Ventricle Weight Research Articles

Exercise improves endothelial nitric oxide synthase (eNOS) dimerization in diabetic rats

The dimeric form of eNOS catalyzes the rate‐limiting step in the synthesis of nitric oxide, while the monomeric form catalyzes the synthesis of peroxynitrite (ONOO), a highly reactive oxidant species (ROS). An increase in the monomer form in the hearts of diabetic animals has previously been reported and this may contribute to cardiac dysfunction. It is unclear if exercise may alter the functional coupling of eNOS. To investigate this question, Goto‐Kakizaki rats were exercise trained for 6‐weeks. Exercise training significantly increased both plantaris cytochrome oxidase activity as well as the left ventricle weight (sed: 0.72±0.02, train; 0.80±0.01 g). Exercise significantly improved glucose tolerance, decreased HbA1c, and fasting blood glucose levels (sed: 205±9.5 mg%; train: 174±9.5 mg%). Exercise training also increased both the total eNOS expression and the ratio of dimer to total eNOS in both the left ventricle (sed: 6.4±2.7%; train: 24.8±5.3%) and the kidney (sed: 12±2%; train: 20.7±3%). The increase in eNOS dimerization would be consistent with increased coupling of the enzyme to facilitate the production of NO at the expense of ROS generation, a shift that could serve to decrease diabetic‐related oxidative stress and that may serve to lessen diabetic‐related complications. Supported in part by the New York Medical College Research Endowment Fund.

Selective increase of angiotensin(1-7) and its receptor in hearts of spontaneously hypertensive rats subjected to physical training

In the present study we investigated the effects of physical training on plasma and cardiac angiotensin(1-7) [Ang(1-7)] levels. In addition, possible changes in expression of the Ang(1-7) Mas receptor in the heart were also evaluated. Normotensive Wistar rats and spontaneously hypertensive rats (SHR) were subjected to an 8 week period of 5% overload swimming training. Blood pressure was determined by a tail-cuff system. Heart and left ventricle weights and cardiomyocyte diameter were analysed to evaluate cardiac hypertrophy. Radioimmunoassay was used to measure angiotensin levels. Expression of Mas was determined by semi-quantitative polymerase chain reaction, immunofluorescence and Western blotting. Physical training induced cardiac hypertrophy in Wistar rats and SHR. A significant decrease of plasma angiotensin II (Ang II) levels in both strains was also observed. Strikingly, trained SHR, but not trained Wistar rats, showed a twofold increase in left ventricular Ang(1-7) levels. No significant changes were observed in plasma Ang(1-7) and left ventricular Ang II concentrations in either strain. Furthermore, Mas mRNA and protein expression in left ventricle were substantially increased in trained SHR. The physical training protocol used did not change blood pressure in either strain. These results suggest that the beneficial effects induced by swimming training in hypertensive rats might include an augmentation of Ang(1-7) and its receptor in the heart.

Evaluation of Olmesartan Medoxomil in the Rat Monocrotaline Model of Pulmonary Hypertension

It is suggested that angiotensin II is involved in the pathogenesis of pulmonary hypertension and subsequent right ventricular hypertrophy; therefore, an angiotensin AT1 receptor antagonist could be beneficial for the treatment of this disease. We tested the effect of the new AT1 receptor antagonist olmesartan medoxomil on monocrotaline-induced pulmonary hypertension in rats. At 3 weeks after a single subcutaneous injection of monocrotaline (50 mg/kg), the lung/body weight ratio, the right ventricle/(left ventricle plus septum) weight ratio [RV/(LV+S)], and right ventricular systolic pressure were increased, indicating establishment of pulmonary hypertension and right ventricular hypertrophy. Oral administration of olmesartan medoxomil (2 or 5 mg/kg/day for 3 weeks) restored RV/(LV+S) and right ventricular systolic pressure, and a higher dose (5 mg/kg/day) improved the lung/body weight ratio. Pulmonary arteries isolated from monocrotaline-treated rats exhibited an increase in basal tone in the resting state, indicating that they had intrinsic tone. Three weeks of treatment with olmesartan decreased this intrinsic tone. These data suggest that long-term treatment with olmesartan has beneficial effects on monocrotaline-induced pulmonary hypertension and subsequent right ventricular hypertrophy.

