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1.
Respir Med ; 104(10): 1410-6, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20483574

ABSTRACT

Omalizumab is a humanized murine monoclonal antibody directed toward a portion of the IgE indicated in Europe for the treatment of severe persistent allergic asthma, inadequately controlled despite high-dose of ICS (mean BDP equivalent dose of inhaled corticosteroid 2224.68microg/die) in association with long-acting beta(2) agonists. Our aim was to describe the experience, efficacy and safety in a cohort of Italian patients treated with omalizumab in a real-life clinical setting. One hundred and forty two patients from 13 Italian Centers were observed and analysed. The dosage of omalizumab was established according to the labelling indication, with a median dose of IgE of 297.38IU/ml or kU/l. During the previous year, all patients experienced frequent exacerbations (mean=4.87), emergency visits (mean=4.45) and hospitalisation (mean=1.53). Following treatment with omalizumab, the annual rate of exacerbations, emergency visits and hospitalisation decreased by 79%, 88% and 95%, respectively. The proportion of patients without exacerbation, not needing emergency visits and hospitalization increased by 610%, 154% and 28%, respectively. The response to omalizumab measured with the GETE (global evaluation of treatment effectiveness) scale rated as good to excellent in 77% of patients. Overall, 9.6% (n=9) of the patients experienced one single adverse effect. Only one patient reported a serious adverse event (local reaction at the site of injection) leading to interruption of treatment. The observed reduction of asthma-related events in particularly poorly controlled patients in this Italian real-life setting is consistent with the results of other observational studies.


Subject(s)
Anti-Allergic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Asthma/drug therapy , Adolescent , Adult , Aged , Antibodies, Anti-Idiotypic , Antibodies, Monoclonal, Humanized , Asthma/physiopathology , Dose-Response Relationship, Drug , Female , Forced Expiratory Volume/drug effects , Forced Expiratory Volume/physiology , Hospitalization/statistics & numerical data , Humans , Italy , Male , Middle Aged , Omalizumab , Severity of Illness Index , Treatment Outcome , Young Adult
2.
Curr Pharm Des ; 15(8): 883-92, 2009.
Article in English | MEDLINE | ID: mdl-19275652

ABSTRACT

Progressions in acute cardiac care have improved survival after acute myocardial infarction, but in contraposition with this, there has been an increase in mortality because of heart failure. For this reason congestive heart failure is an increasingly widespread, costly and deadly disease, frequently named as epidemic of the XXI century. Despite advancement in modern treatment, mortality rate in heart failure patients remains high. In these patients more importance was attributed in the management of the left ventricle dysfunction. In fact, the heart failure patients have still a poor prognosis due to the ineluctable progression of contractile dysfunction and ventricular remodeling. The classical management of left ventricle dysfunction includes the pharmacological treatment with beta-blockers, ACE-inhibitors and aldosterone antagonists, and various surgical or electrophysiological interventions. Emerging evidence suggests that myocardium dysfunction is also due to substrate metabolism alterations. In particular, there is evidence that, in the failing heart, shifting metabolism away from a preference for fatty acids towards more carbohydrate oxidation could recover contractile function. Trimetazidine has been shown to improve symptoms and ventricular function and to have a beneficial effect on the inflammatory profile and endothelial function in these patients. Recently, it has been suggested that trimetazidine could also reduce ventricular remodeling, slowing down the progression of pump failure, and improve prognosis. These results suggest that trimetazidine is a useful adjunct to our current armamentarium for the treatment of heart failure patients.


