scholarly journals HOPX Plays a Critical Role in Antiretroviral Drugs Induced Epigenetic Modification and Cardiac Hypertrophy

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3458
Author(s):  
Shiridhar Kashyap ◽  
Maryam Rabbani ◽  
Isabela de Lima ◽  
Olena Kondrachuk ◽  
Raj Patel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Tissue ◽  
Epigenetic Modification ◽  
Trichostatin A ◽  
Critical Role ◽  
Heart Tissue ◽  
Antiretroviral Drugs ◽  
Neonatal Rat ◽  
People Living With Hiv ◽  
Hiv Patients

People living with HIV (PLWH) have to take an antiretroviral therapy (ART) for life and show noncommunicable illnesses such as chronic inflammation, immune activation, and multiorgan dysregulation. Recent studies suggest that long-term use of ART induces comorbid conditions and is one of the leading causes of heart failure in PLWH. However, the molecular mechanism of antiretroviral drugs (ARVs) induced heart failure is unclear. To determine the mechanism of ARVs induced cardiac dysfunction, we performed global transcriptomic profiling of ARVs treated neonatal rat ventricular cardiomyocytes in culture. Differentially expressed genes were identified by RNA-sequencing. Our data show that ARVs treatment causes upregulation of several biological functions associated with cardiotoxicity, hypertrophy, and heart failure. Global gene expression data were validated in cardiac tissue isolated from HIV patients having a history of ART. Interestingly, we found that homeodomain-only protein homeobox (HOPX) expression was significantly increased in cardiomyocytes treated with ARVs and in the heart tissue of HIV patients. Furthermore, we found that HOPX plays a crucial role in ARVs mediated cellular hypertrophy. Mechanistically, we found that HOPX plays a critical role in epigenetic regulation, through deacetylation of histone, while the HDAC inhibitor, Trichostatin A, can restore the acetylation level of histone 3 in the presence of ARVs.

scholarly journals Antiretroviral Drugs Regulate Epigenetic Modification of Cardiac Cells Through Modulation of H3K9 and H3K27 Acetylation

2021 ◽  
Vol 8 ◽  
Author(s):  
Shiridhar Kashyap ◽  
Avni Mukker ◽  
Deepti Gupta ◽  
Prasun K. Datta ◽  
Jay Rappaport ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epigenetic Modification ◽  
Critical Role ◽  
Heart Tissue ◽  
Antiretroviral Drugs ◽  
Cardiac Cells ◽  
Histone Deacetylation ◽  
People Living With Hiv ◽  
Pcr Array ◽  
Cellular Hypertrophy

Antiretroviral therapy (ART) has significantly reduced the rate of mortality in HIV infected population, but people living with HIV (PLWH) show higher rates of cardiovascular disease (CVD). However, the effect of antiretroviral (ARV) drug treatment on cardiac cells is not clear. In this study, we explored the effect of ARV drugs in cardiomyocyte epigenetic remodeling. Primary cardiomyocytes were treated with a combination of four ARV drugs (ritonavir, abacavir, atazanavir, and lamivudine), and epigenetic changes were examined. Our data suggest that ARV drugs treatment significantly reduces acetylation at H3K9 and H3K27 and promotes methylation at H3K9 and H3K27, which are histone marks for gene expression activation and gene repression, respectively. Besides, ARV drugs treatment causes pathological changes in the cell through increased production of reactive oxygen species (ROS) and cellular hypertrophy. Further, the expression of chromatin remodeling enzymes was monitored in cardiomyocytes treated with ARV drugs using PCR array. The PCR array data indicated that the expression of epigenetic enzymes was differentially regulated in the ARV drugs treated cardiomyocytes. Consistent with the PCR array result, SIRT1, SUV39H1, and EZH2 protein expression was significantly upregulated in ARV drugs treated cardiomyocytes. Furthermore, gene expression analysis of the heart tissue from HIV+ patients showed that the expression of SIRT1, SUV39H1, and EZH2 was up-regulated in patients with a history of ART. Additionally, we found that expression of SIRT1 can protect cardiomyocytes in presence of ARV drugs through reduction of cellular ROS and cellular hypertrophy. Our results reveal that ARV drugs modulate the epigenetic histone markers involved in gene expression, and play a critical role in histone deacetylation at H3K9 and H3K27 during cellular stress. This study may lead to development of novel therapeutic strategies for the treatment of CVD in PLWH.

