Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

2012 ◽  
Vol 303 (6) ◽  
pp. H703-H711 ◽  
Author(s):  
Xiangbin Xu ◽  
Fan Ding ◽  
Jinjiang Pang ◽  
Xue Gao ◽  
Rong-Kun Xu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Disease ◽  
Cardiac Fibrosis ◽  
Spontaneously Hypertensive Rat ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Hypertensive Heart Disease ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Spontaneously Hypertensive

Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by hexarelin treatment. In summary, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis.

scholarly journals Effects of Transgenic Expression of Dopamine Beta Hydroxylase (Dbh) Gene on Blood Pressure in Spontaneously Hypertensive Rats

2016 ◽  
pp. 1039-1044
Author(s):  
M. PRAVENEC ◽  
V. LANDA ◽  
V. ZÍDEK ◽  
P. MLEJNEK ◽  
J. ŠILHAVÝ ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Essential Hypertension ◽  
Spontaneously Hypertensive Rat ◽  
Reduce Blood Pressure ◽  
Left Ventricular ◽  
Brown Norway ◽  
Catecholamine Metabolism ◽  
Mrna Levels ◽  
Spontaneously Hypertensive ◽  
Dopamine Beta Hydroxylase

The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and left ventricular hypertrophy. Catecholamines play an important role in the pathogenesis of both essential hypertension in humans and in the SHR. Recently, we obtained evidence that the SHR harbors a variant in the gene for dopamine beta hydroxylase (Dbh) that is associated with reduced adrenal expression of Dbh mRNA and reduced DBH enzymatic activity which correlated negatively with blood pressure. In the current study, we used a transgenic experiment to test the hypothesis that reduced Dbh expression predisposes the SHR to hypertension and that augmentation of Dbh expression would reduce blood pressure. We derived 2 new transgenic SHR-Dbh lines expressing Dbh cDNA under control of the Brown Norway (BN) wild type promoter. We found modestly increased adrenal expression of Dbh in transgenic rats versus SHR non-transgenic controls that was associated with reduced adrenal levels of dopamine and increased plasma levels of norepinephrine and epinephrine. The observed changes in catecholamine metabolism were associated with increased blood pressure and left ventricular mass in both transgenic lines. We did not observe any consistent changes in brainstem levels of catecholamines or of mRNA levels of Dbh in the transgenic strains. Contrary to our initial expections, these findings are consistent with the possibility that genetically determined decreases in adrenal expression and activity of DBH do not represent primary determinants of increased blood pressure in the SHR model.

Catecholamines, Blood Pressure, Renin and Myocardial Function in the Spontaneously Hypertensive Rat

1976 ◽  
Vol 51 (s3) ◽  
pp. 455s-459s
Author(s):  
Suzanne Oparil ◽  
Lynda Erinoff ◽  
A. Cutilletta
Keyword(s):  
Blood Pressure ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Myocardial Function ◽  
Spontaneously Hypertensive Rat ◽  
Plasma Renin ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Spontaneously Hypertensive ◽  
6 Hydroxydopamine

1. Neither nerve-growth-factor antiserum (NGFAS) administered subcutaneously nor 6-hydroxydopamine administered intraventricularly to immature spontaneously hypertensive rats (SHR) inhibited the development of the hypertensive syndrome. In contrast, NGFAS did not affect blood pressure in normotensive Kyoto/Wistar rats. 2. Peripheral vascular resistance was increased and cardiac index decreased in both NGFAS and 6-hydroxydopamine-treated SHR despite preservation of normal blood pressure. 3. NGFAS treatment did not influence the development of left ventricular hypertrophy in SHR, despite the lowering of blood pressure. In contrast, 6-hydroxydopamine caused an attenuation in the development of left ventricular hypertrophy. 4. Indices of left ventricular contractility were depressed by NGFAS treatment but not by 6-hydroxydopamine. 5. Plasma renin activity was unaffected by NGFAS treatment and increased by 6-hydroxydopamine.

scholarly journals Physical Training as a Blood Pressure Reducer and a Remodeler of Cardiac Fibers in Spontaneously Hypertensive Rats (SHR)