Subject(s)
Heart Failure/metabolism , Trimetazidine/pharmacology , Vasodilator Agents/pharmacology , Heart Failure/drug therapy , Heart Failure/physiopathology , Humans , Prognosis , Risk Assessment , Trimetazidine/therapeutic use , Vasodilator Agents/therapeutic use , Ventricular Function, Left/drug effects , Ventricular Remodeling/drug effects
3.
Heart ; 91(2): 161-5, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15657223

ABSTRACT

OBJECTIVE: To investigate the long term effects of trimetazidine in patients with dilated ischaemic cardiomyopathy. The effects of trimetazidine on left ventricular function as well as its tolerability profile and potential anti-inflammatory effects were studied. DESIGN: 61 patients were randomly assigned either to receive trimetazidine (20 mg thrice daily) in addition to their conventional treatment or to continue their usual drug treatment for 18 months. Patients were evaluated at baseline and at 6, 12, and 18 months with a clinical examination, echocardiography, and biochemical analysis (C reactive protein). RESULTS: Trimetazidine added to the usual treatment significantly improved the patients' functional status (assessed by New York Heart Association functional class). The functional improvement of trimetazidine treated patients was associated with a significant increase in left ventricular ejection fraction (30 (6)%, 32 (8)%, 38 (7)%, and 37 (6)% v 31 (8)%, 30 (7)%, 28 (6)%, and 26 (9)% in control patients at baseline and at 6, 12, and 18 months, respectively) and with a significant effect on ventricular remodelling. C reactive protein plasma concentrations remained stable throughout the study in patients receiving trimetazidine (2.5 (1.0), 2.7 (2.0), 2.7 (3.0), and 3.0 (2.0) mg/l at baseline and at 6, 12, and 18 months, respectively) but increased significantly in the control group (2.4 (1.0), 3.4 (1.2), 6.0 (4.0), and 7.0 (5.0) mg/l, respectively). No significant adverse event or changes in clinical or biochemical parameters were detected. CONCLUSION: Treatment with trimetazidine added to the usual treatment for up to 18 months was well tolerated and induced a functional improvement in patients with dilated cardiomyopathy. Trimetazidine treatment was associated with a significant improvement of left ventricular function and the remodelling process. Results also suggest that the inflammatory response was limited in patients treated with trimetazidine.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , C-Reactive Protein/metabolism , Cardiomyopathy, Dilated/drug therapy , Trimetazidine/therapeutic use , Vasodilator Agents/therapeutic use , Ventricular Dysfunction, Left/drug therapy , Aged , Analysis of Variance , Cardiomyopathy, Dilated/blood , Female , Humans , Long-Term Care , Male , Pilot Projects , Treatment Outcome , Ventricular Dysfunction, Left/blood
5.
Int J Immunopathol Pharmacol ; 15(3): 225-232, 2002.
Article in English | MEDLINE | ID: mdl-12575923

ABSTRACT

We tested the hypothesis of beneficial effects of the calcium-blocker verapamil in a model of ischemia-reperfusion, and investigated its effects against coronary microcirculation and cardiomyocyte apoptosis. Isolated working rat hearts were subjected to 15 min global ischemia and 22-180 min reperfusion in the presence or absence of verapamil (0.25 &mgr;M). We evaluated creatinephosphokinase (CK) in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and cardiomyocyte apoptosis (by 1.5% agarose gel electrophoresis and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling technique). In this model, 0.25 &mgr;M verapamil significantly reduced myocardial damage, CK release and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions; on the contrary, 0.25 &mgr;M verapamil was unable to reduce cardiomyocyte apoptosis. In conclusion, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant verapamil concentration reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte necrotic cell death but it is unable to reduce apoptotic cell death in isolated working rat hearts.