Abstract P460: Role Of Hopx In Antiretroviral Drugs Induced Cardiac Hypertrophy And Epigenetic Modification

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Shiridhar Kashyap ◽  
Olena Kondrachuk ◽  
Manish K Gupta
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Epigenetic Modification ◽  
Trichostatin A ◽  
Antiretroviral Drugs ◽  
Functional Enrichment ◽  
Hiv Patients ◽  
Acetylation Level

Background: Heart failure is the one of the leading causes of death in HIV patients. Application ofantiretroviral therapy (ART) raise the life expectancy of HIV patients, but survival population show higherrisk of cardiovascular disorder. The aim of this study is to understand the underlying molecular mechanismof antiretroviral drugs (ARVs) induced cardiac dysfunction in HIV patients. Method and Results: To determine the mechanism of ARVs induced cardiac dysfunction, we performeda global transcriptomic profiling in primary cardiomyocytes treated with ARVs. Differentially expressedgenes were identified by DESeq2. Functional enrichment analysis of differentially expressed genes wereperformed using clusterProfiler R and ingenuity pathway analysis. Our data show that ARVs treatmentcauses upregulation of several biological function associated with cardiotoxicity and heart failure.Interestingly, we found that ARV drugs treatment significantly upregulates the expression of a set of genesinvolved cardiac enlargement and hypertrophy in the heart. Global gene expression data were validated inthe cardiac tissue isolated from the HIV patients having history of ART treatment. Interestingly, we foundthat the homeodomain-containing only protein homeobox (HOPX) expression was significantly increasedin transcriptional and translational level in cardiomyocytes treated with ARV drugs as well as in heart tissueof ART treated HIV patients. Further, we performed adenovirus mediated gain in and siRNA mediatedknockdown approach to determine the role of HOPX in ARVs mediated cardiac hypertrophy and epigeneticmodifications. Mechanistically, we found that HOPX expression level plays a key role in ARV drugsmediated increased cardiomyocytes cell size and reduced acetylation level of histone 3 at lysine 9 and lysine27. Furthermore, we found that knockdown of HOPX gene expression blunted the hypertrophy effect ofARV drugs in cardiomyocytes. It is known that HOPX reduces cellular acetylation level through interactionwith HDAC2. In our study, we found that histone deacetylase inhibitor Trichostatin A can restore cellularacetylation level in presence of ARVs. Conclusion: ART treatment causes cardiotoxicity through regulation of fatal gene expression incardiomyocytes and in adult heart. Additionally, we found that HOPX expression is critical in ARVsmediated cardiomyocytes remodeling and epigenetic modification.

Abstract 375: Insights Into Molecular Mechanism of Cardiovascular Disorder in HIV+ Patients

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Manish Gupta ◽  
Kaylyn Scanlon ◽  
Avni Mukker ◽  
Deepti Gupta ◽  
Jay Rappaport ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Drug Treatment ◽  
Regulation Of Gene Expression ◽  
Cardiovascular Disorder ◽  
Antiretroviral Drugs ◽  
People Living With Hiv ◽  
Pcr Array ◽  
Hiv Patients ◽  
Antiretroviral Drug