Efeitos da espironolactona sobre as alterações miocárdicas induzidas pelo hormônio tireoideano em ratos

To study the possible role of aldosterone on thyroid hormone-induced myocardium hypertrophy, using spironolactone. To evaluate morphological changes in the myocardium induced by thyroid hormone and the possible effects of spironolactone use on these alterations. Forty Wistar rats were studied. The animals were allocated to four groups and were given: the vehicle used for dilution of the thyroid hormone (C); sodium levothyroxin at 50 microg/rat/day (H); spironolactone, 0.3 mg/kg/day (S); or thyroid hormone plus spironolactone (HS), at the same doses mentioned above, for 28 consecutive days. All the animals were weighed, had blood drawn for hormonal measurements and underwent ECG at the start and the end of the experiment. At the end of experiment all animals were euthanized, the weight of the left ventricle (LV) was determined and LV slices were obtained for morphological analysis. There was an increase in T3 levels, decrease of body weight and higher heart rate in the animals from group H. The LV weight was significantly higher in the H e HS groups. The histometric analyses that measured the diameter of the myocytes showed higher values in group H and a progressive decrease in groups HS, S and C, with a significant difference among all the groups. The addition of spironolactone decreased the transversal myocyte hypertrophy by 14.6%. Rats treated with thyroid hormone present cardiac hypertrophy with increased LV weight and greater myocyte diameter. Spironolactone, when associated with thyroid hormone, can partially prevent this hypertrophy through mechanisms that are yet to be determined.

Effect of Anemia and Red Blood Cell Transfusion in Acute Myocardial Infarction.

Background: The optimal hemoglobin (Hb) in the setting of acute myocardial infarction (MI) is unknown. Anemia reduces the oxygen carrying capacity of blood and may theoretically exacerbate ischemia increasing myocardial injury. The benefit of transfusion to correct anemia in acute coronary syndromes is also controversial. The goal of this study was to determine the optimal Hb in the setting of acute MI and whether transfusion reduces myocardial injury and improves outcome.Experimental design: Ninety-two male Sprague-Dawley rats (170–190g) were divided into 8 groups: 1: Normal Hb, sham operation; 2: Normal Hb, MI; 3: Hb 80–90g/L, sham; 4: Hb 80–90g/L, MI; 5: Hb 70–80g/L, sham; 6: Hb 70–80g/L, MI; 7: Hb 80–90g/L, MI with transfusion to 100g/L; 8: Hb 80–90g/L, MI with transfusion to 120g/L. To determine the effect of blood transfusion, fresh blood was immediately transfused following MI. Induction of myocardial infarction was preformed by left coronary artery ligation. Sham-operated rats underwent the same surgical procedure without ligation. At 24 hours post-MI, rats were re-anaesthetized and hemodynamic measurements preformed. Area at risk and infarct size was measured by Evans blue and triphenyltetrazolium chloride, respectively.Results: In the normal Hb group (140–150g/L), survival following sham or MI surgery was 100%. Reduction of Hb to 80–90 and 70–80g/L significantly decreased survival post-MI to 42% and 47%, respectively. Survival was significantly improved after transfusion of fresh blood to raise the hemoglobin from 80–90g/L to 100g/L (P<0.05). However, there was no improvement in survival when Hb was raised by transfusion to 120g/L (P=NS). Twenty-four hours post-MI, the ischemic to non-ischemic left ventricle (LV) weight ratios were not significantly different between any groups indicating similar areas of myocardial ischemia among all groups (P=NS). However, the infarct size to area at risk ratios were significantly increased in both 70–80g/L and 80–90g/L groups compared to the normal Hb group (P<0.05). Transfusion from Hb 80–90g/L to 100g/L significantly decreased infarct size compared to the Hb 80–90g/L group (P<0.05). However, transfusion to Hb 120g/L resulted in a significantly larger infarct size compared to the Hb 100g/L transfused group (P<0.05). Cardiac function was determined at 24 hours post-MI. Heart rate, MAP, LVSP and LVEDP were not significantly different among all groups but anemic groups 80–90 and 70–80g/L showed a significant decrease in LV +dP/dtmax and −dP/dtmin in both sham and MI rats (P<0.01) with the most significant decrease noted in MI rats compared to sham operated rats (P<0.05). Blood transfusion post-MI from a Hb 80–90 to 100g/L significantly improved LV +dP/dtmax (P<0.05). Transfusion to Hb 120g/L did not result in any further improvement in cardiac function.Conclusions: In the setting of acute MI, anemia increased mortality and infarct size compared to non-anemic controls. At 24 hours post-MI, anemia also impaired cardiac function. Transfusion of anemic animals up to a Hb of 100g/L with fresh RBCs reduced mortality and infarct size and improved cardiac function. However, transfusion to a Hb of 120g/L did not demonstrate any additional benefit and was associated with larger infarcts.