6.
Cardiovasc Res ; 51(2): 283-93, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11470468

ABSTRACT

OBJECTIVE: We tested the hypothesis of beneficial effects of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitor simvastatin in a model of ischemia-reperfusion, and investigated potential mechanisms. METHODS: Isolated working rat hearts were subjected to 15 min global ischemia and 22-180 min reperfusion in the presence or absence of simvastatin (10-100 microM). We evaluated creatinephosphokinase and nitrite levels in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcribed polymerase chain reaction and Western blotting) in the presence or absence of the transcriptional inhibitor actinomycin-D. RESULTS: Simvastatin (25 microM) significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. Protection became less evident at 50 microM and reverted to increased damage at 100 microM. At 25 microM, simvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, probably due to a post-transcriptional regulation since unaltered by animal pretreatment with actinomycin D. Simvastatin also significantly decreased iNOS mRNA and protein, as well as nitrite production after ischemia-reperfusion. The addition of the NOS inhibitor N(pi)-nitro-L-arginine methylester (L-NAME, 30 microM) to 25 microM simvastatin-treated hearts significantly reduced cardioprotection against ischemia-reperfusion. CONCLUSIONS: In this model, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant simvastatin concentration reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by cholesterol-independent, NO-dependent mechanisms.


Subject(s)
Myocardial Reperfusion Injury/prevention & control , Myocardium/metabolism , Nitric Oxide Synthase/antagonists & inhibitors , Simvastatin/pharmacology , Analysis of Variance , Animals , Blotting, Western/methods , Capillary Permeability/drug effects , Creatine Kinase/metabolism , Enzyme Inhibitors/pharmacology , Image Processing, Computer-Assisted , Male , Myocardium/ultrastructure , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Nitrites/metabolism , Organ Size/drug effects , Perfusion , RNA, Messenger/analysis , Rats , Rats, Wistar , Ventricular Function, Left/drug effects
7.
Ann Clin Lab Sci ; 31(2): 179-86, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11337908

ABSTRACT

Several studies suggest that nitric oxide (NO) production is reduced in diabetes and that the decrease of NO may be related to the pathogenesis of diabetic endothelial damage. NO synthase (NOS) catalyses the conversion of L-arginine to L-citrulline in the presence of oxygen and NADPH-diaphorase (NADPH-d). In this study, we evaluated the expression of endothelial NOS (eNOS) enzyme and its co-enzyme in diabetic rat hearts. Male Wistar rats (n = 20, 4 mo old) and 20 male Bio Breeding Wistar (BB/W) rats of the same age were used; the Wistar rats represent the control non-diabetic rats while the BB/W rats represent the diabetic group. After the hearts were excised, the NADPH-d co-enzyme was visualized by a histochemical method and the endothelial isoform of NOS was localized by immunohistochemistry. In addition, eNOS gene expression was estimated by rt-PCR, and eNOS protein level was detected by Western blot analysis. The eNOS visualization, which involved immunoprecipitation, and the NADPH-d visualization, which involved histochemical staining, were both diminished in endothelial cells of the vascular wall of diabetic hearts, compared to non-diabetic hearts. The eNOS protein level, evaluated by Western blotting, was evident as an intense band in cardiac homogenates of non-diabetic and diabetic rats. The expression of mRNA for eNOS did not differ significantly between the two groups. These findings indicate that, in this rat heart model, diabetes does not influence the overall eNOS protein level or its mRNA level. However, there a diminution in the deposition of eNOS in cardiac endothelial cells of diabetic rats, versus non-diabetic controls, suggesting a relation between eNOS and the loss of vasodilatory response that is observed in diabetes.


Subject(s)
Diabetes Mellitus, Type 1/enzymology , Myocardium/enzymology , Nitric Oxide Synthase/analysis , Nitric Oxide Synthase/genetics , Animals , Blotting, Western , Histocytochemistry , Immunohistochemistry , Male , NADPH Dehydrogenase/analysis , Nitric Oxide Synthase Type III , RNA, Messenger/analysis , Rats , Rats, Inbred BB , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction
8.
Allergy ; 56(1): 29-34, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11167349