Background: Antiretroviral therapy (ART) improves the survival of people living with HIV (PLHIV); however, the rate of cardiovascular disorder and heart failure is significantly increased among the PLHIV. Molecular basis of heart failure in the PLHIV undergoing antiretroviral drug treatment is not clear. The aim of this study is to explore the role of antiretroviral drugs in post translational modification of histones and its epigenetic regulation of gene expression in cardiomyocytes. Methods and Results: Primary rat ventricular cardiomyocytes were treated with a combination of antiretroviral drugs (5 μM of Atazanavir, Abacavir, Ritonavir and Lamivudine) for 4, 12 and 24 hours, and expression of major histone marks playing a role in gene activation (H3K9ac and H3K27ac) and repression (H3K27me3, H3K9me3) were evaluated by western blotting. Our data suggest that treatment with antiretroviral drugs leads to de-acetylation at H3K9ac and H3K27ac, and promotes methylation at H3K27me3 and H3k9me3. Additionally, the expression of epigenetic modifying enzymes was examined by PCR array in cardiomyocytes treated with antiretroviral drugs. PCR array data show that histone deacetylase enzyme Sirt1/2, and methyltransferase enzyme Suv39h1 and Ezh12 were upregulated in drug treated cardiomyocytes. Further, western blot data show that Sirt1, Suv39h1 and Ezh2 protein expression was significantly upregulated in drugs treated cardiomyocytes. Moreover, expression analysis of human cardiac tissue further shows that expression of Sirt1, Suv39h1 and Ezh2 was significantly upregulated in HIV+ patients heart compares to healthy donor. Mechanistically, our data show that expression of epigenetic modifying enzymes was differentially regulated in drug treated cardiomyocytes which may lead to epigenetic modifications of histone proteins. Conclusion: Antiretroviral drug treatment promotes epigenetic alteration in the chromatin which may lead to a change in gene expression of cardiomyocytes. This study may lead to novel therapeutic strategies for the treatment of heart failure in PLWHA.

Abstract 372: MicroRNA-9 Inhibits Hyperglycemia-induced Cardiac Pyroptosis by Targeting ELAVL1

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Prince Jeyabal ◽  
Rajarajan A Thandavarayan ◽  
Darukeshwara Joladarashi ◽  
Sahana Suresh Babu ◽  
Shashirekha Krishnamurthy ◽  
...  
Keyword(s):  
Heart Failure ◽  
High Glucose ◽  
Cardiac Tissue ◽  
Critical Role ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Therapeutic Implications ◽  
Caspase 1 ◽  
Ventricular Cardiomyocytes ◽  
Nlrp3 Expression

Diabetic cardiomyopathy is a common complication in patients with diabetes and is associated with underlying chronic inflammation and cardiac cell death, subsequently leading to left ventricular dysfunction and heart failure. ELAV-like protein 1 (ELAVL1, mRNA stabilizing protein) and NLRP3 activation (inflammasome complex protein)-mediated IL-1beta synthesis play a critical role in the progression of heart failure. However, ELAVL1 regulation of pyroptosis (caspase-1-mediated programmed apoptosis) and associated IL-1beta release in cardiomyocytes, especially under diabetic condition, remains elusive. Human diabetic, non-diabetic heart tissues, human ventricular cardiomyocytes and rat cardiomyoblasts exposed to high glucose (HG) were used for our studies. Our data demonstrates that human ventricular cardiomyocytes exposed to high glucose condition showed significant increase in ELAVL1 and NLRP3 expression with a concomitant increase in caspase-1 and IL-1 beta expression. Furthermore, human cardiac tissue from diabetic patients showed increased ELAVL1, caspase-1 and NLRP3 expression as compared to non-diabetic hearts. Intriguingly, ELAVL1 knockdown abrogates TNF-α induced canonical pyroptosis via NLRP3, caspase-1 and IL-1beta suppression. Interestingly, miRNA-9 expression significantly reduces in high glucose treated cardiomyocytes and in human diabetic hearts. Bioinformatics analysis and target validation assays showed that miR-9 directly targets ELAVL1. Inhibition of miR-9 up regulates ELAVL1 expression and activates caspase-1. Alternatively, miR-9 mimics attenuate hyperglycemia-induced ELAVL1 and inhibit cardiomyocyte pyroptosis. To our knowledge, this is the first report to demonstrate the role of miR-9/ELAVL1 in hyperglycemia-induced cardiac pyroptosis. Taken together our study highlights the potential therapeutic implications in preventing cardiomyocyte cell loss in human diabetic failing heart.

