells, and the secreted AM is deduced to dilate blood vessels as an endothelium-derived relaxing factor competing with ET-1.

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Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin, a new inotropic peptide.

P Rintamäki-Kinnunen, P Tavi, M Weckström … (1998)

Adrenomedullin (ADM), a new vasorelaxing and natriuretic peptide, may function as an endogenous regulator of cardiac function, because ADM and its binding sites have been found in the heart. We characterize herein the cardiac effects of ADM as well as the underlying signaling pathways in vitro. In isolated perfused, paced rat heart preparation, infusion of ADM at concentrations of 0.1 to 1 nmol/L for 30 minutes induced a dose-dependent, gradual increase in developed tension, whereas proadrenomedullin N-20 (PAMP; 10 to 100 nmol/L), a peptide derived from the same gene as ADM, had no effect. The ADM-induced positive inotropic effect was not altered by a calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37, or H-89, a cAMP-dependent protein kinase inhibitor. ADM also failed to stimulate ventricular cAMP content of the perfused hearts. Ryanodine (3 nmol/L), a sarcoplasmic reticulum Ca2+ release channel opener, suppressed the overall ADM-induced positive inotropic effect. Pretreatment with thapsigargin (30 nmol/L), which inhibits sarcoplasmic reticulum Ca2+ ATPase and depletes intracellular Ca2+ stores, attenuated the early increase in developed tension produced by ADM. In addition, inhibition of protein kinase C by staurosporine (10 nmol/L) and blockade of L-type Ca2+ channels by diltiazem (1 micromol/L) significantly decreased the sustained phase of ADM-induced increase in developed tension. Superfusion of atrial myocytes with ADM (1 nmol/L) in isolated left atrial preparations resulted in a marked prolongation of action potential duration between 10 and -50 mV transmembrane voltage, consistent with an increase in L-type Ca2+ channel current during the plateau. Our results show that ADM enhances cardiac contractility via cAMP-independent mechanisms including Ca2+ release from intracellular ryanodine- and thapsigargin-sensitive Ca2+ stores, activation of protein kinase C, and Ca2+ influx through L-type Ca2+ channels.

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Author and article information

Journal

Journal ID (nlm-ta): J Hum Kinet

Journal ID (iso-abbrev): J Hum Kinet

Journal ID (publisher-id): JHK

Title: Journal of Human Kinetics

Publisher: Akademia Wychowania Fizycznego w Katowicach

ISSN (Print): 1640-5544

ISSN (Electronic): 1899-7562

Publication date Collection: June 2012

Publication date (Electronic): 04 July 2012

Volume: 33

Pages: 81-89

Affiliations

[1 ]Department of Applied Physiology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

[2 ]Outpatient Cardiac Unit for Diagnosis and Therapy, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.

Author notes

Corresponding author: Dr Krzysztof Krzemiński, Department of Applied Physiology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland, Phone: (4822)6086518, E-mail: krzem@ 123456cmdik.pan.pl

Authors submitted their contribution of the article to the editorial board.

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Publisher ID: jhk-33-81

DOI: 10.2478/v10078-012-0047-z

PMC ID: 3588682

PubMed ID: 23487485

SO-VID: 7b8185d5-3928-4427-8c10-431c75c1f790

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This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

The Relationships Between Plasma Adrenomedullin and Endothelin-1 Concentrations and Doppler Echocardiographic Indices of Left Ventricular Function During Static Exercise in Healthy Men

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Most cited references 28

Endothelin as a regulator of cardiovascular function in health and disease.

Regulation of adrenomedullin production in rat endothelial cells.

Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin, a new inotropic peptide.

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