Metoprolol Treatment Lowers Thrombospondin‐4 Expression in Rats with Myocardial Infarction and Left Ventricular Hypertrophy

Abstract: Thrombospondins are matrix proteins linked to extracellular matrix remodelling but their precise role in the heart is not known. In this study, we characterised left ventricular thrombospondin‐1 and ‐4 expression in rats treated with a beta‐blocker metoprolol during the remodelling process in response to pressure overload and acute myocardial infarction. Left ventricular thrombospondin‐1 and thrombospondin‐4 mRNA levels increased 8.4‐fold (p < 0.001) and 7.3‐fold (p < 0.001) post‐infarction, respectively. Metoprolol infusion by osmotic minipumps (1.5 mg/kg/hr) for 2 weeks after myocardial infarction decreased thrombospondin‐1 and thrombospondin‐4 mRNA levels (55% and 50%, respectively), improved left ventricular function, and attenuated left ventricular remodelling with reduction of left ventricular atrial natriuretic peptide and brain natriuretic peptide gene expression. Thrombospondin‐1 and ‐4 mRNA levels correlated positively with echocardiographic parameters of left ventricular remodelling as well as with atrial natriuretic peptide and brain natriuretic peptide gene expression. Moreover, there was a negative correlation between left ventricular ejection fraction and thrombospondin‐1 mRNA levels. In 12‐month‐old spontaneously hypertensive rats with left ventricular hypertrophy, metoprolol decreased left ventricular thrombospondin‐4 levels and attenuated remodelling while thrombospondin‐1, atrial natriuretic peptide and brain natriuretic peptide mRNA levels as well as left ventricular function remained unchanged. In metoprolol‐treated spontaneously hypertensive rats, thrombospondin‐4 gene expression correlated with parameters of left ventricular remodelling, while no correlations between thrombospondins and natriuretic peptides were observed. These results indicate that thrombospondin‐1 expression is linked exclusively to left ventricular remodelling process post‐infarction while thrombospondin‐4 associates with myocardial remodelling both after myocardial infarction and in hypertensive heart disease suggesting that thrombospondins may have unique roles in extracellular matrix remodelling process.     

Immunosuppression with mycophenolate mofetil attenuates the development of hypertension and albuminuria in deoxycorticosterone acetate‐salt hypertensive rats

1. The interplay between the immune and renin–angiotensin systems is emerging as a crucial factor in the development and progression of hypertension. The aim of the present study was to determine the involvement of immune cells in the hypertension and renal injury produced by a non‐angiotensin II‐dependent form of hypertension, namely deoxycorticosterone acetate (DOCA)‐salt‐induced hypertension, in rats. 2. Male Sprague‐Dawley rats underwent uninephrectomy and received either a sustained‐release pellet of DOCA s.c. and 0.9% NaCl (saline) to drink for 21 days or a placebo pellet and water to drink for 21 days. Additional groups of DOCA‐salt‐ and placebo‐treated rats were treated concurrently with the immune suppressant mycophenolate mofetil (MMF; 30 mg/kg per day). Rats were placed in metabolic cages for 24 h urine collection prior to and at weekly intervals during the 21 day experimental period. 3. Mycophenolate mofetil significantly attenuated the development of hypertension in DOCA‐salt rats compared with untreated DOCA‐salt hypertensive rats (mean arterial pressure by telemetry on Day 18 146 ± 7 vs 180 ± 3 mmHg, respectively; P < 0.001), as well as proteinuria (87 ± 27 vs 305 ± 63 mg/day, respectively, on Day 21) and albuminuria (51 ± 15 vs 247 ± 73 mg/day, respectively, on Day 21). Creatinine clearance was better preserved in MMF‐treated DOCA‐salt rats compared with untreated DOCA‐salt rats (0.74 ± 0.07 vs 0.49 ± 0.09 mL/min, respectively; P < 0.05), but was still significantly reduced compared with that in the placebo group (1.15 ± 0.12 mL/min; P < 0.05). Finally, MMF treatment significantly attenuated the DOCA‐salt‐induced rise in renal cortical T‐lymphocyte and macrophage infiltration (P < 0.05). 4. These data indicate that immune cells play a deleterious role in both the hypertension and renal injury associated with DOCA‐salt hypertension.     

