Association of uncoupling protein-2 expression with increased reactive oxygen species in residual myocardium of the enlarged left ventricle after myocardial infarction

Left ventricular (LV) dilatation following myocardial infarction (MI) is a major determinant of the patients prognosis, and myocardial energy metabolism may play a key role in LV remodeling. We aimed to investigate the relative timing of LV dilatation to LV function, myocardial energy regulation by uncoupling protein (UCP)-2, and cellular damage in the noninfarct zone. Myocardial infarction was produced in Sprague-Dawley rats by ligation of the coronary artery. The LV end-diastolic dimension (mm) increased (8.9 ± 0.3 vs 6.8 ± 0.8 in sham-operated rats, P < 0.01) in association with elevation of the LV end-diastolic pressure (mmHg) (18 ± 5 vs 6 ± 2 in sham-operated rats) at 1 week following the ligation. At 4 weeks, the UCP-2 expression (180% of that in sham-operated rats) and LV end-diastolic dimension increased further (11.1 ± 0.5, P < 0.01) but there was no change in the LV end-diastolic pressure. The mechanisms for LV dilatation were quite different between the early and late stages after MI. In the late stage, augmentation of UCP-2 expression in the noninfarct zone may be related to the LV dilatation. Further examinations regarding the possibility of the protective role of UCP-2 are needed.     

Low Plasma Nitrite in Infantile Hypertrophic Pyloric Stenosis Patients

There is now substantial evidence that reduced expression of neuronal nitric oxide synthase (nNOS) is implicated in the pathogenesis of infantile hypertrophic pyloric stenosis (IHPS). This study aimed to investigate the role of plasma nitric oxide (NO) in patients with IHPS. Blood and pylorous biopsies of 13 IHPS patients were examined. The control group consisted of 19 age-matched healthy infants and 22 age-matched acute gastroenteritis patients. Plasma nitrite (NO₂ ^–) and nitrate (NO₃ ^–) levels were detected with an NO analyzer. Pylorus biopsies of 13 IHPS patients were examined for nitric oxide synthase isoform expression. Plasma nitrite levels in the 13 IHPS patients were significantly lower than in the age-matched healthy controls (0.97 ± 0.19 vs. 3.53 ± 0.79μ M; P < 0.001) and the acute gastroenteritis controls (0.97 ± 0.19 vs.1.39 ± 0.45μ M; P = 0.006). Decreased expression of nNOS in the nerve fibers of the pylorus circular muscle was found in the 13 IHPS patients. The decreased plasma nitrite levels rose to the normal range (3.27 ± 0.77 M) after pyloromyotomy. There was no significant correlation between plasma nitrite levels and muscle wall thickness in IHPS patients. We conclude that NO is implicated in the occurrence of IHPS and the plasma nitrite level is valuable for the diagnosis of IHPS.     

Late coronary artery reperfusion has additive beneficial effects on infarct expansion when combined with early angiotensin converting enzyme inhibitor therapy post myocardial infarction

Background: Individually, late coronary artery reperfusion and early angiotensin converting enzyme (ACE) inhibitor therapy prevent infarct expansion post myocardial infarction (MI). Objectives: To examine the effect of late reperfusion on infarct expansion when added to early ACE inhibitor therapy post MI. Methods: Rats were randomized into two groups: Reperfusion group: rats underwent coronary artery occlusion followed by reperfusion 2 hours after MI, a time too late to reduce infarct size. A control group: rats underwent permanent coronary artery occlusion followed by a sham operation 2 hours after MI. All rats received enalapril (2.0 ± 0.2 mg/kg) daily in drinking water, started immediately after the second operation. Rats were sacrificed 2 weeks after coronary occlusion. Hearts were arrested and fixed at a constant pressure, then sectioned and photographed for morphometric analysis. Results: Infarct size was similar in the reperfusion and control groups (23 ± 2 vs 26 ± 2%, p = NS). Septal thickness was also similar in both groups (1.8 ± 0.1 vs 1.8 ± 0.1 mm, p = NS). There was a trend towards thicker infarcts in the reperfusion group compared to the control group (0.84 ± 0.06 vs 0.72 ± 0.05 mm, p = 0.1). Compared to early ACE inhibition alone, late reperfusion combined with early ACE inhibition limited infarct expansion (expansion index, 1.13 ± 0.12 vs 1.44 ± 0.14, p < 0.05), prevented left ventricular (LV) dilation (LV volume, 0.30 ± 0.02 vs 0.39 ± 0.03 ml, p < 0.01) and prevented LV hypertrophy (LV weight, 0.71 ± 0.18 vs 0.77 ± 0.20 gm, p < 0.05). Conclusions: Late coronary artery reperfusion prevents infarct expansion, LV dilation and hypertrophy even when added to early ACE inhibitor therapy post MI. This suggests that late reperfusion may be beneficial in patients with acute MI treated with early ACE inhibitor therapy.     