Analysis of Gene Expression and Morphology of P19 Cells Cultured in an Apatite-Fiber Scaffold

2012 ◽  
Vol 529-530 ◽  
pp. 370-373 ◽  
Author(s):  
Hide Ishii ◽  
Yuya Mukai ◽  
Mamoru Aizawa ◽  
Nobuyuki Kanzawa
Keyword(s):  
Heart Failure ◽  
Tissue Engineering ◽  
Cardiac Tissue ◽  
Cultured Cells ◽  
Three Dimensional ◽  
Heart Tissue ◽  
Cardiac Tissue Engineering ◽  
Cardiac Differentiation ◽  
Embryonal Carcinoma Cell ◽  
Cells Cultured

Heart disease is the second most common cause of mortality in Japan. Most cases of late stage heart failure can only be effectively treated by a heart transplant. Cardiac tissue engineering is emerging both as a new approach for improving the treatment of heart failure and for developing new cardiac drugs. Apatite-fiber scaffold (AFS) was originally designed as a substitute material for bone. AFS contains two sizes of pores and is appropriate for the three dimensional proliferation and differentiation of osteoblasts. To establish engineered heart tissue, a pluripotent embryonal carcinoma cell line, P19.CL6, was cultured in AFS. P19.CL6 cells seeded into AFS proliferated well. Generally, cardiac differentiation of P19.CL6 cells is induced by treating suspension-cultured cells with dimethyl sulfoxide (DMSO), after which the cells form spheroids. However, our results showed that P19.CL6 cells cultured in AFS differentiated into myocytes without forming spheroidal aggregates, and could be cultured for at least one month. Thus, we conclude that AFS is a good candidate as a scaffold for cardiac tissue engineering.

Selective beta-3 adrenergic receptor blockade increases contractility of human ventricular trabeculae from HFrEF donors

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N Nguyen ◽  
G Page ◽  
N Abi-Gerges ◽  
P.E Miller ◽  
J.W Adams
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptor ◽  
Myocardial Contractility ◽  
Cardiac Tissue ◽  
Heart Tissue ◽  
Myocardial Tissue ◽  
Funding Source ◽  
Force Of Contraction ◽  
Selective Blockade ◽  
Ventricular Trabeculae

Abstract Background Alterations of the beta-adrenergic system have been extensively described in the setting of heart failure (HF). Upregulation of beta-3 adrenergic receptor (β3-AdrR) expression in human failing hearts depresses myocardial contractility and, during an acute decompensation event, can be considered a maladaptive compensatory mechanism that exacerbates cardiac dysfunction. APD418 is a selective β3-AdrR antagonist currently in development for patients who have acute heart failure with reduced ejection fraction (HFrEF). APD418 is designed to improve myocardial contractility by selectively antagonizing the β3-AdrR and thereby avoiding the cAMP/Ca2+ signaling pathway stimulated by current inotropes. Purpose This study evaluated the effect of a selective β3-AdrR antagonist (APD418) on contractile responses in explanted human ventricular trabeculae obtained from normal and HFrEF hearts. Methods Left ventricular trabeculae from normal and HFrEF donors were electrically stimulated (1 Hz) ex-vivo to analyze force generated during contractions. First, BRL37344, a selective β3-AdrR agonist, was applied at increasing concentrations (0.01–10 μM) to confirm β3-AdrR mediated negative inotropy in human myocardial tissue. To test the effect of a selective β3-AdrR antagonist on contractile force, myocardial tissue was pre-treated with APD418 or vehicle for 5 minutes, followed by treatment with non-selective β-AdrR agonists isoproterenol (10 nM) or norepinephrine (5 μM). Results In heart tissue from normal donors, the β3-AdrR agonist BRL37344 did not affect contractile function at 0.01 and 0.1 μM. However, in heart tissue from HFrEF donors, BRL37344 induced a significant decrease in contractility at 0.01, 0.1 and 1 μM (85.9±1.8% with 0.1 μM BRL37344 vs 104.1±2.9% with vehicle). Selective blockade of β3-AdrR with APD418 had no effect on force of contraction induced by norepinephrine in cardiac tissue from normal donors. In contrast, APD418 potentiated the force of contraction induced by either isoproterenol (49.1±20.6% increase with 0.1 μM APD418 compared to baseline) or norepinephrine (26.5±4.9% increase with 0.01 μM APD418 compared to baseline) in cardiac tissue from HFrEF patients. Conclusion This is, to our knowledge, the first evidence showing that selective blockade of β3-AdrR increases contractility of human ventricular trabeculae from HFrEF donors and suggests that further studies evaluating the therapeutic benefit of APD418 in patients with HFrEF are warranted. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Arena Pharmaceuticals