ABSTRACT

BACKGROUND: In allergic rhinitis, allergenic stimulation causes the release of various mediators that induce symptoms and the development of chronic inflammation, which, in turn, is caused by cells involved in the late phase of inflammation, such as eosinophils. The eosinophils also cause damage at the mucosal level through the secretion of eosinophil cationic protein and other preformed factors contained in their granules. The objective was to verify the efficacy of fluticasone propionate aqueous nasal spray in patients with allergic rhinitis; in a retrospective study, we have evaluated mediators of inflammation, making correlations with the clinical symptoms score during and outside the pollen season. METHODS: Forty patients with allergic rhinitis and 15 normal controls were included in our study. Eosinophil cationic protein, eosinophil chemotactic activity, and blood and nasal lavage eosinophil count were evaluated as laboratory parameters. RESULTS: We found a significant increase in nasal lavage levels of eosinophil cationic protein in allergic patients, and this was strictly correlated with the clinical symptoms score. No differences were found in the eosinophil count of allergic patients and in the serum eosinophil cationic protein of patients sensitized to seasonal allergens in comparison with normal subjects. By contrast, an increase in serum eosinophil cationic protein level was found in patients sensitized to perennial allergens. After topical administration of fluticasone propionate aqueous nasal spray, a reduction in nasal lavage eosinophil cationic protein secretion was obtained with a reduction of eosinophil chemotactic activity at the local level. This reduction correlated with an improvement of clinical symptoms. CONCLUSIONS: The clinical improvement and reduction in nasal lavage eosinophil cationic protein and eosinophil chemotactic activity after administration of fluticasone propionate aqueous nasal spray further confirms the role of this treatment in allergic rhinitis.


Subject(s)
Androstadienes/therapeutic use , Anti-Allergic Agents/therapeutic use , Eosinophils/immunology , Rhinitis, Allergic, Perennial/drug therapy , Rhinitis, Allergic, Seasonal/drug therapy , Ribonucleases , Administration, Intranasal , Adolescent , Adult , Androstadienes/administration & dosage , Anti-Allergic Agents/administration & dosage , Blood Proteins/biosynthesis , Chemotaxis , Child , Eosinophil Granule Proteins , Eosinophilia/drug therapy , Eosinophilia/immunology , Female , Fluticasone , Humans , Male , Middle Aged , Nasal Lavage Fluid/cytology , Nasal Lavage Fluid/immunology , Retrospective Studies , Rhinitis, Allergic, Perennial/immunology , Rhinitis, Allergic, Seasonal/immunology
9.
Atherosclerosis ; 155(1): 53-9, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11223426

ABSTRACT

BACKGROUND: the cardiac Renin-Angiotensin system (RAS) plays an important role in the regulation of coronary flow and cardiac function and structure in normal and pathological conditions such as ischemia-reperfusion (I/R) injury. The aim of this study was to investigate the effects of the Angiotensin II type 1 (AT-1) receptor antagonist MK-954 (losartan potassium) on postischemic endothelial dysfunction and NOS mRNA expression (inducible nitric oxide synthase, iNOS; endothelial nitric oxide synthase, eNOS) in isolated working rat hearts. METHODS: isolated working rat hearts were subjected to 15 min global ischemia and 180 min reperfusion. MK-954 was added to perfusion buffer (a modified Krebs-Henseleit solution) at 1 microM concentration. We assessed functional parameters, creatin kinase (CK) release, heart weight changes, microvascular postischemic hyperpermeability (FITC-albumin extravasation) and morphological ultrastructural alterations. eNOS and iNOS mRNA levels were also detected by the means of multiplex RT-PCR technique using glyceraldehyde-3-phosphate dehydrogenase (G3PDH) gene as internal control; results were expressed as densitometric ratio. RESULTS: in Losartan-treated hearts we observed a significant reduction of postischemic contractile dysfunction, CK release and myocardial ultrastructural damage; postischemic FITC-albumin extravasation was significantly reduced respect to controls. Moreover, 1 microM Losartan produced a significant reduction of eNOS/G3PDH respect to untreated hearts submitted to I/R. Regarding iNOS/G3PDH ratio, no significant changes were detected in Losartan-treated hearts compared with controls. CONCLUSIONS: our study revealed that Losartan treatment before ischemia, and during reperfusion, is able to reduce the reperfusion injury of the rat heart by reducing mechanical and microcirculatory dysfunction and necrotic cell death, ameliorating cardiac ultrastructure and endothelial protection, probably inducing eNOS over-expression and reducing post-ischemic hyperpermeability of coronary microcirculation.