Long-acting calcium channel antagonist pranidipine prevents ventricular remodeling after myocardial infarction in rats

Summary The purpose of this study was to examine the effects of the long-acting calcium channel antagonist pranidipine on ventricular remodeling, systolic and diastolic cardiac function, circulating humoral factors, and cardiac mRNA expression in myocardial infarcted rats. Myocardial infarction (MI) was produced by ligation of the coronary artery in Wistar rats. Three mg/kg per day of pranidipine was randomly administered to the infarcted rats. Hemodynamic measurements, Doppler echocardiographic examinations, analyses of the plasma levels of humoral factors, and myocardial mRNA expression were performed at 4 weeks after myocardial infarction. Left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP) increased to 24.2 ± 1.2mmHg and 5.4 ± 0.6mmHg. Pranidipine reduced LVEDP and CVP to 13.6 ± 1.4mmHg (P < 0.01) and 2.5 ± 0.4mmHg (P < 0.01). The weight of the left and right ventricles in MI was significantly higher than in the sham-operated rats (sham, 2.02 ± 0.04 and 0.47 ± 0.02g/kg; MI, 2.18 ± 0.05 and 0.79 ± 0.04g/kg;P < 0.01). Left ventricular end-diastolic dimension (LVDd) in MI increased to 10.3 ± 0.3mm (P < 0.01) (sham, 6.4 ± 0.3mm). Pranidipine prevented an increase in the weight of the left and right ventricles (2.02 ± 0.04 and 0.6 ± 0.03g/kg,P < 0.01) and LVDd (7.9 ± 0.2mm,P < 0.01 to MI). Plasma renin activity (PRA), and plasma epinephrine, norepinephrine, and dopamine concentrations in MI were higher than those of the sham-operated rats. Pranidipine decreased the PRA and plasma cathecolamine levels of the myocardial infarcted rats to the level of the sham-operated rats. Moreover, the rats in MI showed systolic dysfunction, shown by decreased fractional shortening (sham, 31 ± 2% vs MI, 15 ± 1%;P < 0.01) and diastolic dysfunction shown by the E-wave deceleration rate (sham, 12.8 ± 1.1 m/s²; MI, 32.6 ± 2.1m/s²;P < 0.01). Pranidipine significantly prevented systolic and diastolic dysfunction. The increases in β-myosin heavy chain (MHC), α-skeletal actin, and atrial natriuretic polypeptide mRNAs in the noninfarcted left ventricle and right ventricle at 4 weeks after the myocardial infarction were significantly suppressed by the treatment with pranidipine. On the other hand, depressed α-MHC was restored to normal levels by pranidipine in both regions. In conclusion, pranidipine prevents the left ventricular remodeling process accompanied by systolic and diastolic dysfunction, and inhibits abnormal cardiac gene expression after myocardial infarction.     

The Antagonism of Aldosterone Receptor Prevents the Development of Hypertensive Heart Failure Induced by Chronic Inhibition of Nitric Oxide Synthesis in Rats

Summary Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with N^ω-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of aldosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME+Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 ± 7 vs. 141 ± 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 ± 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 ± 2 vs. 38 ± 1%) and E/A ratio (1.7 ± 0.1 vs. 2.1 ± 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 ± 0.6 vs. 13.9 ± 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 ± 2%), E/A ratio (2.2 ± 0.1), and LVEDP (6.2 ± 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism.     