scholarly journals Role of Adipose-Derived Mesenchymal Stem Cells in the Regeneration of Cardiac Tissue and Improvement of Cardiac Function: a Narrative Review

2020 ◽  
Vol 11 (1) ◽  
pp. 8446-8456
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Trichostatin A ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Point Of View

Recent efforts have made in order to novel therapeutic approaches to reduce the heavy cardiovascular burden. The use of cell therapy and applying stem cell-based therapies has received much attention; of particular interest are adipose-derived mesenchymal stem cells (ADSCs). The present review aimed to review the studies which examined and researched various aspects of ADSCs to improve cardiac function. A comprehensive review of all articles assessed and discussed the application of ADSCs in the improvement of cardiac tissue renewing and cardiomyocytes regeneration was planned and conducted by the two reviewers. The initial literature search revealed a total of 153 articles that, of those, 34 were considered eligible. From the perspective of heart tissue regeneration, the inductive role of ADSCs in sensing mechanical stimulation and produce collagen and elastin scaffolds, vascularizing cardiac tissue, and exosomes (vesicles derived from ADSCs) in ADSCs‐mediated myocardial protection has indicated. In the process of ADSCs differentiation to cardiomyocyte- like cells, the role of various targeted pathways have been identified that can be influenced by different elements such as TGF-beta1, phorbol myristate acetate, Angiotensin II, Rho-associated kinases, 5-Azaytidine, Sodium valproate, fibrin scaffold and trichostatin A have been highlighted. In the final, from a therapeutic point of view, the effectiveness of ADMSCs differentiation to cardiomyocytes as improving left ventricular functional state has been discussed. Summarizing the studies confirms a significant improvement in cardiac function following direct application of ADSCs or their transformation to cardiomyocytes by stimulating or inhibiting various cellular pathways leading reducing oxidative stress and inflammatory bed, reducing cardiomyocyte apoptosis, attenuating cardiac fibrosis, reducing the infiltration of immune cells and collagen deposition, and enhancing angiogenesis.

Stanniocalcin-1 is a naturally occurring L-channel inhibitor in cardiomyocytes: relevance to human heart failure

2003 ◽  
Vol 285 (1) ◽  
pp. H442-H448 ◽  
Author(s):  
David Sheikh-Hamad ◽  
Roger Bick ◽  
Gang-Yi Wu ◽  
Birgitte Mønster Christensen ◽  
Peter Razeghi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Structural Changes ◽  
Cardiac Tissue ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Calcium Currents ◽  
Human Heart Failure ◽  
Rat Cardiomyocytes ◽  
Failing Heart ◽  
Mechanical Unloading

Cardiomyocytes of the failing heart undergo profound phenotypic and structural changes that are accompanied by variations in the genetic program and profile of calcium homeostatic proteins. The underlying mechanisms for these changes remain unclear. Because the mammalian counterpart of the fish calcium-regulating hormone stanniocalcin-1 (STC1) is expressed in the heart, we reasoned that STC1 might play a role in the adaptive-maladaptive processes that lead to the heart failure phenotype. We examined the expression and localization of STC1 in cardiac tissue of patients with advanced heart failure before and after mechanical unloading using a left ventricular assist device (LVAD), and we compared the results with those of normal heart tissue. STC1 protein is markedly upregulated in cardiomyocytes and arterial walls of failing hearts pre-LVAD and is strikingly reduced after LVAD treatment. STC1 is diffusely expressed in cardiomyocytes, although nuclear predominance is apparent. Addition of recombinant STC1 to the medium of cultured rat cardiomyocytes slows their endogenous beating rate and diminishes the rise in intracellular calcium with each contraction. Furthermore, using whole cell patch-clamp studies in cultured rat cardiomyocytes, we find that addition of STC1 to the bath causes reversible inhibition of transmembrane calcium currents through L-channels. Our data suggest differential regulation of myocardial STC1 protein expression in heart failure. In addition, STC1 may regulate calcium currents in cardiomyocytes and may contribute to the alterations in calcium homeostasis of the failing heart.

