Early reversal cardiac with esmolol in hypertensive rats: The role of subcellular organelle phenotype.

BACKGROUND: Our group has previously shown that short-term treatment (48 h) with esmolol reduces left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). However, we do not know the mechanism that explain this effect. The aim of this study was to assess the role that the subcellular organelle phenotype plays in early cardiac reverse after short-term treatment with esmolol. METHODS: 14-Month-old male SHRs were randomly assigned to receive esmolol (300 µg/kg/min) (SHR-E) or vehicle (SHR). Age-matched male Wistar-Kyoto rats (WKY) served as controls. After 48 h of treatment, an ultrastructural analysis of heart tissue (left ventricle) was performed. We studied cardiomyocyte ultrastructural remodeling of subcellular organelles by electronic microcopy in all groups. RESULTS: SHR group showed significant morphometric and stereological changes in mitochondria and subcellular organelles (cytoplasm and nucleus, myofibril structure, mitochondria structure, Z-Disk, intercalated disk, T-system and cystern), and also changes in the extracellular matrix (collagen) with respect to WKY group. Esmolol significantly improved the morphology and stereology mitochondrial, reduced the organelle phenotype abnormalities but no produced changes in the extracellular matrix with respect to SHR group. Interesantly, parameters of mitochondria (regularity factor, ellipsoidal form factor and density of volume), and all parameters of subcellular organelles returned to the normality in SHR-E. CONCLUSION: Our results show that left ventricular hypertrophy reversal after short-term treatment with esmolol is associated with reversal of subcellular organelle phenotype.

Impact of a Multichannel Blocker in Attenuating Intramyocardial Artery Remodeling in Hypertensive Rats through Increased Nitric Oxide Bioavailability.

Dronedarone is recommended for the treatment of atrial fibrillation. However, we do not know its effect on vascular remodeling. This study was designed to assess whether dronedarone has the potential to improve the intramyocardial artery remodeling induced by chronic hypertension. Ten-month-old male spontaneously hypertensive rats (SHR) were randomly assigned to receive dronedarone (100 mg/kg) or vehicle. Age-matched male Wistar-Kyoto rats served as controls. After 14 days of treatment, we studied the structure (geometry and fibrosis) of the intramyocardial artery using histological analysis. Nitric oxide (NO) in plasma was analyzed. In the untreated SHR, we observed a significant increase in external diameter, lumen diameter, wall width, cross-sectional area, and collagen volume density, as was expected in the experimental model. Dronedarone induced a significant decrease in wall width, cross-sectional area, and collagen volume density in SHR-D in comparison with untreated SHR. The values obtained in SHR-D were similar in the WKY control group. We found significantly higher NO levels in plasma in SHR-D than in untreated SHR. Dronedarone improves the intramyocardial artery remodeling induced by chronic hypertension in SHR through increased nitric oxide bioavailability.

The protective effect of dronedarone on the structure and mechanical properties of the aorta in hypertensive rats by decreasing the concentration of symmetric dimethylarginine (SDMA).

BACKGROUND AND AIMS: Dronedarone is a new multichannel-blocking antiarrhythmic for the treatment of patients with atrial fibrillation. Our group has demonstrated that dronedarone produces regression of cardiac remodeling; however, its effect on the remodeling of the elastic arteries has not yet been reported. We aim to assess the effects of dronedarone on the regression of thoracic aortic remodeling in spontaneously hypertensive rats (SHRs). METHOD: Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where the animals received dronedarone treatment (100 mg/kg), to a control group (SHR) where rats were given vehicle, or to a group (SHR-A) where they were given amiodarone. A fourth group of normotensive control rats (Wistar-Kyoto rats, WKY) was also added. After two weeks of treatment, we studied the structure, the elastic fiber content of the thoracic aorta using histological techniques and confocal microscopy, and the vascular mechanical properties using an organ bath and isometric tension analysis. A mass spectrometric determination of symmetric dimethylarginine (SDMA) concentrations was performed. RESULTS: SHR group developed the classic remodeling expected from the experimental model: outward hypertrophic remodeling, increased elastic fiber content and wall stiffness. However, the SHR-D group showed statistically significantly lower values for aortic tunica media thickness, wall to lumen ratio, external diameter, cross-sectional area, volume density of the elastic fibers, wall stiffness, and aortic SDMA concentration when compared to the SHR group. These parameters were similar in the SHR and SHR-A groups. Interestingly, the values for tunica media thickness, volume density of the elastic fibers, wall stiffness, and SDMA concentration obtained from the SHR-D group were similar to those measured in the WKY group. CONCLUSION: These results suggest that dronedarone improves the structure and passive mechanical properties of the thoracic aorta in hypertensive rats, and that this protective effect could be associated with a reduction in the concentration of aortic SDMA.