Reinitiation of compensatory lung growth after subsequent lung resection

In experimental animals, pneumonectomy results in rapid, hyperplastic compensatory growth of the remaining lung. The limits of this induced growth are unknown. We tested the hypothesis that compensatory growth can be reinitiated in the same lung after subsequent lung resection. A left thoracotomy (Sham group) or left pneumonectomy (PNX group) was performed in Sprague-Dawley rats. A third group underwent left pneumonectomy followed 4 weeks later by a bilobectomy of the right upper and middle lobes (PNX+LBX group). Four weeks after bilobectomy in the PNX+LBX group (8 weeks in the Sham and PNX groups), right ventricular pressures were measured by using the open chest technique, and total lung weight and lower plus cardiac lobe weight indices were measured. Lungs were inflation fixed at 25 cm H2O to measure lobe volume index and to perform morphometric measurements on lung sections. Right ventricle/left ventricle plus septum weight index was measured as another index of pulmonary hypertension. Total lung weight index was similar in all groups. Pneumonectomy resulted in increased lower plus cardiac lobe weight and volume indices, which were significantly augmented in the PNX+LBX group. The PNX+LBX group underwent a significant increase in total volume of respiratory region, airspace, and tissue and a decrease in alveolar surface density versus the PNX group. The PNX+LBX group also had significantly increased right ventricular systolic pressure and right ventricle/left ventricle plus septum index. These results demonstrate that compensatory growth can be reinitiated in lungs that had previously undergone postpneumonectomy compensatory growth. This subsequent growth, however, is more hypertrophic, and pulmonary hypertension develops despite subsequent compensatory growth.

Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity

Intermittent hypoxia (IH) resulting from sleep apnea can lead to pulmonary hypertension (PH) and right heart failure, similar to chronic sustained hypoxia (CH). Supplemental CO(2), however, attenuates hypoxic PH. We therefore hypothesized that, similar to CH, IH elicits PH and associated increases in arterial endothelial nitric oxide synthase (eNOS) expression, ionomycin-dependent vasodilation, and receptor-mediated pulmonary vasoconstriction. We further hypothesized that supplemental CO(2) inhibits these responses to IH. To test these hypotheses, we measured eNOS expression by Western blot in intrapulmonary arteries from CH (2 wk, 0.5 atm), hypocapnic IH (H-IH) (3 min cycles of 5% O(2)/air flush, 7 h/day, 2 wk), and eucapnic IH (E-IH) (3 min cycles of 5% O(2), 5% CO(2)/air flush, 7 h/day, 2 wk) rats and their respective controls. Furthermore, vasodilatory responses to the calcium ionophore ionomycin and vasoconstrictor responses to the thromboxane mimetic U-46619 were measured in isolated saline-perfused lungs from each group. Hematocrit, arterial wall thickness, and right ventricle-to-total ventricle weight ratios were additionally assessed as indexes of polycythemia, arterial remodeling, and PH, respectively. Consistent with our hypotheses, E-IH resulted in attenuated polycythemia, arterial remodeling, RV hypertrophy, and eNOS upregulation compared with H-IH. However, in contrast to CH, neither H-IH nor E-IH increased ionomycin-dependent vasodilation. Furthermore, H-IH and E-IH similarly augmented U-46619-induced pulmonary vasoconstriction but to a lesser degree than CH. We conclude that maintenance of eucapnia decreases IH-induced PH and upregulation of arterial eNOS. In contrast, increases in pulmonary vasoconstrictor reactivity following H-IH are unaltered by exposure to supplemental CO(2).