Acetyl‐l‐Carnitine Ameliorates Caerulein‐induced Acute Pancreatitis in Rats

Abstract: In the present study, we have addressed the possible protective role of acetyl‐l ‐carnitine in caerulein‐induced acute pancreatitis in male Swiss albino rats. Acute pancreatitis paradigm was developed by challenging animals with a supramaximal dose of caerulein (20 µg/kg, SC) four times at hourly intervals. Caerulein induced acute pancreatitis that was well‐characterized morphologically and biochemically. Severe oedema with marked increased relative pancreatic weight, marked atrophy of acini with increased interacinar spaces, vacuolization, and extensive leucocytic infiltration were diagnostic fingerprints of the pancreatitis phenotype. A biochemical test battery that confirmed the model comprised increased plasma amylase and lipase activities, calcium levels as well as increased pancreatic enzymatic myeloperoxidase and glutathione‐S‐transferase activities, beside increased pancreatic contents of nitric oxide and malondialdehyde and reduced pancreatic glutathione level. Prior administration of acetyl‐l ‐carnitine (200 mg/kg, IP) for seven consecutive days ahead of caerulein challenge alleviated all the histological and biochemical manifestations of acute pancreatitis. These results suggest a possible protective role of the carnitine ester in such a murine acute pancreatitis model probably via regulation of the oxidant/antioxidant balance, beside modulation of the myeloperoxidase and nitric oxide systems, which are involved in the inflammatory cascade that most often associate the disease.     

Improved cardiovascular function with aminoguanidine in DOCA-salt hypertensive rats

The ability of aminoguanidine (AG), an inhibitor of collagen crosslinking, to prevent changes in cardiac and vascular structure and function has been determined in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat as a model of the cardiovascular remodelling observed in chronic human hypertension.Uninephrectomized rats (UNX) administered DOCA (25 mg every fourth day s.c.) and 1% NaCl in drinking water for 28 days developed cardiovascular remodelling shown as systolic hypertension, left ventricular hypertrophy, increased thoracic aortic and left ventricular wall thickness, increased left ventricular inflammatory cell infiltration together with increased interstitial collagen and increased passive diastolic stiffness, impaired contractility, prolongation of the action potential duration and vascular dysfunction.Treatment with AG (0.05-0.1% in drinking water; average 182+/-17 mg kg(-1) day(-1) in DOCA-salt rats) decreased blood pressure (DOCA-salt 176+/-4; +AG 144+/-5 mmHg; (*)P<0.05 vs DOCA-salt), decreased left ventricular wet weights (DOCA-salt 3.17+/-0.07; +AG 2.66+/-0.08 mg g(-1) body wt(*)), reduced diastolic stiffness constant (DOCA-salt 30.1+/-1.2; +AG 24.3+/-1.2(*) (dimensionless)), improved cardiac contractility (DOCA-salt 1610+/-130; +AG 2370+/-100 mmHg s(-1)(*)) and vascular reactivity (3.4-fold increase in maximal contractile response to noradrenaline, 3.2-fold increase in maximal relaxation response to acetylcholine, twofold increase in maximal relaxation response to sodium nitroprusside) and prolonged the action potential duration at 50% repolarization without altering collagen content or inflammatory cell infiltration.Thus, cardiovascular function in DOCA-salt hypertensive rats can be improved by AG independent of changes in collagen content. This suggests that collagen crosslinking is an important cause of cardiovascular dysfunction during cardiovascular remodelling in hypertension.     