2021 ◽  
pp. 22-30
Author(s):  
Mariana Molinar Mauad Cintra ◽  
Matheus Ribeiro Bizuti ◽  
Octávio Barbosa Neto ◽  
Marlene Antônia dos Reis ◽  
Lenaldo Branco Rocha ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Physical Training ◽  
Spontaneously Hypertensive Rats ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Type Iii Collagen ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Type Iii

Background: Hypertension is the most prevalent of all cardiovascular diseases, reaching target organs such as the heart. Blood pressure control is critical for preventing organ damage induced by hypertension. Objective: To analyze blood pressure, heart rate, left ventricular thickness, the percentage of cardiac fibrosis and the percentage of type III collagen in Spontaneously Hypertensive Rats (SHR) submitted to swimming physical training. Methods: The experimental groups were composed of male Wistar Kyoto (WKY) rats (309-311g), which were divided into: 1) Normotensive Sedentary group (SN) (n = 6); 2) Trained Normotensive group (TN) (n = 6); 3) Sedentary Hypertensive group (SH) (n = 6); 4) Trained Hypertensive group (TH) (n = 6). After the end of the protocol, the animals were initially anesthetized to measure blood pressure. Results: Physical training was responsible for decreasing blood pressure (F = 16,968; p <0.001) and heart rate (F = 10.710; p = 0.004) in the trained groups (normotensive and hypertensive). Moreover, training was responsible for providing an increase in the thickness of the left ventricle (F = 7,254; p = 0.014) and a reduction in the percentage of cardiac fibrosis (F = 16,081; p <0.001). Furthermore, it was observed that the trained group had lower values of type III collagen (F = 13,166; p = 0.002). Conclusions: Physical swimming training triggered a decrease in blood pressure, heart rate, the percentage of fibrosis and the percentage of type III collagen. In addition, there was also a cardiac remodeling due to the increase in left ventricular hypertrophy.

scholarly journals Heart lesions in individuals with arterial hypertension of various risk levels: the possibility of diagnosis and treatment

2020 ◽  
Vol 11 (2) ◽  
pp. 35-38
Author(s):  
Anatolii N. Britov ◽  
Elena M. Platonova ◽  
Nina A. Eliseeva
Keyword(s):  
Heart Disease ◽  
Ventricular Hypertrophy ◽  
Heart Diseases ◽  
Hypertensive Heart Disease ◽  
Left Ventricular ◽  
Diagnostic Methods ◽  
Risk Levels ◽  
Increased Risk ◽  
Outpatient Practice ◽  
Heart Lesions

Based on scientific literature and own data, the article discusses the problem of hypertensive heart disease in real outpatient practice and especially in conducting preventive examinations in the working population. It is shown that the use of modern diagnostic methods, in particular electrocardiography with dopplerography, including pulse-wave tissue mode, should be an integral study included in the professional examination, as well as medical examination, which covers an increasing number of the population of our country. Echocardiography should be performed to clarify the cardiovascular risk and confirm the electrocardiographic diagnosis of left ventricular hypertrophy (LVH), left atrial dilatation, or suspected heart diseases (coronary heart disease, atrial fibrillation, other rhythm disorders). It has been shown that concentric LVH is the strongest predictor of an increased risk of heart failure, although the degree of LVH is not always directly related to the degree of hypertension and the duration of the disease.

Abstract 485: Mito-Targeted Antioxidant Superior to Non-Targeted Isoform in Modulating Energy Metabolism and Preventing Cardiovascular Remodelling in Spontaneously Hypertensive Rat

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Sherin Saheera ◽  
Ajay Godwin Potnuri ◽  
Raunak R Nair
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Spontaneously Hypertensive Rat ◽  
Heart Diseases ◽  
Left Ventricular ◽  
Metabolic Switch ◽  
Spontaneously Hypertensive ◽  
Beneficial Effects ◽  
Hypertensive Rat ◽  
2D Echocardiography