Swimming training exacerbates pathological cardiac hypertrophy in kinin B2 receptor-deficient mice

Kallikrein–kinin system exerts cardioprotective effects against pathological hypertrophy. These effects are modulated mainly via B2 receptor activation. Chronic physical exercise can induce physiological cardiac hypertrophy characterized by normal organization of cardiac structure. Therefore, the aim of this work was to verify the influence of kinin B2 receptor deletion on physiological hypertrophy to exercise stimulus. Animals were submitted to swimming practice for 5 min or for 60 min, 5 days a week, during 1 month and several cardiac parameters were evaluated. Results showed no significantly difference in heart weight between both groups, however an increased left ventricle weight and myocyte diameter were observed after the 60 min swimming protocol, which was more pronounced in B2−/− mice. In addition, sedentary B2−/− animals presented higher left ventricle mass when compared to wild-type (WT) mice. An increase in capillary density was observed in exercised animals, however the effect was less pronounced in B2−/− mice. Collagen, a marker of pathological hypertrophy, was increased in B2−/− mice submitted to swimming protocol, as well as left ventricular thickness, suggesting that these animals do not respond with physiological hypertrophy for this kind of exercise. In conclusion, our data suggest an important role for the kinin B2 receptor in physiological cardiac hypertrophy.

The effect of dietary l‐carnitine supplementation on pulmonary hypertension syndrome mortality in broilers exposed to low temperatures

Oxidative stress is involved in the development of pulmonary hypertension syndrome (PHS) in broilers. l-Carnitine has an antiperoxidative effect and supplemental l-carnitine has been revealed to increase broiler heart weight. The present study was conducted to evaluate the effect of an addition of 100 mg/kg l-carnitine to the basal diets on PHS mortality in cold-exposed broilers. Two-hundred and forty mixed-sex broilers were equally assigned to three groups. The control group was reared in normal temperatures throughout the experiment. Starting on day 14 continuing until the end of the experiment, the other two groups were subjected to a step-down temperature programme (by lowering the temperature 1-2 degrees C per day down to 12-14 degrees C) with or without l-carnitine added to the basal diets. Cold exposure increased the right/total ventricle ratio (RV/TV) and plasma malondialdehyde (MDA), reduced superoxide dismutase (SOD) and led to pulmonary vascular remodelling in birds without feeding additional l-carnitine. Supplemental l-carnitine reduced plasma MDA, increased SOD, inhibited remodelling and postponed the occurrence of PHS for 1 week in cold-exposed broilers; nevertheless, it did not significantly influence the cumulative PHS mortality (p > 0.05). On days 24 and 32, birds fed supplemental l-carnitine had lower RV/TV and higher total ventricle/body weight (p < 0.05) but unchanged right ventricle/body weight ratios (p > 0.05) compared to their cold-exposed counterparts, indicating an increase in left ventricle weight. However, from day 39 on, their RV/TV ratios were suddenly increased (p < 0.05). It was suggested that the l-carnitine-induced increase in left heart weight might partially account for the postponed occurrence of pulmonary hypertension in the early stage by elevating cardiac output, which might, in turn, lead to the resulting increase in pulmonary pressure. In view of its complex effects on cardiopulmonary haemodynamics, l-carnitine supplementation may be impractical for reducing PHS.

Cardiac angiotensin II type I and type II receptors are increased in rats submitted to experimental hypothyroidism

This study assessed the behaviour of angiotensin II (Ang II) receptors in an experimental hypothyroidism model in male Wistar rats. Animals were subjected to thyroidectomy and resting for 14 days. The alteration of cardiac mass was evaluated by total heart weight (HW), right ventricle weight (RVW), left ventricle weight (LVW), ratio of HW, RVW and LVW to body weight (BW) and atrial natriuretic factor (ANF) expression. Cardiac and plasma Ang II levels and serum T3 and T4 were determined. The mRNA and protein levels of Ang II receptors were investigated by RT-PCR and Western blotting, respectively. Functional analyses were performed using binding assays. T3 and T4 levels and the haemodynamic parameters confirmed the hypothyroid state. HW/BW, RVW/BW and LVW/BW ratios and the ANF expression were lower than those of control animals. No change was observed in cardiac or plasma Ang II levels. Both AT1/AT2 mRNA and protein levels were increased in the heart of hypothyroid animals due to a significant increase of these receptors in the RV. Experiments performed in cardiomyocytes showed a direct effect promoted by low thyroid hormone levels upon AT1 and AT2 receptors, discarding possible influence of haemodynamic parameters. Functional assays showed that both receptors are able to bind Ang II. Herein, we have identified, for the first time, a close and direct relation of elevated Ang II receptor levels in hypothyroidism. Whether the increase in these receptors in hypothyroidism is an alternative mechanism to compensate the atrophic state of heart or whether it may represent a potential means to the progression of heart failure remains unknown.