Changes in hepatic lipogenic and oxidative enzymes and glucose homeostasis induced by an acetyl‐l‐carnitine and nicotinamide treatment in dyslipidaemic insulin‐resistant rats

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l‐Arginine Attenuates Cardiac Dysfunction,But Further Down‐Regulates α‐Myosin Heavy Chain Expression in Isoproterenol‐Induced Cardiomyopathy

In view of previously reported increased capacity for nitric oxide production, we suggested that l ‐arginine (ARG), the nitric oxide synthase (NOS) substrate, supplementation would improve cardiac function in isoproterenol (ISO)‐induced heart failure. Male Wistar rats were treated with ISO for 8 days (5 mg/kg/day, i.p.) or vehicle. ARG was given to control (ARG) and ISO‐treated (ISO+ARG) rats in water (0.4 g/kg/day). ISO administration was associated with 40% mortality, ventricular hypertrophy, decreased heart rate, left ventricular dysfunction, fibrosis and ECG signs of ischaemia. RT‐PCR showed increased mRNA levels of cardiac hypertrophy marker atrial natriuretic peptide, but not BNP, decreased expression of myosin heavy chain isoform MYH6 and unaltered expression of pathological MYH7. ISO increased the protein levels of endothelial nitric oxide synthase, but at the same time it markedly up‐regulated mRNA and protein levels of gp91phox, a catalytical subunit of superoxide‐producing NADPH oxidase. Fibrosis was markedly increased by ISO. ARG treatment moderately ameliorated left ventricular dysfunction, but was without effect on cardiac hypertrophy and fibrosis. Combination of ISO and ARG led to a decrease in cav‐1 expression, a further increase in MYH7 expression and a down‐regulation of MYH6 that inversely correlated with gp91phox mRNA levels. Although ARG, at least partially, improved ISO‐impaired basal left ventricular systolic function, it failed to reduce cardiac hypertrophy, fibrosis, oxidative stress and mortality. The protection of contractile performance might be related to increased capacity for nitric oxide production and the up‐regulation of MYH7 which may compensate for the marked down‐regulation of the major MYH6 isoform.     

Potential excitatory role of nitric oxide on 2‐deoxy‐d‐glucose‐induced gastric motility in rats

Previous studies have shown that 2‐deoxy‐d ‐glucose (2‐DG) increases gastric motility via the vagus nerve, but the underlying mechanism remains elusive. Since nitric oxide (NO) is involved in gastric motility, a possible interplay between 2‐DG and NO can be suggested. In the present study, Wistar rats (250‐350 g) of both sexes were intravenously injected with 2‐DG (200 mg/kg), and the effects of the intravenous injection of the nitric oxide synthase (NOS) inhibitors; nitro‐l ‐arginine methyl ester (l ‐NAME, 10 mg/kg) and N^ω‐nitro‐l ‐arginine (l ‐NNA, 10 mg/kg) were investigated. Animals were anaesthetized and cannulated for intravenous drug injections while the left vagal nerve was electrically stimulated (0.1‐10 Hz, 0.5 ms duration, 12 V, for 60 seconds), and intragastric pressure and gastric motility changes were monitored using a latex gastric balloon. 2‐DG increased the mean intragastric pressure (baseline, 5.0±0.4 cmH₂O; after 2‐DG, 14.4±1.5 cmH₂O; P=.0156) and significantly increased the gastric motility index, while NOS inhibitors significantly attenuated both parameters. However, pretreatment with NOS inhibitors significantly augmented the gastric responses to peripheral electrical vagal stimulation. These results suggest that NO plays an excitatory role in gastric responsiveness to 2‐DG and that this function may be effected in the central nervous system.     

Pharmacological Evaluation of a β‐Hydroxyphosphonate Analogue of l‐Carnitine in Obese Zucker fa/fa Rats

In this study, we evaluated the effect of an analogue of l ‐carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty‐four rats were treated for 5 weeks with l ‐carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l ‐carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l ‐carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l ‐carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l ‐carnitine and improves the pharmacological profile of l ‐carnitine.     

