Rat intermedin1-47 does not improve functional recovery in postischemic hearts

Münzel, Gerald; Schlier, Alexander; Schreckenberg, Rolf; Abdallah, Yaser; Schlüter, Klaus‐Dieter

doi:10.1007/s00210-011-0680-4

Cited by 5 publications

(4 citation statements)

References 29 publications

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“…In our study, myocardial NOS activity and NO were significantly decreased in both nondiabetic and diabetic animals after MI/R. Previously, intermedin has been shown to exert negative inotropic effects in Langendorff-perfused rat hearts, an effect blocked by inhibition of nitric oxide synthesis [57]. Another study demonstrated IMD increased endothelial nitric oxide synthase (eNOS) phosphorylation nearly three-fold at Ser (1177), significantly enhancing eNOS activity [58].…”

Section: Discussionsupporting

confidence: 48%

Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats

Bian

Zhang

et al. 2013

Cardiovasc Diabetol

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BackgroundDiabetic patients, through incompletely understood mechanisms, endure exacerbated ischemic heart injury compared to non-diabetic patients. Intermedin (IMD) is a novel calcitonin gene-related peptide (CGRP) superfamily member with established cardiovascular protective effects. However, whether IMD protects against diabetic myocardial ischemia/reperfusion (MI/R) injury is unknown.MethodsDiabetes was induced by streptozotocin in Sprague–Dawley rats. Animals were subjected to MI via left circumflex artery ligation for 30 minutes followed by 2 hours R. IMD was administered formally 10 minutes before R. Outcome measures included left ventricular function, oxidative stress, cellular death, infarct size, and inflammation.ResultsIMD levels were significantly decreased in diabetic rats compared to control animals. After MI/R, diabetic rats manifested elevated intermedin levels, both in plasma (64.95 ± 4.84 pmol/L, p < 0.05) and myocardial tissue (9.8 ± 0.60 pmol/L, p < 0.01) compared to pre-MI control values (43.62 ± 3.47 pmol/L and 4.4 ± 0.41). IMD administration to diabetic rats subjected to MI/R decreased oxidative stress product generation, apoptosis, infarct size, and inflammatory cytokine release (p < 0.05 or p < 0.01).ConclusionsBy reducing oxidative stress, inflammation, and apoptosis, IMD may represent a promising novel therapeutic target mitigating diabetic ischemic heart injury.

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Section: Discussionsupporting

confidence: 48%

Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats

Bian

Zhang

et al. 2013

Cardiovasc Diabetol

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“…This contradiction may be due to the contribution of NO. In cultures of cardiomyocytes, ADM2/IMD 1–47 has a positive inotropic effect through the cAMP‐Ca 2+ pathway, but in isolated hearts, ADM2/IMD 1–47 has an opposite effect in an NO‐dependent manner (Munzel et al , ). The negative inotropic effect of ADM2/IMD 1–47 depends on the endothelium through the CGRP/AM 1/2 receptor‐eNOS‐cGMP pathway.…”

Section: Cardiovascular Effects Of Adm2mentioning

confidence: 99%

Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases

Zhang

Wang

2017

British J Pharmacology

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Adrenomedullin (ADM) 2/intermedin (IMD) is a short peptide that belongs to the CGRP superfamily. Although it shares receptors with CGRP, ADM and amylin, ADM2 has significant and unique functions in the cardiovascular system. In the past decade, the cardiovascular effect of ADM2 has been carefully analysed. In this review, progress in understanding the effects of ADM2 on the cardiovascular system and its protective role in cardiometabolic diseases are summarized. LINKED ARTICLESThis article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc Abbreviations AAC, abdominal aortic constriction; ACS, acute coronary syndrome; ADM, adrenomedullin; AMPK, AMP-activated protein kinase; AMY, amylin; CRLR, calcitonin receptor-like receptor; ER, endoplasmic reticulum; I/R, ischaemia/reperfusion; RAMP, receptor activity-modifying protein; SHR, spontaneously hypertensive rat; TAC, transverse aortic contraction; VSMC, vascular smooth muscle cell Takei et al., 2004). It is one of the members of the ADM family which are all found in fish but, in mammals, only three peptides -ADM, ADM2 and ADM5 -have been found (Takei et al., 2008). These ADM peptides are themselves a part of the CGRP superfamily. ADM2 is also called intermedin (IMD), owing to its high expression in the intermediate lobe of the pituitary. Both terms, 'ADM2' and 'IMD', are widely used in the literature. However, because IMD was used as the former name for α-melanocyte stimulating hormone, we will use the terms ADM2, ADM2/IMD 1-53 , ADM2/IMD 1-47 and ADM2/IMD 1-40 in this review to avoid confusion. ADM2 shares receptors with CGRP, ADM and amylin (AMY) (Hay et al., 2005) and is widely expressed throughout the body. Recently, progress has been made on the physiological roles of ADM2 in cardiovascular homeostasis and as a protective agent against cardiometabolic diseases. In this review, the structure and expression of ADM2 and the pharmacology of ADM2, in the context of the cardiovascular system and cardiometabolic diseases, are summarized. ADM2 and ADM2 receptorsThe structure of ADM2The Adm2 gene is located on the distal arm of human chromosome 22q13.33 and encodes a pre-pro-peptide containing 148 amino acid residues with a signal sequence at the N terminus . ADM2 belongs to the CGRP superfamily, which includes α-CGRP, β-CGRP, calcitonin receptor-stimulating peptide, AMY, ADM and ADM5 (Hong et al., 2012). ADM2 shares the same structural characteristics with the other family members, including an intramolecular ring of six amino acids residues flanked by a disulfide bond and a putative amidation signal at the C terminus .Sequence alignment has shown that ADM2 shares only 28% sequence identity with its closest paralogue, ADM.However, ADM2 is highly conserved in the orthologues of different species. The mature human ADM2 shares over 60% similarity with fish and 87% identity with the rodent peptides . The property of high con...