Role of Rac1 GTPase Activation in Atrial Fibrillation

We aimed to study the role of Rac1 GTPase in atrial fibrillation (AF). The signal transduction associated with AF is incompletely understood. We hypothesized that activation of Rac1 GTPase contributes to the pathogenesis of AF via activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and production of reactive oxygen species. Old mice with cardiac-specific overexpression of constitutively active V12Rac1 (RacET) were compared with wild-type (WT) and WT undergoing transaortic constriction (TAC). In addition, samples of human left atrial appendages were analyzed in patients with sinus rhythm (SR) compared with patients with permanent AF matched for atrial diameter. At age 16 months, 75% of RacET but no WT or TAC mice showed AF. Treatment of RacET with statins for 10 months did not alter weight or fibrosis of atria or ventricles but decreased cardiac Rac1 and NADPH oxidase activity and reduced the incidence of AF by 50%. The left atria of patients with AF showed increased fibrosis, up-regulation of NADPH oxidase activity, a 4-fold increase of Rac1 total protein and membrane expression as well as up-regulation of Rac1 activity. Chronic cardiac overexpression of Rac1 represents a novel mouse model for AF. Rac1 GTPase contributes to the pathogenesis of AF and identifies a target for the prevention and treatment of AF.

N-acetylcysteine attenuates PKCβ2overexpression and myocardial hypertrophy in streptozotocin-induced diabetic rats

Oxidative stress-mediated activation of protein kinase C (PKC) beta(2) in the myocardium has been implicated in the development of cardiomyopathy. Overexpression of PKCbeta(2) is associated with increased expression of connective tissue growth factor (CTGF) in myocardium, resulting in myocardial hypertrophy. We hypothesized that chronic treatment with the antioxidant N-acetylcysteine (NAC) would normalize oxidative stress-mediated overexpression of myocardial PKCbeta(2) and CTGF and attenuate the development of myocardial hypertrophy. Control and streptozotocin-induced diabetic rats were treated with NAC in drinking water for 8 weeks. At termination rats were surgically prepared for hemodynamic measurement, subsequent to which their hearts were removed to evaluate cardiac performance and histological and biochemical changes. Further, the role of PKCbeta(2) in hyperglycemia-induced cardiomyocyte hypertrophy was tested in cultured neonatal cardiomyocytes. Myocardial hypertrophy, characterized by an increased ratio of ventricle weight to body weight and cardiomyocyte cross-sectional area was found to be higher in untreated diabetic rats. Further, in myocardium, increased levels of 15-F(2t)-isoprostane were accompanied by an increased expression of membrane-bound PKCbeta(2) and CTGF. N-acetylcysteine treatment not only attenuated these changes but also prevented hyperglycemia-induced hypertrophy in cultured neonatal rat cardiomyocytes. The results suggest that PKCbeta(2) overexpression represents a mechanism causing hyperglycemia-mediated myocardial hypertrophy, which can be prevented by the antioxidant N-acetylcysteine.