Adverse remodeling of the obtuse marginal artery in compensatory hypertrophied myocardium from spontaneously hypertensive rats.

BACKGROUND: Spontaneously hypertensive rats (SHR) serve as a model of genetic hypertension. Adverse remodeling of a coronary artery has been reported in SHR. This model is used to study new therapies in regression vascular remodeling. However, no data are available that show remodeling of the intramyocardial branch of the obtuse marginal artery in 10-month-old SHR. This study was designed to assess remodeling (changes in vascular structure and fibrosis) of this coronary artery. METHODS AND RESULTS: The study was performed on 10-month-old male SHR (n=7) and normotensive control Wistar Kyoto rats (WKY) (n=7). Using histology, we show that the external diameter, lumen diameter, wall width, and cross-sectional area of the intramyocardial artery were significantly greater in SHR than in WKY. The wall-to-lumen ratio was similar in SHR and WKY. The collagen volume density of the intramyocardial artery in SHR was significantly greater than in WKY. CONCLUSIONS: Our results show hypertrophic outward remodeling in the intramyocardial branch of the obtuse marginal artery of the left ventricle in SHR. This artery can serve as a new vascular bed from adult SHR to study novel therapies in regression coronary artery remodeling.

Dronedarone produces early regression of myocardial remodelling in structural heart disease.

BACKGROUND AND AIMS: Left ventricular hypertrophy (LVH) in hypertension is associated with a greater risk of sustained supraventricular/atrial arrhythmias. Dronedarone is an antiarrhythmic agent that was recently approved for the treatment of atrial fibrillation. However, its effect on early regression of LVH has not been reported. We tested the hypothesis that short-term administration of dronedarone induces early regression of LVH in spontaneously hypertensive rats (SHRs). METHODS: Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where animals received dronedarone treatment (100 mg/kg) for a period of 14 days, or to a control group (SHR) where rats were given vehicle. A third group with normotensive control rats (WKY) was also added. At the end of the treatment with dronedarone we studied the cardiac anatomy and function in all the rats using transthoracic echocardiogram, cardiac metabolism using the PET/CT study (2-deoxy-2[18F]fluoro-D-glucose) and cardiac structure by histological analysis of myocyte size and collagen content. RESULTS: The hypertensive vehicle treated SHR rats developed the classic cardiac pattern of hypertensive cardiomyopathy as expected for the experimental model, with increases in left ventricular wall thickness, a metabolic shift towards an increase in glucose use and increases in myocyte and collagen content. However, the SHR-D rats showed statistically significant lower values in comparison to SHR group for septal wall thickness, posterior wall thickness, ventricular mass, glucose myocardial uptake, size of left ventricular cardiomyocytes and collagen content. All these values obtained in SHR-D rats were similar to the values measured in the normotensive WKY control group. CONCLUSION: The results suggest by three alternative and complementary ways (analysis of anatomy and cardiac function, metabolism and histological structure) that dronedarone has the potential to reverse the LVH induced by arterial hypertension in the SHR model of compensated ventricular hypertrophy.

Early regression of coronary artery remodeling with esmolol and DDAH/ADMA pathway in hypertensive rats.

Our preclinical study demonstrated that esmolol produces early regression of left ventricular hypertrophy in arterial hypertension. The aim of this study was to assess the effects of short-term esmolol therapy on the regression of left anterior descending artery remodeling in spontaneously hypertensive rats (SHRs), and to determine whether the asymmetric dimethylarginine (ADMA)/dimethylarginine dimethylaminohydrolase (DDAH) pathway, a regulator of nitric oxide (NO) bioavailability, accounted for this regression. Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=15) or esmolol (SHR-E, n=20) (300 µg kg-1 min-1). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=15) served as controls. SHRs were also treated with nitroglycerin (SHR-N, n=5). After 48 h, the left anterior descending artery structure and morphology were assessed, and dose-response curves for 5-hydroxytryptamine (5-HT, 10-9-3 × 10-5 mol l-1) were constructed. ADMA concentrations in plasma and left ventricle and DDAH activity in tissue were analyzed. Wall thickness and cross-sectional area were significantly lower after treatment with esmolol in SHR-E than in SHR. Media thickness and smooth muscle cell count were lower in SHR-E than in SHR. Esmolol induced a significant reduction in adventitial cell count in SHR-E. The area under the concentration-response curves was significantly higher in SHR than in SHR-E, as were the esmolol normalized coronary artery contracting responses to 5-HT. We found significantly lower ADMA levels and significantly higher DDAH activity in the ventricle in SHR-E than in SHR. The protective effect of esmolol on the regression of left anterior descending artery remodeling may be related to the reduction in ADMA levels.