Reverse chamber remodelling following adrenergic-induced advanced cardiac dilatation and pump dysfunction

As adrenergic-induced cardiac dilatation is associated with cardiomyocyte cell death, whether cessation of excessive adrenergic effects can achieve complete reverse chamber remodelling in established cardiac dilatation and pump dysfunction has been questioned. We assessed whether following the development of cardiac dilatation and pump dysfunction subsequent to 6 months of daily β-adrenergic receptor agonist administration (isoproterenol [ISO] at 0.01 mg/kg daily) to rats, withdrawal of ISO administration for a further 4 months (ISO + recovery) reverses the adverse effects on the heart. Chronic ISO administration and the withdrawal of ISO administration were associated with changes in cardiomyocyte apoptosis, but not myocardial necrosis (pathological score). After 6 months of ISO administration, left ventricular (LV) end diastolic and systolic diameters, and the volume intercept of the LV diastolic pressure–volume relationship (LV V ₀), were markedly increased and LV endocardial fractional shortening (FS_end), LV end systolic chamber (slope of the systolic pressure–volume relationship-Ees) and myocardial (slope of the systolic stress–strain relationship-En) contractility were substantially decreased. Chronic ISO administration produced a 2.5 times increase in LV V ₀ (ISO = 0.40 ± 0.04 vs. saline = 0.16 ± 0.01, P < 0.001). Following a 6-month period of ISO administration and a subsequent withdrawal period for a further 4 months, LV chamber diameters, LV V ₀ (ISO + recovery = 0.21 ± 0.02 vs. saline = 0.23 ± 0.02, P < 0.001), FS_end, LV Ees and LV En were all noted to be similar to control rats. The proportion of ISO + recovery rats with LV chamber diameters, LV V ₀, FS_end, LV Ees and LV En values above or below the 95% confidence interval for the saline + recovery rats was similar to the proportion of saline + recovery rats above or below their own 95% confidence intervals. In conclusion, even in the presence of adrenergic-induced cardiomyocyte apoptosis, marked cardiac dilatation and pump dysfunction produced by chronic β-adrenergic receptor activation can be completely reversed by withdrawal of the excessive adrenergic stimulus.     

Nipradilol, a new β-adrenergic blocker, reduces left ventricular remodeling following myocardial infarction in spontaneously hypertensive rats

Summary Left ventricular (LV) cavity dilation (remodeling) following myocardial infarction (MI) is a risk factor for morbidity and mortality. This study was undertaken to determine whether nipradilol, a new -adrenergic blocker with vasodilating action, reduces LV remodeling after MI produced by coronary ligation in spontaneously hypertensive rats. The effects on LV remodeling of the following drugs, which were administered orally for 4 weeks, were evaluated by assessing LV end-diastolic volume index (LVEDVI): (1) vehicle, (2) nipradilol, 10mg/kg per day, (3) propranolol, 50mg/kg per day, and (4) captopril, 30mg/kg per day. Since LVEDVI depends on infarct size, the effects of the drugs on LVEDVI were compared between rats with a similar infarct size, i.e., moderate, 20%–40%; and large, 40%–60%, on the basis of the histological determination of infarct size. The nipradilol-treated and captopriltreated rats had significantly smaller LVEDVI than did the vehicle-treated rats with both moderate and large infarction (large infarct: 2.48 ± 0.12ml/kg for the vehicle group, 1.69 ± 0.10ml/kg for the nipradilol group,P < 0.01, and 1.79 ± 0.14ml/kg for the captopril group,P < 0.01). In contrast, LVEDVI in the propranololtreated rats was significantly greater than that in the vehicle-treated rats with a moderate infarct (2.09 ± 0.09ml/kg for the vehicle group versus 2.44 ± 0.10ml/kg for the propranolol group,P < 0.05). The results indicate that nipradilol and captopril reduce LV remodeling after MI, whereas propranolol promotes it.     

Coronary extravascular compression influences systolic coronary blood flow

Summary The purpose of this study was to determine whether a relation exists between systolic coronary blood flow and systolic coronary extravascular compressive forces. Studies were performed in seven open-chest dogs in which the left anterior descending coronary artery was cannulated and perfused from the left carotid artery. Pressure within the left ventricular subepicardium, a measure of coronary extravascular compression in the subepicardium, was measured with a 1-mm-diameter catheter-tip micromanometer inserted directly into the myocardium in the region of perfusion. Systolic extravascular compressive forces were augmented by a local intracoronary injection of 1µg isoproterenol. Measurements were made in the presence of coronary vasomotor tone and were repeated following local maximal vasodilatation with adenosine. In the regulated coronary bed, systolic coronary flow decreased (18±4 vs –2±4 ml/min,P<0.01) as intramyocardial pressure increased (127±5 vs 222±12 mmHg,P<0.001). Similarly, in the maximally vasodilated coronary bed, systolic coronary flow decreased (103±16 vs 38±11 ml/min,P<0.001) as intramyocardial pressure increased (112±6 vs 204±16 mmHg,P<0.001). These observations indicate that an augmentation of coronary extravascular compressive forces during systole is accompanied by a diminution of systolic coronary flow irrespective of coronary vasomotor tone.Supported, in part, by the American Heart Association of Michigan. Address reprints request to: Paul D. Stein, M.D., Henry Ford Heart and Vascular Institute, 2799 West Grand Boulevard, Detroit, MI 48202, USA     