Subject(s)
Angiotensin Receptor Antagonists , Endothelium, Vascular/drug effects , Losartan/pharmacology , Myocardial Reperfusion Injury/prevention & control , Nitric Oxide Synthase/metabolism , Animals , Capillary Permeability , Coronary Circulation , Creatine Kinase/metabolism , Endothelium, Vascular/pathology , In Vitro Techniques , Male , Myocardial Contraction/drug effects , Myocardial Ischemia/pathology , Myocardial Ischemia/physiopathology , Myocardial Reperfusion Injury/enzymology , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Myocardium/enzymology , Myocardium/ultrastructure , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction
10.
Biochim Biophys Acta ; 1524(2-3): 203-11, 2000 Dec 15.
Article in English | MEDLINE | ID: mdl-11113569

ABSTRACT

Induction of endothelial nitric oxide synthase (eNOS) contributes to the mechanism of heart protection against ischemia-reperfusion damage. We analyzed the effects of hypoxia and hyperoxia on eNOS expression in isolated working rat hearts after ischemia-reperfusion damage. Adult male Wistar rats were submitted to chronic hypoxia (2 weeks) and hyperoxia (72 h). The hearts were submitted to 15 min of ischemia and reperfused for 60 min, then we evaluated hemodynamic parameters and creatine phosphokinase (CPK) release. eNOS expression was estimated by RT-PCR; enzyme localization was evaluated by immunohistochemistry and the eNOS protein levels were detected by Western blot. All hemodynamic parameters in hypoxic conditions were better with respect to other groups. The CPK release was lower in hypoxic (P<0.01) than in normoxic and hyperoxic conditions. The eNOS deposition was significantly higher in the hypoxic group versus the normoxic or hyperoxic groups. The eNOS protein and mRNA levels were increased by hypoxia versus both other groups. Chronic hypoxic exposure may decrease injury and increase eNOS protein and mRNA levels in heart subjected to ischemia-reperfusion.


Subject(s)
Endothelium, Vascular/metabolism , Heart/physiopathology , Myocardial Ischemia/physiopathology , Nitric Oxide Synthase/metabolism , Reperfusion Injury/physiopathology , Animals , Blotting, Western , Creatine Kinase/analysis , Endothelium, Vascular/enzymology , Hemodynamics , Hyperoxia/physiopathology , Hypoxia/physiopathology , Immunohistochemistry , Male , Myocardium/metabolism , Myocardium/pathology , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase Type III , Organ Culture Techniques , Protein Biosynthesis , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic , Ventricular Function, Left
13.
Cardiologia ; 44(7): 667-74, 1999 Jul.
Article in Italian | MEDLINE | ID: mdl-10476593

ABSTRACT

BACKGROUND: The aim of this study was to evaluate, in the model of isolated working rat heart, the effects of verapamil on postischemic changes in cardiac mechanical function and microvascular coronary permeability, and the possible role of nitric oxide. METHODS: We used 72 male Wistar rats, weighing 250-300 g, divided into six groups: Group A, hearts perfused with modified Krebs-Henseleit solution (KH); Group B, hearts perfused with KH + verapamil 0.25 microM; Group C, hearts perfused with KH + verapamil 0.5 microM; Group D, hearts perfused with KH + verapamil 1 microM; Group E, hearts perfused with KH + NG-nitro-L-arginine methyl ester (L-NAME) 30 microM; Group F, hearts perfused with KH + verapamil 0.25 microM + L-NAME 30 microM. Hemodynamic parameters, necrosis enzyme release and fluoroscein isothiocyanate-albumin extravasation were evaluated. RESULTS: We observed a clear preservation of cardiac mechanical function and microvascular function in Group B (low dose verapamil) compared to groups A (control), C and D (high dose verapamil); the inhibition of nitric oxide-synthase in the presence of verapamil, obtained in Group F, elicited a loss of myocardial protective effects of verapamil. CONCLUSIONS: Our data suggest that low dose verapamil is effective on postischemic damage reduction and most probably nitric oxide plays a determinant role in this effect.