Corrigendum to "Effects of Sevoflurane and Propofol on Organ Blood Flow in Left Ventricular Assist Devices in Pigs".

[This corrects the article DOI: 10.1155/2015/898373.].

Short-term esmolol attenuates remodeling of the thoracic aorta in hypertensive rats by decreasing concentrations of ADMA down-regulated by oxidative stress.

Esmolol produces early regression of left ventricular hypertrophy and improves coronary artery remodeling, although the impact of short-term treatment with this beta-blocker on remodeling in large arteries has not yet been studied. We hypothesized that even a short (48h) course of esmolol might alter remodeling of the aorta in the spontaneously hypertensive rat (SHR). Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=8) or esmolol (SHR-E, n=8) (300µg/kg/min). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=8) served as controls. After 48h, we studied the structure, volume density of elastic fibers, and passive mechanical properties of the aorta. Determination of asymmetrical dimethylarginine concentrations and total protein carbonyls in the aorta were analyzed. Esmolol significantly attenuated abnormal aortic wall thickness, cross-sectional area, wall-to-lumen ratio, volume density of elastic fibers, and wall stiffness. The protective effect of esmolol could be related to a decrease in asymmetrical dimethylarginine levels after down-regulation by oxidative stress. These findings could play a key role in the selection of antihypertensive therapy in patients with hypertension and aortic remodeling.

Effects of Sevoflurane and Propofol on Organ Blood Flow in Left Ventricular Assist Devices in Pigs.

The aim of this study was to assess the effect of sevoflurane and propofol on organ blood flow in a porcine model with a left ventricular assist device (LVAD). Ten healthy minipigs were divided into 2 groups (5 per group) according to the anesthetic received (sevoflurane or propofol). A Biomedicus centrifugal pump was implanted. Organ blood flow (measured using colored microspheres), markers of tissue injury, and hemodynamic parameters were assessed at baseline (pump off) and after 30 minutes of partial support. Blood flow was significantly higher in the brain (both frontal lobes), heart (both ventricles), and liver after 30 minutes in the sevoflurane group, although no significant differences were recorded for the lung, kidney, or ileum. Serum levels of alanine aminotransferase and total bilirubin were significantly higher after 30 minutes in the propofol group, although no significant differences were detected between the groups for other parameters of liver function, kidney function, or lactic acid levels. The hemodynamic parameters were similar in both groups. We demonstrated that, compared with propofol, sevoflurane increases blood flow in the brain, liver, and heart after implantation of an LVAD under conditions of partial support.

Short-term esmolol improves coronary artery remodeling in spontaneously hypertensive rats through increased nitric oxide bioavailability and superoxide dismutase activity.

The aim of this study was to assess the effects of short-term esmolol therapy on coronary artery structure and function and plasma oxidative stress in spontaneously hypertensive rats (SHR). For this purpose, 14-month-old male SHR were treated for 48 hours with esmolol (SHR-E, 300 µ g/kg/min). Age-matched untreated male SHR and Wistar Kyoto rats (WKY) were used as hypertensive and normotensive controls, respectively. At the end of intervention we performed a histological study to analyze coronary artery wall width (WW), wall-to-lumen ratio (W/L), and media cross-sectional area (MCSA). Dose-response curves for acetylcholine (ACh) and sodium nitroprusside were constructed. We also assessed several plasma oxidative stress biomarkers, namely, superoxide scavenging activity (SOSA), nitrites, and total antioxidant capacity (TAC). We observed a significant reduction in WW (P < 0.001), W/L (P < 0.05), and MCSA (P < 0.01) and improved endothelium-dependent relaxation (AUC(SHR-E) = 201.2 ± 33 versus AUC(SHR) = 97.5 ± 21, P < 0.05) in SHR-E compared with untreated SHR; no differences were observed for WW, MCSA, and endothelium-dependent relaxation by ACh at higher concentrations (10(-6) to 10(-4) mol/l) for SHR-E with respect to WKY. SOSA (P < 0.001) and nitrite (P < 0.01) values were significantly higher in SHR-E than in untreated SHR; however, TAC did not increase after treatment with esmolol. Esmolol improves early coronary artery remodeling in SHR.

Early regression of left ventricular hypertrophy after treatment with esmolol in an experimental rat model of primary hypertension.