Moderate Pulmonary Arterial Hypertension in Male Mice Lacking the Vasoactive Intestinal Peptide Gene

Vasoactive intestinal peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, has been reported absent in pulmonary arteries from patients with idiopathic pulmonary arterial hypertension (PAH). We have tested the hypothesis that targeted deletion of the VIP gene may lead to PAH with pulmonary vascular remodeling. We examined VIP knockout (VIP-/-) mice for evidence of PAH, right ventricular (RV) hypertrophy, and pulmonary vascular remodeling. Relative to wild-type control mice, VIP-/- mice showed moderate RV hypertension, RV hypertrophy confirmed by increased ratio of RV to left ventricle plus septum weight, and enlarged, thickened pulmonary artery and smaller branches with increased muscularization and narrowed lumen. Lung sections also showed perivascular inflammatory cell infiltrates. No systemic hypertension and no arterial hypoxemia existed to explain the PAH. The condition was associated with increased mortality. Both the vascular remodeling and RV remodeling were attenuated after a 4-week treatment with VIP. Deletion of the VIP gene leads to spontaneous expression of moderately severe PAH in mice during air breathing. Although not an exact model of idiopathic PAH, the VIP-/- mouse should be useful for studying molecular mechanisms of PAH and evaluating potential therapeutic agents. VIP replacement therapy holds promise for the treatment of PAH, and mutations of the VIP gene may be a factor in the pathogenesis of idiopathic PAH.

Cardioprotective role of cardiotrophin-1 gene transfer in a murine model of myocardial infarction

We observed the effect of cardiotrophin-1 (CT-1) gene transfer on cardiomyocytes in a murine model of myocardial infarction. Sixty male CD-1 mice weighing approximately 40 g were used in the study. Forty mice were subjected to left coronary artery ligation and randomized to receive AdCT-1 vector (treated group) or AdLacZ vector (control group) treatment, with 20 mice for each group. AdCT-1 or AdLacZ vector was directly injected into the border zone of the ischemic myocardium at six sites, 10 min after ligation (10 μl/site, 2.5 × 106 PFU/100 μl). Twenty mice undergoing thoracotomy and injection of an equal volume of phosphate-buffered saline solution but not coronary ligation served as sham group. Hemodynamics, histopathology and cardiomyocyte apoptosis were detected at 2 weeks after injection. Four animals in sham, nine in control, and six in treated groups died during the experiment. The remaining 41 mice were included in the study. Mean arterial pressure, left ventricular systolic pressure, and the maximum rate of left ventricular pressure rise or fall were significantly higher in treated group than in control group (P < 0.01 for all), whereas left ventricular end-diastolic pressure, infarct size, the ratio of right ventricle or lung weight to body weight, and apoptotic index were significantly lower in treated group than in control group (P < 0.01 for all). The caspase-3 activation and mitochondrial cytochrome c release were also lower in treated group than in control group (P < 0.01 for each). AdCT-1 injection significantly inhibited Fas, Bax and p53, and increased CT-1 and Bcl-2 expression in myocardium. Our results suggest that AdCT-1 vector can be effectively transfected and continued to express bioactive CT-1 protein in myocardium. CT-1 plays an important cardioprotective effect on myocardial damage in the murine model of myocardial infarction.

Hypercapnia attenuates intermittent hypoxia‐induced pulmonary hypertension

Sleep apnea with resultant exposure to intermittent hypoxia/hypercapnia (IHHC) is characterized by pulmonary hypertension (PH) and right ventricle (RV) hypertrophy similar to that observed with chronic sustained hypoxia (CH). However, CH-induced PH, associated with enhanced vasoconstrictor reactivity, polycythemia and arterial remodeling, is inhibited by chronic hypercapnia. We therefore hypothesized that hypercapnia coincident with intermittent hypoxia (IH) similarly inhibits increases in agonist-mediated pulmonary vasoconstriction and PH. To test this hypothesis, we compared vasoconstrictor responses to the thromboxane analog U-46619 in isolated, saline-perfused lungs from rats exposed to IH (3 min cycles of 5% O2/air flush), IHHC (3 min cycles of 5% O2, 5% CO2/air flush) or air (air/air cycling) for 7 hr/day for 2 wk. Hematocrit, arterial wall thickness and the ratio of RV to total ventricle weight were measured as indices of polycythemia, arterial remodeling and PH, respectively. Consistent with our hypothesis, hypercapnia prevented IH-induced polycythemia, vascular remodeling and RV hypertrophy. However, IH and IHHC similarly augmented vasoconstriction to U-46619. We conclude that hypercapnia protects against IH-induced PH. In contrast, increases in pulmonary vasoconstrictor reactivity following IH are unaltered by combined exposure with hypercapnia.