Subject(s)
Calcium Channel Blockers/pharmacology , Coronary Circulation/drug effects , Myocardial Ischemia/physiopathology , Nitric Oxide/physiology , Verapamil/pharmacology , Animals , Coronary Circulation/physiology , In Vitro Techniques , Male , Microcirculation/drug effects , Microcirculation/physiopathology , Myocardial Reperfusion Injury/physiopathology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/drug effects , Rats , Rats, Wistar
14.
Cardiologia ; 44(1): 69-74, 1999 Jan.
Article in Italian | MEDLINE | ID: mdl-10188333

ABSTRACT

Recent studies have suggested that simvastatin may exert endothelial-protective and anti-ischemic effects via nitric oxide (NO) mechanisms. The aim of this study was to evaluate, in isolated working rat hearts, the effect of acute simvastatin administration on endothelial and inducible NO-synthase (eNOS and iNOS) mRNA and on myocytic apoptosis after ischemia-reperfusion. We used isolated working rat hearts submitted to 15 min global, no-flow, normothermic ischemia and 180 min reperfusion. To detect myocytic apoptosis we used DNA agarose gel electrophoresis and Tunel technique; eNOS and iNOS expression were evaluated by multiplex reverse transcriptase-polymerase chain reaction; glyceraldehyde-3-phosphate dehydrogenase (G3PDH) was used as standard. The eNOS and iNOS mRNAs were expressed as G3PDH/eNOS and G3PDH/iNOS densitometric ratio (BioRad Gel Doc 1000). Hearts were divided into four groups: A) hearts excised and used as histological controls; B) untreated hearts submitted to ischemia and reperfusion; C) actinomicin D-treated (1.5 mg/kg) hearts, perfused with 25 microM simvastatin, subjected to ischemia and reperfusion; D) hearts treated with simvastatin 25 microM and submitted to ischemia and reperfusion. In Group B we evidenced a significant myocytic apoptotic damage, reduced in groups C and D. In Group B an increase in G3PDH/eNOS ratio vs Group A was detected; in Group D a reduction in G3PDH/eNOS ratio vs Group B occurred; no significant changes were observed between groups C and D. As for G3PDH/iNOS ratio, it was significantly increased in Group D with respect to groups A and B. Our data suggest that simvastatin in acute may modulate NO-synthase mRNA expression (induction of eNOS mRNA by means of post-transcriptional mechanisms and inhibition of iNOS postischemic overexpression) and reduce myocytic apoptosis.


Subject(s)
Apoptosis/drug effects , Disease Models, Animal , Endothelium, Vascular/drug effects , Heart/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Myocardial Reperfusion Injury/drug therapy , Myocardium/pathology , Nitric Oxide Synthase/drug effects , Simvastatin/pharmacology , Acute Disease , Animals , Drug Evaluation, Preclinical , Endothelium, Vascular/enzymology , Endothelium, Vascular/pathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Myocardial Reperfusion Injury/enzymology , Myocardial Reperfusion Injury/pathology , Myocardium/enzymology , Nitric Oxide Synthase/metabolism , Rats , Rats, Wistar , Simvastatin/therapeutic use
15.
J Med ; 29(3-4): 137-58, 1998.
Article in English | MEDLINE | ID: mdl-9865455