Certain ß-adrenergic blockers have proven useful in the regression of ventricular remodeling when administered as long-term treatment. However, early regression of left ventricular hypertrophy (LVH) has not been reported, following short-term administration of these drugs. We tested the hypothesis that short-term administration of the cardioselective ß-blocker esmolol induces early regression of LVH in spontaneously hypertensive rats (SHR). Fourteen-month-old male SHRs were treated i.v. with vehicle (SHR) or esmolol (SHR-E) (300 µg kg(-1) min(-1)). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 h, left ventricular morphology and function were assessed using M-mode echocardiograms (left ventricular mass index (LVMI), ejection fraction and transmitral Doppler (early-to-atrial filling velocity ratio (E/A), E-wave deceleration time (Edec time)). The standardized uptake value (SUV) was applied to evaluate FDG (2-deoxy-2[18F]fluoro-D-glucose) uptake by the heart using PET/CT. Left ventricular subendocardial and subepicardial biopsies were taken to analyze changes in cross-sectional area (CSA) of left ventricular cardiomyocytes and the fibrosis was expressed as collagen volume fraction (CVF). LVMI was lower in SHR-E with respect to SHR (P=0.009). There were no significant differences in EF, E/A ratio or Edec time in SHR-E compared with SHR (P=0.17, 0.55 and P=0.80, respectively). PET acquisitions in SHR-E showed lower (18)F-FDG uptake than SHR (P=0.003). Interestingly, there were no significant differences in SUV in either SHR-E or WKY (P=0.63). CSA in subendocardial and subepicardial regions was minor in SHR-E with respect to SHR (P<0.001), and there were no significant differences in CVF between both groups. Esmolol reverses early LVH in the SHR model of stable compensated ventricular hypertrophy. This is the first study to associate early regression of LVH with administration of a short-term ß-blocker.

Does the epiphyseal cartilage of the long bones have one or two ossification fronts?

Epiphyseal cartilage is hyaline cartilage tissue with a gelatinous texture, and it is responsible for the longitudinal growth of the long bones in birds and mammals. It is located between the epiphysis and the diaphysis. Epiphyseal cartilage also is called a growth plate or physis. It is protected by three bone components: the epiphysis, the bone bar of the perichondrial ring and the metaphysis. The epiphysis, which lies over the epiphyseal cartilage in the form a cupola, contains a juxtaposed bone plate that is near the epiphyseal cartilage and is in direct contact with the epiphyseal side of the epiphyseal cartilage. The germinal zone corresponds to a group of cells called chondrocytes. These chondrocytes belong to a group of chondral cells, which are distributed in rows and columns; this architecture is commonly known as a growth plate. The growth plate is responsible for endochondral bone growth. The aim of this study was to elucidate the causal relationship between the juxtaposed bone plate and epiphyseal cartilage in mammals. Our hypothesis is that cells from the germinal zone of the epiphyseal side of the epiphyseal cartilage are involved in forming a second ossification front that is responsible for the origin of the juxtaposed bone plate. We report the following: (a) The juxtaposed bone plate has a morphology and function that differs from that of the epiphyseal trabeculae; (b) on the epiphyseal edge of the epiphyseal cartilage, a new ossification front starts on the chondrocytes of the germinal area, which forms the juxtaposed bone plate. This ossification front is formed by chondrocytes from the germinal zone through a process of mineralisation and ossification, and (c) the process of mineralisation and ossification has a certain morphological analogy to the process of ossification in the metaphyseal cartilage of amphibians and differs from the endochondral ossification process in the metaphyseal side of the growth plate. The close relationship between the juxtaposed bone plate and the epiphyseal cartilage, in which the chondrocytes that migrate from the germinal area play an important role in the mineralisation and ossification process of the juxtaposed bone plate, supports the hypothesis of a new ossification front in the epiphyseal layer of the epiphyseal plate. This hypothesis has several implications: (a) epiphyseal cartilage is a morphological entity with two different ossification fronts and two different functions, (b) epiphyseal cartilage may be a morphological structure with three parts: perichondrial ring, metaphyseal ossification front or growth plate, and epiphyseal ossification front, (c) all disease (traumatic or dysplastic) that affects some of these parts can have an impact on the morphology of the epiphyseal region of the bone, (d) there is a certain analogy between metaphyseal cartilage in amphibians and mammalian epiphyseal cartilage, although the former is not responsible for bone growth, (e) comparative histological and anatomy studies are also warranted, to shed light on the phylogenetic study of epiphyseal cartilage throughout the changes that occur in the animal species.