Modulation of Nitric Oxide Synthase Activity in Brain,Liver, and Blood Vessels of Spontaneously Hypertensive Rats by Ascorbic Acid: Protection from Free Radical Injury

End organ damage in essential hypertension has been linked to increased oxygen free radical generation, reduced antioxidant defense, and/or attenuation of nitric oxide synthase (NOS) activity. Ascorbic acid (AA), a water-soluble antioxidant, has been reported as a strong defense against free radicals in both aqueous and nonaqueous environment. In this study we examined the hypothesis that antioxidant ascorbic acid may confer protection from increased free radical activity in brain, liver, and blood vessels of spontaneously hypertensive rats (SHR). Male SHRs were divided into groups: SHR + AA (treated with AA, 1 mg/rat/day; for 12 weeks) or SHR (untreated). Wister-Kyoto rats (WKY) served as the control. Mean systolic blood pressure (SBP) in treated and untreated SHR was 145 ± 7 mmHg and 142 ± 8 mmHg, respectively. AA treatment prevented the increase in systolic blood pressure in SHR by 37 ± 1% (p < 0.05). NOS activity in the brain, liver, and blood vessels of WKY rat was 1.82 ± 0.02, 0.14 ± 0.003, and 1.54 ± 0.06 pmol citruline/mg protein, respectively. In SHR, total NOS activity was significantly reduced by 52 ± 1%, 21 ± 3%, and 44 ± 4%, respectively. AA increased NOS activity in brain, liver, and blood vessels of SHR from 0.87 ±.03, 0.11 ±.01, and 0.87 ±.08 pmol citruline/mg protein to 0.93 ± 0.01, 0.13 ± 0.001, and 1.11 ± 0.03 pmol citruline/mg protein (p < 0.05), respectively. Lipid peroxides in the brain, liver, and blood vessels from WKY rats were 0.87 ± 0.06, 0.11 ± 0.005, and 0.47 ± 0.04 nmol MDA equiv/mg protein, respectively. In SHR, lipid peroxides in brain, liver, and blood vessels were significantly increased by 40 ± 3%, 64 ± 3%, and 104 ± 13%, respectively. AA reduced lipid peroxidation in liver and blood vessels by 17 ± 1% and 34 ± 3% but not in brain. Plasma lipid peroxides were almost doubled in SHR (p < 0.01) together with a reduction in total antioxidant status (6 ± 0.1%; p < 0.05), nitrite (53 ± 2%; p < 0.05) and superoxide dismutase (SOD) activity (36 ± 2%; p < 0.05). AA treatment reduced plasma lipid peroxide (p < 0.001), and increased TAS (p < 0.001), nitrite (p < 0.001), and SOD activity (p < 0.001). From this study, we conclude that brain, liver, and blood vessels in SHR are susceptible to free radical injury, which reduces the availability of NO either by scavenging it or by reducing its production via inhibiting NOS. In addition, brain, liver, and blood vessels in SHR; may be protected by antioxidant, which improves total antioxidant status, and SOD thus may prevent high blood pressure and its complications.     

Relationship between exhaled nitric oxide and IgE sensitisation in patients with asthma: influence of steroid treatment

Introduction: The influence of the degree of immunoglobulin E (IgE) sensitisation on the fraction of expired nitric oxide (FE_NO) in asthma patients being treated with inhaled corticosteroids (ICS) is not well known. Objectives: To investigate the relationship between IgE sensitisation and FE_NO, and the effect of a step‐up in ICS treatment on this relationship, in patients with allergic asthma. Methods: A primary health care centre recruited 20 non‐smoking patients with perennial allergic asthma (18 years–50 years, six male) outside the pollen season. At every visit (0, 2, 4, 8 weeks), FE_NO was measured and an exposure questionnaire was completed. ICS dose was adjusted according to FE_NO (≥22 ppb prescribed increase in ICS). Quantitative analyses of serum IgE (eight common aeroallergens) confirmed allergy. Results: At baseline, FE_NO and the sum of IgE antibody titres for perennial allergens correlated significantly (r = 0.47, P = 0.04). After a step‐up in ICS treatment, this correlation had disappeared. Nine patients had persistently elevated FE_NO at last visit (mean 35 ppb vs 16 ppb). This group was more frequently exposed to relevant allergens or colds (89% vs 27% of patients, P < 0.05) and had higher IgE antibody titres (perennial allergens) compared with the normalised group (mean 28.9 kU/L vs 10.7 kU/L, P < 0.05). Conclusion: Serum IgE against perennial allergens and FE_NO correlate in patients with allergic asthma. However, this relationship disappears after a high‐dose ICS regimen, suggesting that FE_NO relates to bronchial inflammation and not IgE levels per se. High degree of IgE sensitisation together with allergen exposure may lead to ICS‐resistant airways inflammation. Please cite this paper as: Syk J, Undén AL and Alving K. Relationship between exhaled nitric oxide and IgE sensitisation in patients with asthma: influence of steroid treatment. The Clinical Respiratory Journal 2009; 3: 143–151.     