Hypertension induced left ventricular hypertrophy (LVH) augments the risk of cardiovascular anomalies. Oxidative stress leads to the activation of the hypertrophic program with a metabolic switch from fatty acid to glucose oxidation. Mitochondria, the major source of free radicals, exhibit alterations in hypertensive heart diseases. Targeted antioxidants are expected to reduce mitochondrial reactive oxygen species more effectively than general antioxidants. This study was designed to assess whether mito-targeted antioxidant, MitoTempol is more effective than general oxidant, Tempol on hypertension, hypertrophy and cardiac energy metabolism. Spontaneously Hypertensive Rat were administered either Tempol (20mg/kg/day) or Mito Tempol (2mg/kg/day) orally for 30 days. Post treatment, animals were subjected to 2D-echocardiography. The Myocardial lysates were subjected to Insolution digestion followed by RPLC - LTQ-Orbitrap-MS analysis. Mid-ventricular sections were probed for markers of energy metabolism and fibrosis. The beneficial effect on cardiovascular structure and function was significantly higher for Mito Tempol. Increase in mitochondrial antioxidants and stimulation of fatty acid metabolism with significant improvement in cardiovascular function was apparent in SHR treated with Mito Tempol. The study indicates that Mito Tempol is superior to its non- targeted isoform in preventing hypertension induced LVH, and the beneficial effects on heart are possibly mediated by reversal of metabolic remodelling.

scholarly journals Superiority of Out-of-Office Blood Pressure for Predicting Hypertensive Heart Disease in Non-Hispanic Black Adults

Hypertension ◽  
2019 ◽  
Vol 74 (5) ◽  
pp. 1192-1199 ◽  
Author(s):  
Florian Rader ◽  
Stanley S. Franklin ◽  
James Mirocha ◽  
Wanpen Vongpatanasin ◽  
Robert W. Haley ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Disease ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Hypertensive Heart Disease ◽  
Left Ventricular ◽  
Office Blood Pressure ◽  
Black Adults ◽  
Black And White ◽  
White Adults

Black Americans suffer disproportionately from hypertension and hypertensive heart disease. Out-of-office blood pressure (BP) is more predictive for cardiovascular complications than clinic BP; however, the relative abilities of clinic and out-of-office BP to predict left ventricular hypertrophy in black and white adults have not been established. Thus, we aimed to compare associations of out-of-office and clinic BP measurement with left ventricular hypertrophy by cardiac magnetic resonance imaging among non-Hispanic black and white adults. In this cross-sectional study, 1262 black and 927 white participants of the Dallas Heart Study ages 30 to 64 years underwent assessment of standardized clinic and out-of-office (research staff-obtained) BP and left ventricular mass index. In multivariable-adjusted analyses of treated and untreated participants, out-of-office BP was a stronger determinant of left ventricular hypertrophy than clinic BP (odds ratio per 10 mm Hg, 1.48; 95% CI, 1.34–1.64 for out-of-office systolic BP and 1.15 [1.04–1.28] for clinic systolic BP; 1.71 [1.43–2.05] for out-of-office diastolic BP, and 1.03 [0.86–1.24] for clinic diastolic BP). Non-Hispanic black race/ethnicity, treatment status, and lower left ventricular ejection fraction were also independent determinants of hypertrophy. Among treated Blacks, the differential association between out-of-office and clinic BP with hypertrophy was more pronounced than in treated white or untreated participants. In conclusion, protocol-driven supervised out-of-office BP monitoring provides important information that cannot be gleaned from clinic BP assessment alone. Our results underscore the importance of hypertension management programs outside the medical office to prevent hypertensive heart disease, especially in high-risk black adults. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00344903.

scholarly journals Inhibition of the late sodium current slows t-tubule disruption during the progression of hypertensive heart disease in the rat

2013 ◽  
Vol 305 (7) ◽  
pp. H1068-H1079 ◽  
Author(s):  
Gary L. Aistrup ◽  
Deepak K. Gupta ◽  
James E. Kelly ◽  
Matthew J. O'Toole ◽  
Amanda Nahhas ◽  
...  
Keyword(s):  
Heart Disease ◽  
Sodium Current ◽  
Hypertensive Heart Disease ◽  
Left Ventricular ◽  
Spontaneously Hypertensive ◽  
Plasmic Reticulum ◽  
Echocardiographic Study ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
Width Measurements