The length‐dependent activation of contraction is equally impaired in impuberal male and female rats in monocrotaline‐induced right ventricular failure

The length‐dependent activation of contraction is attenuated in the failing myocardium of adult male rats. This pathological change is not seen in adult female rats, possibly because of a protective effect of sex hormones. The present study evaluated length‐dependent changes in isometric twitch, Ca²⁺ transient (CaT) and action potential (AP) in the right ventricular myocardium of impuberal healthy male and female rats (control) and in rats treated with a single injection of 50 mg/kg monocrotaline (MCT). Compared with sex‐matched control rats, MCT‐treated male and female rats exhibited increased right ventricular weight (134% and 142% of control, respectively), decreased left ventricular weight (72% and 79%), twitch attenuation (48.8 ± 2.7% and 57.5 ± 1.2%) and prolongation (125 ± 3% and 127 ± 2%), CaT attenuation (37.8 ± 0.4% and 39.1 ± 1.1%) and prolongation (114 ± 1% and 116 ± 1%) and AP prolongation at 90% repolarization (195 ± 2% and 203 ± 1%). The MCT‐treated male rats exhibited a 50% lower integral magnitude and an approximately 25% larger time‐to‐peak ‘bump’ compared with control male rats. These parameters in MCT‐treated female rats tended to show similar changes to those seen in the control female rats, with no significant difference between the two groups. In all groups, integral magnitude and time‐to‐peak ‘bump’ increased with length. In conclusion, the length‐dependent activation of contraction was equally blunted in the failing right ventricular myocardium of impuberal male and female rats. This was related to changes in CaT and AP, which were similar between male and female rats. Therefore, puberty is necessary for manifestation of the protective effects of sex hormones on this remodelling.     

Reversal of cardiac dysfunction by selective ET-A receptor antagonism

The effectiveness of a selective endothelin receptor-A (ET-A) antagonist, A-127722 (approximately 10 mg kg(-1) day(-1) as 200 mg kg(-1) powdered food), to reverse existing cardiac remodelling and prevent further remodelling was tested in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Uninephrectomised rats (UNX) administered DOCA (25 mg every fourth day s.c.) and 1% NaCl in drinking water for 28 days developed hypertension (systolic blood pressure (BP): UNX 128+/-6 mmHg, DOCA-salt 182+/-5* mmHg; *P<0.05 vs UNX), left ventricular hypertrophy (UNX 1.99+/-0.06 mg kg(-1) body wt, DOCA-salt 3.30+/-0.08* mg kg(-1) body wt), decreased left ventricular internal diameter (UNX 6.69+/-0.18 mm, DOCA-salt 5.51+/-0.37* mm), an increased left ventricular monocyte/macrophage infiltration together with an increased interstitial collagen from 2.7+/-0.3 to 11.7+/-1.3%, increased passive diastolic stiffness (UNX 21.1+/-0.5, DOCA-salt 30.1+/-1.3*), prolongation of the action potential duration at 20 and 90% of repolarisation (APD20-UNX 6.8+/-1.1, DOCA-salt 10.1+/-1.5* ms; APD90-UNX 34.4+/-3.5 ms, DOCA-salt 64.3+/-10.4* ms) and vascular dysfunctions (2.6-fold decrease in maximal contractile response to noradrenaline, 3.5-fold decrease in maximal relaxation response to acetylcholine). Administration of A-127722 for 14 days starting 14 days after surgery attenuated the increases in systolic BP (150+/-6** mmHg, **P<0.05 vs DOCA-salt), left ventricular wet weight (2.65+/-0.06** mg kg(-1) body wt) and internal diameter (6.39+/-0.31** mm), prevented left ventricular monocyte/macrophage accumulation, attenuated the increased left ventricular interstitial collagen (7.6+/-1.3%**), reversed the increased passive diastolic stiffness (22.1+/-1.2**), attenuated the action potential duration prolongation (APD20 - 7.6+/-1.4**, APD90 - 41.5+/-6.9** ms) and normalised changes in vascular function. ET-A receptor antagonism both reverses and prevents the cardiac and vascular remodelling in DOCA-salt hypertension and improves cardiovascular function.     