Effects of chronic neutral endopeptidase inhibition on the progression of left ventricular dysfunction and remodeling in dogs with moderate heart failure

Background. The diuretic actions of endogenously produced atrial natriuretic factor (ANF) may be beneficial in the treatment of chronic heart failure (CHF). Neutral endopeptidase (NEP) is the primary enzyme responsible for the degradation of ANF. The present study investigates the effects of long-term NEP inhibition on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure. Methods. LV dysfunction was produced in 12 dogs by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction (EF) was between 30–40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with the NEP inhibitor ecadotril (100 mg, once daily, n = 6) or to no therapy at all (control, n = 6). Results. During the 3 months of follow-up, LV EF in control dogs decreased from 37 ± 1% to 28 ± 1% (P < 0.01) and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 72 ± 3 vs. 84 ± 5 ml, P < 0.01); ESV: 45 ± 1 vs. 60 ± 4 ml, P < 0.01). In dogs treated with ecadotril, LV EF (34 ± 1% vs. 37 ± 2%), EDV (79± 5 vs. 78± 6 ml) and ESV (52 ± 3 vs. 49 ± 4) remained essentially unchanged after 3 months of therapy. Histomorphometric measurements at the termination of the study showed that ecadotril was associated with significantly reduced cardiomyocyte hypertrophy compared to control. Conclusion. Early, long-term NEP inhibition with ecadotril prevents the progression of LV dysfunction and attenuates progressive LV remodeling in dogs with moderate heart failure.     

Exhaled nitric oxide decreases during exercise in non‐asthmatic children

Introduction: Exhaled nitric oxide (FE_NO) measurements are recommended to be performed before spirometry and exercise challenge tests because forced breathing might influence FE_NO values. Information on the effect of exercise on FE_NO is lacking in non‐asthmatic children. Aim: To investigate the effect on FE_NO of a standardized exercise challenge test on a treadmill in non‐asthmatic children with and without allergic rhinoconjunctivitis (AR) symptoms. Methods: From the case‐control study ‘Asthma and allergy among school children in Nordland’, 330 non‐asthmatic pupils age 8–16 years were enrolled. FE_NO was measured at baseline and at 1 min and 30 min after exercise challenge test by the single breath technique with EcoMedics Exhalazer® (Eco Physics, Duernten, Switzerland). Results: Pair‐wise comparison of FE_NO from baseline demonstrated a highly significant reduction in FE_NO post‐exercise for all children at 1 min (27.4%) and at 30 min (16.1%) (P < 0.001). The AR group had a significantly higher decline in FE_NO value at 1 min post‐exercise compared to the non‐AR group, 4.2 parts per billion (ppb) vs 2.6 ppb (P < 0.001). Decline in FE_NO immediately post‐exercise was more significant if baseline FE_NO was ≥ 20 ppb; mean reduction 9.9 (95% CI: 8.7–11.4) ppb. Conclusion: FE_NO is reduced by 27.4% immediately after a standardized treadmill exercise test in non‐asthmatic children. Pupils reporting AR symptoms demonstrate a larger decline in FE_NO value at 1 min post‐exercise compared to pupils without AR symptoms. These findings confirm that children should refrain from physical activity before FE_NO measurement. Please cite this paper as: Evjenth B, Hansen TE and Holt J. Exhaled nitric oxide decreases during exercise in non‐asthmatic children. Clin Respir J 2013; 7: 121–127.     