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“…vasodilator, vasodepressor) (Takei et al 2004) and in the heart both were shown to modulate myocardial function Fontes-Sousa et al 2009;Pires et al 2012). However, in contrast to the normal heart where its action has been comprehensively studied (Roh et al 2004;Takei et al 2004;Munzel et al 2011;Pires et al 2012) the myocardial effects of IMD in the diseased heart remain unexplored. With this in mind, we investigated in the present study the myocardial action of IMD 1−47 and the underlying mechanisms in well-known rat models of left ventricular (LV) hypertrophy due to pressure overload (transverse aortic constriction, TAC) or nitric oxide (NO) deficiency associated with chronic NO synthase inhibition…”

Section: Introductionmentioning

confidence: 99%

Reverse myocardial effects of intermedin in pressure‐overloaded hearts: role of endothelial nitric oxide synthase activity

Pires

Pinho

Alves

et al. 2013

The Journal of Physiology

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Key points• Intermedin (IMD) is a cardiac endogenous peptide upregulated in several models of heart disease.• We show a depressant effect of IMD 1−47 on contractility of the normal myocardium, mediated by increased nitric oxide (NO) production due to endothelial nitric oxide synthase (eNOS) phosphorylation.• In rat models of cardiac hypertrophy or NO deficiency, IMD 1−47 enhances contractility and hastens relaxation associated with phospholamban phosphorylation.• This opposing response in normal and diseased myocardium is due to impairment of IMD 1−47 -induced eNOS phosphorylation.• The results reveal distinct myocardial effects and subcellular mechanisms for IMD 1−47 in the hypertrophic heart, suggesting a key role of cardiac endothelial dysfunction with potential pathophysiological relevance.Abstract Intermedin (IMD) is a cardiac peptide synthesized in a prepro form, which undergoes a series of proteolytic cleavages and amidations to yield the active forms of 47 (IMD 1−47 ) and 40 amino acids ). There are several lines of evidence of increased IMD expression in rat models of cardiac pathologies, including congestive heart failure and ischaemia; however, its myocardial effects upon cardiac disease remain unexplored. With this in mind, we investigated the direct effects of increasing concentrations of IMD 1−47 (10 −10 to10 −6 M) on contraction and relaxation of left ventricular (LV) papillary muscles from two rat models of chronic pressure overload, one induced by transverse aortic constriction (TAC), the other by nitric oxide (NO) deficiency due to chronic NO synthase inhibition (NG-nitro-L-arginine, L-NAME), and respective controls (Sham and Ctrl). In TAC and L-NAME rats, exogenous administration of IMD 1−47 elicited concentration-dependent positive inotropic and lusitropic effects. By contrast, in Sham and Ctrl rats, IMD 1−47 induced a negative inotropic response without a significant effect on relaxation. Both TAC and L-NAME rats presented LV hypertrophy, elevated LV systolic pressures, preserved systolic function and elevated peroxynitrite levels. In the normal myocardium (Ctrl and Sham), IMD 1−47 induced a 3-fold increase of endothelial nitric oxide synthase (eNOS) phosphorylation at Ser 1177 , indicating enhanced eNOS activity. In TAC and L-NAME rats, eNOS phosphorylation was increased at baseline, and its response to IMD 1−47 was blunted. In addition, the distinct myocardial response to IMD 1−47 was accompanied by distinct subcellular mechanisms. While in Sham rats the addition of IMD 1−47 induced the phosphorylation of cardiac troponin I due to NO/cGMP activation, in TAC rats IMD 1−47 induced phospholamban phosphorylation possibly associated with cAMP/protein kinase A activation. Therefore, we demonstrated for the first time a reversed myocardial response to IMD 1−47 neurohumoral stimulation due to impairment of eNOS activation in TAC and L-NAME rats. These results not only reveal the distinct myocardial effects and subcellular mechanisms for IMD 1−47 in normal and hypertrophic hearts, but also highlig...

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Rat intermedin1-47 does not improve functional recovery in postischemic hearts

Cited by 5 publications

References 29 publications

Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats

Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats

Adrenomedullin 2/intermedin: a putative drug candidate for treatment of cardiometabolic diseases

Reverse myocardial effects of intermedin in pressure‐overloaded hearts: role of endothelial nitric oxide synthase activity

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