Rosuvastatin Attenuates Heart Failure and Cardiac Remodelling in the Ageing Spontaneously Hypertensive Rat

Abstract: 3‐hydroxy‐3‐methylglutaryl(HMG)‐Coenzyme(Co)A reductase inhibitors such as rosuvastatin may improve clinical status in patients with hypertension and heart failure. The ageing spontaneously hypertensive rat (SHR) closely mimics the chronic heart failure disease process observed in humans. This study examined the structural and functional changes in the cardiovascular system of 15‐month‐old SHR and normotensive Wistar‐Kyoto (WKY) rats treated with rosuvastatin (20 mg/kg/day perorally) for 24 weeks. Cardiovascular structure and function were monitored serially by echocardiography. At 21 months, ex vivo Langendorff, electrophysiological or histological studies were performed. Chronic rosuvastatin treatment attenuated elevations of left ventricular wet weight (mg/g body weight: 21‐month WKY, 2.30 ± 0.04; 15‐month SHR, 3.03 ± 0.08; 21‐month SHR, 4.09 ± 0.10; 21‐month SHR + rosuvastatin, 3.50 ± 0.13), myocardial extracellular matrix content (% left ventricular area: 21‐month WKY, 7.6 ± 0.5; 15‐month SHR, 13.2 ± 0.8; 21‐month SHR 19.6 ± 1.0; 21‐month SHR with rosuvastatin 14.6 ± 1.2) and diastolic stiffness (κ: 21‐month WKY, 24.9 ± 0.6; 15‐month SHR, 26.4 ± 0.4; 21‐month SHR, 33.1 ± 0.8; 21‐month SHR + rosuvastatin, 27.5 ± 0.6) as well as attenuating the deterioration of systolic and diastolic function (fractional shortening %: 21‐month WKY, 66 ± 2; 15‐month SHR, 51 ± 3; 21‐month SHR, 38 ± 3; 21‐month SHR + rosuvastatin, 52 ± 4). There was no effect on the increased systolic blood pressure, plasma low‐density lipoprotein concentrations or the prolonged action potential duration. Thus, chronic rosuvastatin treatment may attenuate myocardial dysfunction in heart failure by preventing fibrosis.     

Mildronate treatment alters γ-butyrobetaine and l-carnitine concentrations in healthy volunteers

Objectives In this study, we aimed to investigate the effects of long‐term administration of the cardioprotective drug mildronate on the concentrations of l ‐carnitine and γ‐butyrobetaine in healthy volunteers. Methods Mildronate was administered perorally, at a dosage of 500 mg, twice daily. Plasma and urine samples were collected weekly. Daily meat consumption within an average, non‐vegetarian diet was monitored. l ‐Carnitine, γ‐butyrobetaine and mildronate concentrations were measured using the UPLC/MS/MS method. Key findings After 4 weeks, the average concentrations of l ‐carnitine in plasma significantly decreased by 18%. The plasma concentrations of γ‐butyrobetaine increased about two‐fold, and this effect was statistically significant in both the male and female groups. In urine samples, a significant increase in l ‐carnitine and γ‐butyrobetaine levels was observed, which provides evidence for increased excretion of both substances during the mildronate treatment. At the end of the treatment period, the plasma concentration of mildronate was 20 µm on average. There were no significant differences between the effects observed in female and male volunteers. Meat consumption partially reduced the l ‐carnitine‐lowering effects induced by mildronate. Conclusions Long‐term administration of mildronate significantly lowers l ‐carnitine plasma concentrations in non‐vegetarian, healthy volunteers.     

Ventricular PKC‐ϵ and humoral signaling in DOCA‐Salt rats treated with labedipinedilol‐A