Treatment of post-dialytic orthostatic hypotension with an inflatable abdominal band in hemodialysis patients

The purpose of this study was to ascertain whether abdominal compression with an inflatable abdominal band, a device we developed, improved post-dialytic orthostatic hypotension (OH) in hemodialysis (HD) patients. Twenty-five chronic HD patients with intractable post-dialytic OH were recruited. Post-HD changes in systolic blood pressure (DeltaSBP) in the supine and standing positions were compared in the patients, measured with or without the use of the band. The study showed DeltaSBP after HD without the band was significantly greater than that measured before HD (-36.1+/-18.2 vs -13.1+/-16.8 mm Hg; P<0.0001). DeltaSBP after HD with the band was reduced significantly in comparison to DeltaSBP after HD without the band (-19.4+/-21.2 vs -36.1+/-18.2 mm Hg; P<0.002). Use of the band did not cause an elevation in SBP in the supine position (149.0+/-29.6 vs 155.4+/-25.7 mm Hg); however, it did increase SBP upon standing (129.6+/-27.3 vs 117.2+/-22.6 mm Hg; P<0.05). Eight patients in whom an increase in SBP of 25 mm Hg or more was achieved with the band were classified as responders. Ejection fraction was significantly higher (76.4+/-11.1 vs 61.9+/-13.6%; P<0.02) and atrial natriuretic peptide concentration significantly lower (27.9+/-22.0 vs 68.9+/-47.5 pg/ml; P<0.02) in responders than in non-responders. We conclude that the abdominal band was effective for overcoming post-dialytic OH, without elevating supine SBP in some patients.

Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats

Accumulating evidences have demonstrated that RhoA/Rho-kinase pathway plays a pivotal role in various cellular functions. The aim of this study was to explore whether RhoA/Rho-kinase pathway is involved in the pathogenesis of high flow induced pulmonary hypertension and whether long-term inhibition of RhoA/Rho-kinase pathway with fasudil could attenuate high flow induced pulmonary artery remodeling in rats. Wistar rats in the shunt groups and treated groups were underwent left common carotid artery–external jugular vein shunt operation, rats in control groups were sham-operated animals. Rats in treated groups received fasudil treatment, the others received same dose of saline. At week 4, 8 of the study, rats were underwent haemodynamics measurements, pulmonary artery morphologic assessments, detection of pulmonary artery smooth muscle cells (SMCs) proliferation and apoptosis. RhoA and Rho-kinase activity in pulmonary arteries were also analyzed. Compared with the control groups, exposure to high blood flow induced a significant elevation of right ventricle systolic pressure at week 8, significant increase of the mean percentage of media wall thickness (%MT) in moderate size pulmonary arteries both at weeks 4 and 8, marked elevation of right ventricle (RV) to left ventricle plus septum (LV + SP) weight ratio at week 8, significant increase of PCNA-positive SMCs percentage at week 4 and significant decrease of TUNEL-positive SMCs percentage both at weeks 4 and 8. High pulmonary blood flow also induced 3.19 ± 0.28-fold increase of RhoA and 3.63 ± 0.52-fold increase of Rho-kinase over the control group at week 4, 1.57 ± 0.35-fold increase of RhoA and 2.36 ± 0.39-fold increase of Rho-kinase over the control group at week 8. Compared with the shunt groups, fasudil treatment significantly suppressed Rho-kinase activity at both weeks 4 and 8, improved pulmonary hypertension at week 8, attenuated right ventricular hypertrophy at week 8, and enhanced pulmonary vascular remodeling both at weeks 4 and 8, which were associated with suppressed pulmonary artery smooth muscle cells proliferation at week 4 and apoptosis both at weeks 4 and 8. These results indicated that RhoA/Rho-kinase mediated pathway participated in the process of high flow induced pulmonary artery remodeling; inhibition of Rho kinase with fasudil could attenuate pulmonary artery remodeling.