A Single Intravenous sTNFR-Fc Administration at the Time of Reperfusion Limits Infarct Size—Implications in Reperfusion Strategies in Man

Background  Reperfusion of the ischemic myocardium is associated with increased inflammatory processes that can exert deleterious effects and therefore contribute to cardiac dysfunction. The aim of the present study was to verify whether the administration of sTNFR-Fc, a scavenger of the pro-inflammatory cytokine TNF-α, at the time of reperfusion would protect against myocardial infarction and reduce the severity of early mechanical dysfunction. Methods  Male Wistar rats were subjected to 60 min coronary occlusion followed by reperfusion. A bolus of sTNFR-Fc (10 μg/kg, i.v.) (MI + sTNFR-Fc group) or a placebo (MI group) was injected prior to reperfusion. Cardiac geometry was assessed by echocardiography 1, 3 and 7 days after reperfusion. Eight days after reperfusion, left ventricular (LV) function was evaluated under basal conditions and during an experimental challenge of volume overload. Finally, infarct size was measured after euthanasia. Results  sTNFR-Fc administration markedly reduced infarct size (P < 0.01) and decreased LV dilation as assessed by the echocardiographic measurement of the LV end diastolic area, 7 days post-MI (P < 0.01). Moreover, LV end-diastolic pressure was significantly preserved by sTNFR-Fc 1 week after myocardial infarction, under basal conditions (P < 0.05) as well as during cardiac overload (P < 0.05). Conclusion  A single administration of sTNFR-Fc at the time of reperfusion after myocardial infarction is able to limit infarct size and to reduce early LV diastolic dysfunction in rats. These findings suggest that intravenous neutralization of TNF-α during surgical cardiac reperfusion might improve the outcome of myocardial infarction in humans.     

Effect of Cilazapril on Ventricular Remodeling Assessed by Doppler-Echocardiographic Assessment and Cardiac Gene Expression

The purpose of this study is to determine whether the administration of the ACE inhibitor cilazapril can lessen the adverse effects of ventricular remodeling, including systolic and diastolic dysfunction, modulation of fetal gene expression, increase of collagen genes, and depression of the sarcoplasmic reticulum (SR) Ca²⁺ ATPase gene in a myocardial infarcted (MI) rat model. At 1 day after MI, the animals were randomly assigned to cilazapril treatment or no treatment. We performed Doppler-echocardiographic examinations and measured cardiac mRNA in rats at 1 month and 3 months after MI (each group n = 8). The weights of the right (RV) and left ventricles (LV) in 1- and 3-month MI rats were significantly larger than those of the control rats. Cilazapril significantly prevented the increase. The MI rats showed systolic dysfunction, as evidenced by decreased fractional shortening (control, 34 ± 3% vs. MI, 17 ± 3%; P <0.01) and ejection fraction measured by the modified Simpsons method (control, 61 ± 2% vs. MI, 36 ± 3%; P < 0.01) in rats at 1 month after operation. MI rats showed diastolic dysfunction, defined as increased peak early filling velocity, increased deceleration rate of the early filling wave, decreased late filling velocity, and an increase in the ratio of early filling to late filling velocity. Cilazapril significantly prevented systolic and diastolic dysfunction in rats after MI. The increases in -MHC, -skeletal actin, ANP, and collagen I and III mRNAs in the nonischemic LV and RV were significantly suppressed by treatment with cilazapril. Depressed SR Ca²⁺-ATPase mRNA (nonischemic LV, 0.7-fold, P < 0.05 vs. control; RV, 0.5-fold, P < 0.05 vs. control) at 3 months after MI was significantly restored to normal levels by cilazapril. Cilazapril improved the adverse remodeling process by attenuating the progression of systolic and diastolic dysfunction, and prevented abnormal cardiac gene expression following MI.     

Role of Propolis on Tyrosine Hydroxylase Activity and Blood Pressure in Nitric Oxide Synthase-Inhibited Hypertensive Rats

Reduction in the synthesis or bioavailability of nitric oxide plays a significant role in the development of hypertension. Propolis is a resinous product collected by honeybees from various plant sources. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of catecholamines. The aim of this study was to examine the effect of propolis on blood pressure (BP), TH, and total RNA levels in the adrenal medulla, heart, and hypothalamus tissues in chronic nitric oxide synthase (NOS)-inhibited rats by N_w-nitro-l-arginine methyl ester (L-NAME). Rats received NOS inhibitor (L-NAME) for 15 days to produce hypertension and propolis for the last 5 days. TH activity and total RNA levels significantly increased in adrenal medulla, heart, and hypothalamus tissues in L-NAME-treated groups (P < .05). TH activity and total RNA levels of L-NAME+propolis-treated rats reduced (P < .05) compared with L-NAME-treated groups. TH activity in propolis-treated rats was reduced to the control values. L-NAME led to a significant increase in BP compared with the control group. Propolis administration to L-NAME-treated rats reduced BP but this was not statistically significant compared to L-NAME-treated groups. These results suggest that propolis decreases TH activity in NOS-inhibited hypertensive rats and thereby may modulate the synthesis of catecholamine and BP.     