ABSTRACT

An acute increase of myocardial interstitial fluid may affect ventricular function. In the present study we evaluated the effects of acute changes of myocardial tissue fluid on cardiac function and ultrastructural morphometry. Isolated rat hearts were perfused for 100 min in the working heart mode. Hearts were distributed into 5 groups: controls [perfused with Krebs-Henseleit (KH) isotonic buffer to rat plasma, KH, 287 mOsm], moderate hyposmotic perfusion (75% Hyposm: perfusion with 75% diluted KH, 216 mOsm), highly hyposmotic perfusion (60% Hyposm: perfusion with 60% diluted KH, 170 mOsm), afterload increase (Pre-over: isotonic perfused hearts subjected to an increase of afterload from 72 to 145 cm H2O) and ion dilution (Ion-dil: hearts perfused with a 60% KH with 115 mM sucrose, isotonic, 287 mOsm). We evaluated functional changes, markers of cellular necrosis or damage (CPK, LDH and purine release in coronary effluent), heart weight changes (weight gain and ww/dw ratio) and ultrastructural morphometry (analysis of cell damage, interstitial area, and mitochondrial alterations by a computerized image analysis system). The ww/dw ratio increased significantly only in 60% Hyposm (+140%, p < 0.001) and Pre-over (+63%, p < 0.001 vs control) groups. An impaired myocardial function in 60% Hyposm, Pre-over and Ion-dil groups was observed with cardiac failure at 50, 60 and 60 min, respectively. Enzyme release was significant higher in 60% Hyposm and Pre-over groups and was related to heart weight gain (r = 0.85, p < 0.001). Ultrastructural analysis confirmed a significant increase of interstitial space area (ISA) and mitochondrial damage in 60% Hyposm and Pre-over groups (p < 0.001); a significant (p < 0.05) increase was observed in the Ion-dil group; in 75% Hyposm group, a significant increase of mitochondrial damage was detected (p < 0.05). In brief, a higher functional and morphological deterioration was observed in hearts in which a more evident interstitial edema was detected (60% Hyposm and Pre-over groups). We conclude that, in the experimental condition, an acute increase of myocardial interstitial tissue fluid directly compromises left ventricular function and contributes to the ultrastructural damage to the myocardium.


Subject(s)
Extracellular Space/physiology , Heart/physiology , Ventricular Function, Left/physiology , Animals , Blood Pressure/physiology , Enzymes/metabolism , Myocardial Contraction/physiology , Myocardium/metabolism , Purines/metabolism , Rats , Rats, Wistar
17.
Cardiologia ; 43(4): 387-93, 1998 Apr.
Article in Italian | MEDLINE | ID: mdl-9659796

ABSTRACT

Recent studies suggest that A1 adenosine receptor antagonists may prevent reperfusion injury in the lung and heart. The pathophysiology of this protective effect is unclear; a possible inhibition of superoxide anion release from neutrophils, or leukocyte activation and platelet aggregation are reported. We tested the hypothesis of a blood-independent cardioprotection following A1 adenosine receptor antagonism with 1,3 dipropyl,8-cyclopentylxanthine (DPCPX). Isolated working rat hearts were submitted to 10 and 20 min global ischemia in order to assess functional alterations, necrosis enzyme and purine release in coronary effluent, arrhythmias, heart weight, ultrastructural morphometry and microvascular permeability by FITC-albumin diffusion technique. DPCPX (100 nM) was administered to the perfusion buffer before ischemia. In untreated hearts we detected a significant impairment of function, associated with a significant enzyme and purine release, myocardial edema and ultrastructural damage. In DPCPX-treated hearts functional and histological damage was significantly reduced compared to controls. Moreover, a significant reduction in postischemic endothelial permeability (FITC-albumin diffusion, p < 0.02) and ultrastructural damage was observed. Our data suggest that A1 adenosine receptor antagonism with DPCPX significantly reduces ischemia-reperfusion damage in isolated, crystalloid perfused rat heart by a direct reduction of endothelium damage, fluid diffusion within the interstitium and improvement of coronary microcirculation.


Subject(s)
Adenosine/antagonists & inhibitors , Coronary Circulation/drug effects , Microcirculation/drug effects , Receptors, Purinergic P1/drug effects , Animals , Disease Models, Animal , Myocardial Ischemia , Myocardial Reperfusion/adverse effects , Rats , Rats, Wistar
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