The treatment of heart failure (HF) is challenging and morbidity and mortality are high. The goal of this study was to determine if inhibition of the late Na+ current with ranolazine during early hypertensive heart disease might slow or stop disease progression. Spontaneously hypertensive rats (aged 7 mo) were subjected to echocardiographic study and then fed either control chow (CON) or chow containing 0.5% ranolazine (RAN) for 3 mo. Animals were then restudied, and each heart was removed for measurements of t-tubule organization and Ca2+ transients using confocal microscopy of the intact heart. RAN halted left ventricular hypertrophy as determined from both echocardiographic and cell dimension (length but not width) measurements. RAN reduced the number of myocytes with t-tubule disruption and the proportion of myocytes with defects in intracellular Ca2+ cycling. RAN also prevented the slowing of the rate of restitution of Ca2+ release and the increased vulnerability to rate-induced Ca2+ alternans. Differences between CON- and RAN-treated animals were not a result of different expression levels of voltage-dependent Ca2+ channel 1.2, sarco(endo)plasmic reticulum Ca2+-ATPase 2a, ryanodine receptor type 2, Na+/Ca2+ exchanger-1, or voltage-gated Na+ channel 1.5. Furthermore, myocytes with defective Ca2+ transients in CON rats showed improved Ca2+ cycling immediately upon acute exposure to RAN. Increased late Na+ current likely plays a role in the progression of cardiac hypertrophy, a key pathological step in the development of HF. Early, chronic inhibition of this current slows both hypertrophy and development of ultrastructural and physiological defects associated with the progression to HF.

scholarly journals Progression of myocardial remodeling and mechanical dysfunction in the spontaneously hypertensive rat

2012 ◽  
Vol 303 (11) ◽  
pp. H1353-H1365 ◽  
Author(s):  
Ian J. LeGrice ◽  
Adèle J. Pope ◽  
Gregory B. Sands ◽  
Gillian Whalley ◽  
Robert N. Doughty ◽  
...  
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Systolic Function ◽  
Three Dimensional ◽  
Hypertensive Heart Disease ◽  
Left Ventricular ◽  
Morphological Data ◽  
Systemic Hypertension ◽  
Myocardial Remodeling ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto

The progression of hypertensive heart disease (HHD) to heart failure (HF) is associated with myocardial remodeling. Corresponding changes in three-dimensional organization of cardiac extracellular matrix have not been quantified or related fully to the development of HF. Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto controls were studied at 3, 12, 18, and 24 mo. Hemodynamic and morphological data, brain natriuretic peptide levels, and echocardiography demonstrate four distinct disease stages: systemic hypertension, diastolic dysfunction, early systolic failure, and decompensated HF. Passive left ventricular (LV) pressure-volume relationships were determined in vitro. Transmural specimens from the anterior LV free wall were imaged using extended-volume confocal microscopy, and three-dimensional myocardial architecture was quantified. In SHRs, LV compliance was reduced at 12 mo and increased progressively thereafter. However, it was less than in controls for filling pressures <10 mmHg and not significantly different at ≥10 mmHg. Myocyte cross section was enlarged, with increased variability from 12 mo, while collagen fraction increased progressively. Perimysial collagen fraction remained unchanged with age, although endomysial collagen increased from 12 mo. Perimysial collagen between adjacent muscle layers fused at 12 mo and continued to thicken subsequently, while muscle layers became more dispersed and disordered. We conclude that LV dilatation, which accompanies decompensated HF in this model of HHD, is not due to LV “softening.” While perimysial (and endomysial) collagen networks are substantially remodeled, they are not dissolved, as has been proposed. We argue that progressive disruption of the laminar organization of LV myocardium may contribute to impaired systolic function in HHD.

scholarly journals Effect of Lower Blood Pressure Goals on Left Ventricular Structure and Function in Patients With Subclinical Hypertensive Heart Disease