Beneficial effects of adrenomedullin on left ventricular remodeling after myocardial infarction in rats

OBJECTIVE: We previously reported that plasma adrenomedullin (AM) levels increase in patients with acute myocardial infarction (MI) and AM inhibits growth of rat cardiac myocytes and fibroblasts. The aim of this study was to examine the effects of long-term administration of AM on left ventricular (LV) remodeling, hemodynamic and hormonal parameters in a rat model of MI. METHODS: Rats with MI induced by left coronary ligation were intravenously infused with 1.0 microg/h of recombinant human AM or saline by osmotic mini-pump. After infusion for 4 weeks, hemodynamic and hormonal studies were performed, and the myocyte size and collagen volume in non-infarct LV area were quantified morphometrically. RESULTS: When compared with the MI rats infused with saline, continuous infusion of AM reduced the heart weight/body weight (4.4+/-0.2 vs. 3.6+/-0.1 g/kg, P<0.01), myocyte size (922+/-23 vs. 868+/-10 microm(2), P<0.05) and collagen volume fraction of non-infarct LV area (7.6+/-0.8 vs. 4.8+/-0.5%, P<0.05), without affecting the infarct size. The AM infusion had no significant effect on the arterial pressure, but decreased the LV end-diastolic pressure (8.8+/-1.8 vs. 4.4+/-0.5 mmHg, P<0.05) in the MI rats. The plasma level of endogenous rat AM in the MI rats infused with human AM was reduced by 27% (P<0.05), with a slight reduction of plasma atrial natriuretic peptide, compared with the control. CONCLUSIONS: Continuous administration of AM had beneficial effects on LV remodeling and hemodynamics in MI rats, suggesting the possibility that this peptide could be a useful therapeutic tool for acute MI.     

Activity of Angiotensin‐Converting Enzyme After Treatment with L‐Arginine in Renovascular Hypertension

The renin‐angiotensin system plays a role in the pathophysiology of renovascular hypertension. In addition, some studies have demonstrated a beneficial effect of L‐arginine (L‐Arg), the precursor of nitric oxide (NO), in this model of hypertension. This study was designed to investigate the effects of L‐Arg on cardiovascular parameters and on the activity of the angiotensin‐converting enzyme (ACE), after 14 days of renovascular hypertension. The experiments were performed on conscious male Wistar rats. Two‐kidney, one‐clip renovascular hypertension (2K1C) was initiated in rats by clipping the left renal artery during 14 days, while control rats were sham‐operated. One group was submitted to a similar procedure and treated with L‐Arg (10 mg/ml; average intake of 300mg/day) from the 7th to the 14th day after surgery, whereas the respective control group received water instead. At the end of the treatment period, the mean arterial pressure (MAP) was measured in conscious animals. The rats were sacrificed and the ACE activity was assayed in heart and kidneys, using Hip‐His‐Leu as substrate. In a separate group, the heart was removed, the left ventricle (LV) was weighed and the LV/body weight ratios (LV/BW) were determined. We observed significant differences in MAP between the L‐Arg‐treated and untreated groups (129 ± 7 vs. 168 ± 6 mmHg; P < 0.01). The cardiac hypertrophy described for this model of hypertension was attenuated in the 2K1C‐L‐Arg‐treated group (14th day, wet LV/BW: 2K1C‐L‐Arg = 1.88 ± 0.1; 2K1C = 2.20 ± 0.1 mg/g; P < 0.05). L‐Arg administration caused an important decrease in cardiac ACE activity (2K1C‐L‐Arg: 118 ± 15; 2K1C: 266 ± 34 µmol/min/mg; P < 0.01). L‐Arg also decreased the ACE activity in the clipped kidney by 47% (P < 0.01), but not in the nonclipped kidney. These data suggest that increased NO formation and reduced angiotensin II formation are involved in the anthihypertensive effect of orally administered L‐arginine.     