Dexfenfluramine does not worsen but moderates progression of chronic hypoxia-induced pulmonary hypertension

This study shows for the first time, that dexfenfluramine, a 5-HT 2 receptor agonist, attenuates the development of chronic hypoxia-induced pulmonary hypertension. Chronic exposure to hypoxia, 4 weeks, induced hypoxic pulmonary hypertension in adult rat as haemodynamic and cardiac measurements showed significant modifications in right ventricle parameters (free wall right ventricle thickness; pulmonary acceleration time and velocity time integral) in chronic hypoxic control when compared to normoxic control animals. We observed that free wall right ventricle thickness and pulmonary velocity time integral were significantly less in chronic hypoxic rats treated with dexfenfluramine when compared to chronic hypoxic control rats. Similarly, rats exposed to chronic hypoxia exhibited an increase in both right ventricle pressure and weight by comparison to normoxic control animals but those variations were significantly diminished in dexfenfluramine-treated rats, indicating the moderating influence exerted by dexfenfluramine on chronic hypoxia-induced pulmonary hypertension and cardiac alterations. Thus, we report here the ability of dexfenfluramine to limit chronic hypoxia-induced pulmonary hypertension, emphasizing the importance of the time after the dexfenfluramine treatment discontinuation to assess the influence of this 5-HT receptor agonist on the development of chronic hypoxia-induced pulmonary hypertension.

Identification and Characterization of Novel Angiotensin-Converting Enzyme Inhibitors Obtained from Goat Milk

The aim of the present study was to identify and characterize new inhibitory peptides of angiotensin I-converting enzyme (ACE) from goat milk and to analyze the effect of long-term intake of a goat milk hydrolysate-supplemented (GP-hyd) diet on the development of hypertension in spontaneously hypertensive rats (SHR). Three new inhibitory peptides for ACE (TGPIPN, SLPQ, and SQPK) were isolated. The inhibitory concentration 50% (IC50) values of individual peptides were 316, 330, and 354μmol/L, respectively. Only TGPIPN was found to pass intact a monolayer of Caco-2 cells in small amounts. The SHR fed for 12wk a diet (GP-hyd) enriched in a hydrolysate containing these peptides (estimated intake of TGPIPN was 230mg/kg per d) showed lower (approximately 15mmHg) systolic blood pressure than animals fed a control diet. The ACE activities in the aorta, left ventricle, and kidney were significantly decreased in the GP-hyd group compared with those of the control group and were similar to those found in SHR fed captopril (130mg/kg per d). Impaired endothelium-dependent relaxation to acetylcholine by aortic rings from SHR was improved in those fed the GP-hyd diet. The left ventricle weight and kidney weight index were significantly reduced in the GP-hyd group and captopril groups. Moreover, long-term treatment of SHR with a diet enriched in goat milk hydrolysate, or captopril, attenuated the development of hypertension, cardiac and renal hypertrophy, and endothelial dysfunction. These effects might be related to the in vivo inhibitory effects of the hydrolysate on tissue ACE activity.

O Treinamento físico por natação atenua o remodelamento miocárdico e congestão pulmonar em ratas wistar com insuficiência cardíaca secundária a infarto do miocárdio

To evaluate the effects of swimming on pulmonary water content in animals with heart failure (HF) after myocardial infarction (MI). After coronary occlusion, MI size 20%<MI<40% of the left ventricle (LV) were considered moderate and those > 40% of the LV large. The animals swam for 60 min/day, 5 days/week for 8 weeks. The wet weight of lung, liver, atriums, LV and right ventricle (RV) as well as the dry weight of the liver and lung were determined. ANOVA and Tukey test were used for statistical analysis. An increase in the atrium/body weight ratio was noted in the sedentary animals with moderate (MImod-SED: n=8) and large (MIlg-SED: n=10) infarctions in comparison to the sedentary control (C-SED: n=14) and trained (C-TR: n=16) rats. An increase in the RV/body weight and LV/body weight ratios was noted in the MIlg-SED. The heart/body weight ratio was higher in MIlg-SED when compared to the other groups. The infarcted trained animals presented diminished hypertrophy. The pulmonary water content was higher in MIlg-SED animals (81+/-0.4%) than in C-SED animals (79+/-0.4%). No differences were found for the other comparisons (C-TR: 79+/-0.4%; MImod-SED: 80+/-0.3%; MImod-TR: 80+/-0.6%; MIlg-TR: 79+/-0.7%). The increase of cardiac mass and pulmonary water content presented by MIlg-SED was diminished in the trained animals. The results suggest that the practice of physical exercise can diminish HF and contribute to favorable cardiac remodeling.