Effects of oral antihypertensive monotherapy with labedipinedilol‐A, labetalol, atenolol, amlodipine, prazosin (20 mg kg^?1 day^?1), and short‐acting nifedipine (3 mg kg^?1 day^?1) on DOCA‐salt‐induced translocation of ventricular protein kinase C‐?(PKC‐?), humoral signaling, and the cardiovascular system were investigated in rats for 4 weeks. The triple blocking activities of labedipinedilol‐A (α/β‐adrenoceptor blockade and calcium entry blockade) were compared with single blocking activities of selective drugs. Cytosolic PKC‐? immunoreactivity was decreased by labedipinedilol‐A, short‐acting nifedipine, amlodipine, prazosin, labetalol, atenolol, and losartan. Membranous PKC‐? immunoreactivity was significantly decreased by labedipinedilol‐A, amlodipine, prazosin, labetalol, and atenolol. Labedipinedilol‐A and prazosin more potently decreased membranous than cytosolic PKC‐? expression. Labedipinedilol‐A, labetalol, and atenolol effectively inhibited DOCA‐salt‐induced increases in angiotensin II (Ang II). All antihypertensive agents reduced endothelin‐1 (ET‐1) levels in urine and cardiac weight growth. Treatments with labedipinedilol‐A, labetalol, atenolol, and amlodipine normalized DOCA‐salt‐induced ANP increases. Prazosin did not decrease ANP. Short‐acting nifedipine elevated ANP. During long‐term antihypertensive therapy in DOCA‐salt hypertensive rats, single blockade drugs did not fully inhibit ventricular PKC‐? translocation or Ang II, ET‐1, and ANP humoral signaling. However, triple blockade labedipinedilol‐A therapy had a wide range of α/β‐adrenergic receptor and calcium channel inhibitory activities, including diminished reflux tachycardia, inhibition of PKC‐? translocation, and reduction of Ang II, ET‐1, and ANP formation. Drug Dev. Res. 59:307–315, 2003. 2003 Wiley‐Liss, Inc.     

Role of 5‐HT2B receptors in cardiomyocyte apoptosis in noradrenaline‐induced cardiomyopathy in rats

1. Serotonin (5‐hydroxytryptamine; 5‐HT) plays important roles in the development of cardiac hypertrophy via activation of 5‐HT receptors. The aim of the present study was to investigate the role of 5‐HT_2B receptors in the development of cardiomyocyte apoptosis and hypertrophy associated with noradrenaline (NA) overload. 2. Cardiac hypertrophy was induced in rats by intraperitoneal injection of 1.5 mg/kg NA for 4 weeks. Starting from Day 15, 5‐HT2B receptor antagonist SB 204741 (i.p., 0.5 or 2 mg/kg) or SDZ SER 082 (i.p., 1 mg/kg) was injected twice daily for another 14 days. Whole‐cell patch‐clamp techniques were used to record ionic currents in freshly isolated ventricular cardiomyocytes. Western blot and terminal deoxyribonucleotidyl transferase‐mediated dUTP–digoxigenin nick end‐labelling (TUNEL) assays were used to assess myocardial apoptosis. 3. Expression of 5‐HT_2B receptors was enhanced in the hypertrophic left ventricle induced by NE overload in vivo. The 5‐HT_2B receptor antagonist SB 204741 partially reversed cardiac hypertrophy induced by NE overload (P < 0.05) and decreased L‐type calcium currents in ventricular cardiomyocytes (P < 0.05). In addition, SB 204741 notably attenuated myocardial apoptosis, as evidenced by downregulation of Bax and caspase 3 (P < 0.05) and upregulation of the anti‐apoptotic Bcl‐2 protein (P < 0.05). 4. In conclusion, the data suggest an involvement of 5‐HT_2B receptors in the generation of apoptotic events associated with cardiac remodelling during increased adrenergic stimulation.     

Total triterpene acids,active ingredients from Fructus Corni,attenuate diabetic cardiomyopathy by normalizing ET pathway and expression of FKBP12.6 and SERCA2a in streptozotocin‐rats