scholarly journals Loss of the Long Non-coding RNA OIP5-AS1 Exacerbates Heart Failure in a Sex-Specific Manner

2021 ◽  
Author(s):  
Aowen Zhuang ◽  
Anna C. Calkin ◽  
Shannen Lau ◽  
Helen Kiriazis ◽  
Daniel G. Donner ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Function ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Heart Function ◽  
Pressure Overload ◽  
Enrichment Analysis ◽  
Heart Tissue ◽  
Gene Set Enrichment Analysis ◽  
Knock Out

AbstractBackgroundLong ncRNAs (lncRNAs) are known to influence numerous biological processes including cellular differentiation and tissue development. They are also implicated in the maintenance, health and physiological function of many tissues including the heart. Indeed, manipulating the expression of specific lncRNAs has been shown to improve pathological cardiac phenotypes such as heart failure. One lncRNA studied in various settings is OIP5-AS1 (also known as 1700020I14Rik and Cyrano), however its role in cardiac pathologies remains mostly uncharacterised.MethodsWe used data generated from FACS sorted murine cardiomyocytes, human iPSC derived cardiomyocytes, as well as heart tissue from various animal models to investigate OIP5-AS1 expression in health and disease. Using CRISPR we engineered a global OIP5-AS1 knock out (KO) mouse model and performed cardiac pressure overload experiments to study heart failure in these animals. RNA-sequencing of left ventricles provided mechanistic insight between WT and KO mice.ResultsWe demonstrate that OIP5-AS1 expression is regulated during cardiac development and cardiac specific pathologies in both rodent and human models. Moreover, we demonstrate that global female OIP5-AS1 KO mice develop exacerbated heart failure, but male mice do not. Transcriptomics and gene set enrichment analysis suggests that OIP5-AS1 may regulate pathways that impact mitochondrial function.ConclusionsOIP5-AS1 is regulated in cardiac tissue and its deletion leads to worsening heart function under pressure overload in female mice. This may be due to impairments in mitochondrial function, highlighting OIP5-AS1 as a gene of interest in sex-specific differences in heart failure.

Blood pressure and cardiac tissue responses to prostacyclin (PGI2) in various species

1982 ◽  
Vol 60 (2) ◽  
pp. 134-139 ◽  
Author(s):  
G. A. Collins ◽  
B. A. MacLeod ◽  
M. J. A. Walker
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Cardiac Tissue ◽  
Isolated Heart ◽  
Heart Tissue ◽  
Neonatal Rat ◽  
Heart Cells ◽  
Camp Content ◽  
Rat Atria

The effect of prostacyclin (PGI2) on blood pressure and heart rate (in vivo) and on isolated heart tissue has been investigated in different species. Isolated cardiac tissue had limited resposes to PGI2 tested at 10−13 to 10−5 M. Cultured neonatal rat heart cells did not respond to PGI2, neither did intact rat hearts or rabbit cardiac tissue. Guinea pig and rat atria showed limited dose-dependent responses to PGI2 at concentrations greater than 10−7 M. In rat atria, 10−5 M PGI2 produced a limited elevation of tissue cAMP content. When given by intravenous injection or infusion, PGI2 produced hypotension in anaesthetized primates (three species), rat, rabbit, pig, and dog. As a vasodepressor in all species, PGI2 (on a weight basis) was more active than prostaglandins of the B or E type and, in most species tested, it was approximately five times more active than PGE2. Heart responses in intact animals were often paradoxical in that decreases in heart rate often accompanied blood pressure falls.

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