Performance et rendement du ventricule gauche chez l’hypertendu sans hypertrophie ventriculaire gauche : étude échographique par modélisation du couplage ventriculo-aortique

Because the functional interaction between the LV and arterial systems, termed ventricular-arterial coupling, is recognized as a key determinant of LV performance, the objective of the present study was to assess the impact of uncomplicated HT without LVH on LV performance using simultaneously echocardiography and carotid tonometry. LV maximal power (PmaxVG), cardiac power output (CPO), LV efficiency (CPO/PmaxVG), input aortic and output LV elastance (Ea and Ees) were assessed in 20 normotensive control subjects (NT) and 10 patients with untreated HT. PmaxVG was calculated according to the integral of the product of LV wall stress with strain rate (as an index of gradient velocity). Cyclic variation of wall thickness and SR were measured by speckel-tracking. Ea and Ees were derived and modelized from the pressure–volume curve. No difference in age, BMI and sex ratio was observed between NT and HT. Systolic BP (160 ± 18 vs. 119 ± 10 mmHg), LV mass (99 ± 15 vs. 76 ± 12 g/m²), PWV (9.7 ± 2 vs. 6.9 ± 1 m/s) were significantly higher (P < 0.01) in HT when compared to NT. In HT increased of CPO and Ea was compensated by an increase of LV (15 ± 4 vs. 12 ± 3%, P < 0.02) and Ees (5.5 ± 2 vs. 4.5 ± 1.5 mmHg/mL), which are significantly elevated in HT (P < 0.05). No difference was observed in Ea/Ees between NT and HT. In conclusion at the early phase of HT, in patients without LVH, LV performance and ventricular-arterial coupling were adapted to post-load elevation. This adaptation may be the result of an increased of LV contractility.     

Long-term captopril treatment improves diastolic filling more than systolic performance in rats with large myocardial infarction

Objectives. This study sought determine the effects of long-term angiotensin-converting enzyme (ACE) inhibition on left ventricular (LV) diastolic filling in postinfarction heart failure.Background. Long-term treatment with ACE inhibitors is beneficial in experimental animals and patients with heart failure. Because this treatment typically produces only small improvements in LV systolic function, we hypothesized that improvements in LV diastolic filling might contribute to the overall beneficial effects of ACE inhibitors after myocardial infarction (MI).Methods. We performed transthoracic echocardiographic-Doppler examinations in rats 1 and 6 weeks after transmural MI or sham operation. Rats with MI were randomized to no treatment (n = 10) or captopril (2 g/liter in drinking water, n = 8) after the baseline echocardiogram.Results. Six weeks after MI, untreated rats bad significant LV dilation compared with sham-operated rats (LV diastolic dimension [mean ± SEM] 10.7 ± 0.3 vs. 8.5 ± 0.3 mm, p < 0.05). Rats with untreated MI also had impaired fractional shortening (9 ± 1% vs. 34 ± 2%, p < 0.05) and depressed systolic thickening of the noninfarcted posterior wall (37 ± 3% vs. 65 ± 9%, p < 0.05). Rats with MI showed progressively restricted LV diastolic filling as assessed by transmitral Doppler recordings. At 6 weeks, peak early filling velocity (E) was increased (97 ± 3 vs. 77 ± 2 cm/s, p < 0.05), E wave deceleration was more rapid (23 ± 3 vs. 12 ± 1 m/s², p < 0.05), isovolumetric relaxation time was decreased (18 ± 1 vs. 24 ± 1 ms, p < 0.05), and late filling velocity was lower (26 ± 7 vs. 34 ± 1 cm/s, p < 0.05) in rats with MI versus sham-operated rats. Compared with rats with untreated MI, rats receiving captopril had similar LV diastolic dimensions (10.5 ± 0.35 vs. 10.7 ± 0.35 mm), slightly higher fractional shortening (16 ± 2% vs. 9 ± 1%, p < 0.05 [captopril MI vs. untreated MI]) and unchanged posterior wall thickening (49 ± 12% vs. 37 ± 3%, p = 0.3). In contrast, captopril almost completely normalized diastolic filling abnormalities (E velocity 82 ± 5 cm/s, p < 0.05 [captopril MI vs. untreated MI]; E wave deceleration rate 15 ± 2 m/s², p < 0.05 [captopril MI vs. untreated MI]; isovolumetric relaxation time 20 ± 1 ms).Conclusions. Long-term captopril treatment in rats with a large MI modestly limits LV remodeling and the development of systolic dysfunction but markedly improves the restrictive diastolic filling abnormalities that are seen in untreated rats.