2020 ◽  
Vol 33 (9) ◽  
pp. 837-845
Author(s):  
Phillip D Levy ◽  
Michael J Burla ◽  
Michael J Twiner ◽  
Alexander L Marinica ◽  
James J Mahn ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Disease ◽  
Cardiac Function ◽  
Hypertensive Heart Disease ◽  
Left Ventricular ◽  
Reverse Remodeling ◽  
Secondary Outcome ◽  
Mixed Effect ◽  
Post Hoc Analysis ◽  
Post Hoc

Abstract BACKGROUND Subclinical hypertensive heart disease (SHHD) is a precursor to heart failure. Blood pressure (BP) reduction is an important component of secondary disease prevention in patients with SHHD. Treating patients with SHHD utilizing a more intensive BP target (120/80 mm Hg), may lead to improved cardiac function but there has been limited study of this, particularly in African Americans (AAs). METHODS We conducted a single center, randomized controlled trial where subjects with uncontrolled, asymptomatic hypertension, and SHHD not managed by a primary care physician were randomized to standard (&lt;140/90 mm Hg) or intensive (&lt;120/80 mm Hg) BP therapy groups with quarterly follow-up for 12 months. The primary outcome was the differences of BP reduction between these 2 groups and the secondary outcome was the improvement in echocardiographic measures at 12 months. RESULTS Patients (95% AAs, 65% male, mean age 49.4) were randomized to the standard (n = 65) or the intensive (n = 58) BP therapy groups. Despite significant reductions in systolic BP (sBP) from baseline (−10.9 vs. −19.1 mm Hg, respectively) (P &lt; 0.05), no significant differences were noted between intention-to-treat groups (P = 0.33) or the proportion with resolution of SHHD (P = 0.31). However, on post hoc analysis, achievement of a sBP &lt;130 mm Hg was associated with significant reduction in indexed left ventricular mass (−6.91 gm/m2.7; P = 0.008) which remained significant on mixed effect modeling (P = 0.031). CONCLUSIONS In post hoc analysis, sBP &lt;130 mm Hg in predominantly AA patients with SHHD was associated with improved cardiac function and reverse remodeling and may help to explain preventative effects of lower BP goals. CLINICAL TRIALS REGISTRATION Trial Number NCT00689819.

scholarly journals Role of Higenamine in Heart Diseases: A Mini-Review

2022 ◽  
Vol 12 ◽  
Author(s):  
Jianxia Wen ◽  
Mingjie Li ◽  
Wenwen Zhang ◽  
Haoyu Wang ◽  
Yan Bai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Heart Disease ◽  
Reperfusion Injury ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia

Higenamine, a natural product with multiple targets in heart diseases, is originally derived from Aconitum, which has been traditionally used in China for the treatment of heart disease, including heart failure, arrhythmia, bradycardia, cardiac ischemia/reperfusion injury, cardiac fibrosis, etc. This study is aimed to clarify the role of higenamine in heart diseases. Higenamine has effects on improving energy metabolism of cardiomyocytes, anti-cardiac fibroblast activation, anti-oxidative stress and anti-apoptosis. Accumulating evidence from various studies has shown that higenamine exerts a wide range of cardiovascular pharmacological effects in vivo and in vitro, including alleviating heart failure, reducing cardiac ischemia/reperfusion injury, attenuating pathological cardiac fibrosis and dysfunction. In addition, several clinical studies have reported that higenamine could continuously increase the heart rate levels of healthy volunteers as well as patients with heart disease, but there are variable effects on systolic blood pressure and diastolic blood pressure. Moreover, the heart protection and therapeutic effects of higenamine on heart disease are related to regulating LKB1/AMPKα/Sirt1, mediating the β2-AR/PI3K/AKT cascade, induction of heme oxygenase-1, suppressing TGF-β1/Smad signaling, and targeting ASK1/MAPK (ERK, P38)/NF-kB signaling pathway. However, the interventional effects of higenamine on heart disease and its underlying mechanisms based on experimental studies have not yet been systematically reviewed. This paper reviewed the potential pharmacological mechanisms of higenamine on the prevention, treatment, and diagnosis of heart disease and clarified its clinical applications. The literature shows that higenamine may have a potent effect on complex heart diseases, and proves the profound medicinal value of higenamine in heart disease.

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