Total triterpene acids (TTAs) isolated from Cornus officinalis Sieb., one of the herbs contained in Liuwei Dihuang decoction, were aimed at alleviating diabetic cardiomyopathy. We hypothesized that the benefits of TTAs may result from suppressing the endothelin‐reactive oxidative species (ET‐ROS) pathway in the myocardium. Diabetes was produced by a single injection of streptozotocin (STZ, 60 mg kg⁻¹, i.p.) in rats. Assessment of cardiac function, calcium handling proteins, endothelin‐1 (ET‐1) and redox system was conducted 8 weeks after STZ injection. Medication with TTAs (50 mg kg⁻¹, i.g.) was installed in the last 4 weeks. The compromised cardiac function was characterized by depressed contractility (LVSP and LV+dp/dt_max) and relaxation (LVEDP and ‐LVdp/dt_min) in association with hyperglycaemia (30.2 ± 2.6 mmol L⁻¹) in STZ‐injected rats. Down‐regulated expression of FKBP12.6 (calstabin 2), sarcoplasmic reticulum Ca²⁺‐ATPase 2a (SERCA2a) and phospholamban (PLB) were also found. These changes occurred in connection with an increased ET‐1, up‐regulated mRNA of propreET‐1 and endothelin converting enzyme (ECE), and a state of oxidant stress was found by increased malondialdehyde (MDA), decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH‐px) activity, and an enhanced activity and expression of inducible nitric oxide synthase (iNOS) in the diabetic myocardium. After 4 weeks of treatment with TTAs, these changes were alleviated dramatically despite a mild reduction in hyperglycaemia (26.9 ± 3.4 mmol L⁻¹). In conclusion, TTAs, as active ingredients of Liuwei Dihuang decoction, alleviated diabetic cardiomyopathy by normalizing the abnormality of FKBP12.6 and SERCA2a and ET‐ROS pathway in the myocardium rather than by hypoglycaemic activity.     

OBESITY INDUCED RENAL OXIDATIVE STRESS CONTRIBUTES TO RENAL INJURY IN SALT-SENSITIVE HYPERTENSION

• 1 In the present study, we determined the role of hypertension, oxidative stress and inflammation on kidney damage in a rodent model of obesity and diabetes. Hypertension was induced in male obese (db/db) mice and lean (db/m) mice by implantation of deoxycorticosterone acetate (DOCA) pellets and mice were allowed to drink water containing 1% salt. Mice were divided into six groups as follows: obese and lean control, obese and lean 1% salt (salt) and obese and lean DOCA plus 1% salt (DOCA‐salt).
• 2 Blood pressure was significantly increased in lean and obese DOCA‐salt groups relative to their respective controls; however, there was no difference in blood pressure between the lean and obese control and salt groups. Urinary 8‐isoprostane was increased in obese control compared with lean control mice (1464 ± 267 vs 493 ± 53 pg/µmol creatinine, respectively) and this elevation was further increased in the obese DOCA‐salt treated mice (2430 ± 312 pg/µmol creatinine). Urinary monocyte chemoattractant protein‐1 excretion and CD68‐positive cells were also increased in both obese and lean DOCA‐salt groups compared with their respective controls. Furthermore, DOCA‐salt treatment increased collagen IV excretion in both obese and lean mice compared with controls, but there was no difference between obese and lean DOCA‐salt groups. Urinary albumin excretion was significantly increased in the obese compared with the lean DOCA‐salt mice (507 ± 160 vs 202 ± 48 µg/day, respectively).
• 3 These data suggest that obese DOCA‐salt hypertensive mice exhibit greater renal injury than lean DOCA‐salt hypertensive mice in a manner independent of blood pressure and that this renal injury is associated with obesity related pre‐existing renal oxidative stress.

     

Increased brain l‐arginine availability facilitates cutaneous heat loss induced by running exercise

The effects of increased brain availability of l ‐arginine (l ‐arg), a precursor for nitric oxide synthesis, on core body temperature (T_core) and cutaneous heat loss were evaluated in running rats. One week prior to the experiments, adult male Wistar rats received the following implants: a chronic guide cannula in the lateral cerebral ventricle and a temperature sensor in the abdominal cavity. On the day of the experiments, the rats were assigned to receive a 2‐μL intracerebroventricular injection of either NaCl (0.15 mol/L) or l ‐arg solution (0.825, 1.65 or 3.30 mol/L); T_core and tail skin temperature were measured while the rats ran at a speed of 18 m/min until they were fatigued. l ‐arginine induced a dose‐dependent reduction in the threshold T_core required for cutaneous heat loss (38.09 ± 0.20°C for 3.30‐mol/L l ‐arg vs 38.61 ± 0.10°C for saline; P < 0.05), which attenuated the exercise‐induced hyperthermia. Although the rats treated with l ‐arg presented a lower T_core at the end of exercise (~0.7°C lower after treatment with the highest dose), no changes in the time to fatigue were observed relative to the control trial. These results suggest that brain l ‐arg controls heat loss during exercise, most likely by modulating the sympathetic vasoconstrictor tonus to skin vessels. Furthermore, despite facilitating cutaneous heat loss mechanisms, increased brain l ‐arg availability did not enhance physical performance.     

Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: Role of autophagy

The present study aimed to test the hypothesis that berberine, a plant‐derived anti‐oxidant, attenuates adverse left ventricular remodelling and improves cardiac function in a rat model of myocardial infarction (MI). Furthermore, the potential mechanisms that mediated the cardioprotective actions of berberine, in particular the effect on autophagy, were also investigated. Acute MI was induced by ligating the left anterior descending coronary artery of Sprague‐Dawley rats. Cardiac function was assessed by transthoracic echocardiography. The protein activity/levels of autophagy related to signalling pathways (e.g. LC‐3B, Beclin‐1) were measured in myocardial tissue by immunohistochemical staining and western blot. Four weeks after MI, berberine significantly prevented cardiac dysfunction and adverse cardiac remodelling. MI rats treated with low dose berberine (10 mg/kg per day) showed higher left ventricular ejection fraction and fractional shortening than those treated with high‐dose berberine (50 mg/kg per day). Both doses reduced interstitial fibrosis and post‐MI adverse cardiac remodelling. The cardioprotective action of berberine was associated with increased LC‐3B II and Beclin‐1 expressions. Furthermore, cardioprotection with berberine was potentially related to p38 MAPK inhibition and phospho‐Akt activation. The present in vivo study showed that berberine is effective in promoting autophagy, and subsequently attenuating left ventricular remodelling and cardiac dysfunction after MI. The potential underlying mechanism is augmentation of autophagy through inhibition of p38 MAPK and activation of phospho‐Akt signalling pathways.     

The CD147/MMP‐2 signaling pathway may regulate early stage cardiac remodelling in spontaneously hypertensive rats

Previous studies have reported that decreased matrix metalloproteinase‐2 (MMP‐2) is associated with early stage (age 8–16 weeks) ventricular remodelling in spontaneously hypertensive rats (SHR). We hypothesized that inhibited CD147/MMP‐2 signalling might down‐regulate MMP‐2 expression and augment remodelling in spontaneously hypertensive rats. Twenty‐nine male SHR (8 weeks) were randomly assigned to SHR, CD147, and CD147+DOX groups. The control group included eight age‐matched WKY rats. CD147 and CD147+DOX groups received recombinant human CD147 (600 ng/kg in 1.5 mL saline, weekly). The SHR and WKY groups received the vehicle. The CD147+DOX group also received doxycycline, an inhibitor of MMPs (daily, 30 mg/kg in 1.5 mL saline, iG). On day 56 echocardiography and left ventricular mass index (LVWI) measurements were collected and histological sections were stained for cell and collagen content. Myocardium MMP‐2, TIMP‐1, CD147, and collagens types I and III were estimated by western blot. CD147 and the ratio of MMP‐2/TIMP‐1 were lower in SHR than WKY rats (P<.05). Myocyte hypertrophy, partial fibre breaks, plasmolysis, necrosis and collagen content (collagen volume fraction [CVF], I and III) in SHR were above control levels (P<.05). CD147 rats showed CD147, MMP‐2 and MMP‐2/TIMP‐1 were increased (P<.05), CVF, LVWI, and collagen I and III were decreased (P<.05) and myocyte morphology was improved. CD147 levels did not differ between CD147+DOX and CD147 groups, CVF, collagens type I and III and partial fiber breaks were more abundant in CD147+DOX (P<.05). In summary, an inhibited CD147/MMP‐2 pathway was associated with early stage cardiac remodelling, and CD147 supplementation may attenuate this response.