RESUMO
There is evidence that reactive oxygen species (ROS) are involved in the pathophysiology of psychiatric disorders such as schizophrenia. Indirect biochemical alterations of ROS formation have been shown for patients treated with antipsychotics as well as for untreated patients. Only one study measured directly the ROS formation after treatment with antipsychotics by using electron spin resonance spectroscopy. The aim of the present examination was to demonstrate the effects of haloperidol, clozapine and olanzapine in concentrations of 18, 90 and 180 µg/mL on the formation of ROS in the whole blood of rats by using electron spin resonance spectroscopy after incubation for 30 min. To test the protective capacity of vitamin C we incubated the highest concentration of each drug with vitamin C (1 mM). Under all treatment conditions, olanzapine led to a significantly higher formation of ROS compared with control conditions, whereas in the cases of haloperidol and clozapine the two higher concentrations induced a significantly enhanced formation of ROS. Vitamin C reduced the ROS production of all drugs tested and for haloperidol and clozapine the level of significance was reached. Our study demonstrated that antipsychotics induce the formation of ROS in the whole blood of rats, which can be reduced by the application of vitamin C.
Assuntos
Antioxidantes/química , Antipsicóticos/farmacologia , Ácido Ascórbico/química , Sangue/efeitos dos fármacos , Espécies Reativas de Oxigênio/sangue , Animais , Antipsicóticos/toxicidade , Benzodiazepinas/farmacologia , Benzodiazepinas/toxicidade , Clozapina/farmacologia , Clozapina/toxicidade , Espectroscopia de Ressonância de Spin Eletrônica , Haloperidol/farmacologia , Haloperidol/toxicidade , Olanzapina , Concentração Osmolar , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/químicaRESUMO
Despite the causative role of oxidative stress in renal ischemia-reperfusion (I-R) injury effects of preservation solutions on reactive oxygen species (ROS) release have not been sufficiently evaluated. We compared the effects of most common solutions in kidney transplantation, University of Wisconsin (UW) and Histidine-Tryptophan-Ketoglutarate (HTK). ROS formation in isolated perfused rat kidney was detected by electron spin resonance spectroscopy using spin label 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine. Donor kidneys from Lewis rats were pretreated with saline (controls), in therapeutic groups, kidneys underwent 18 h of cold storage (CS) preserved by HTK or UW solution. Experimental protocol included a stabilization period followed by additional I-R. Kidneys preserved by HTK produced highest ROS values in the control period after CS, whereas levels in UW and control group did not vary significantly. A peak release induced by additional I-R was also significantly highest in HTK kidneys, and UW did not differ from controls. During reperfusion, levels in HTK exceeded control and UW values. Renal vascular resistance, caspase-3-activity, and tissue hydration were enhanced in HTK compared with UW group, whereas ATP concentration was less reduced in UW-preserved tissue. These data show the greater antioxidative potential of UW solution, which also attenuated organ impairment after CS in the early reperfusion period.
Assuntos
Rim , Soluções para Preservação de Órgãos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Adenosina/farmacologia , Alopurinol/farmacologia , Animais , Diurese , Espectroscopia de Ressonância de Spin Eletrônica , Glutationa/farmacologia , Insulina/farmacologia , Preservação de Órgãos/métodos , Perfusão , Rafinose/farmacologia , Ratos , Ratos Endogâmicos Lew , Circulação Renal , Resistência VascularRESUMO
Radiology plays a key role when the indications for arthroplasties of the hand and finger joints are determined and for the postoperative follow-up. On the one hand, the degree of inflammatory changes in all affected compartments is to be evaluated and graded; on the other hand, conventional radiograms allow for a first assessment of possible joint instability and impaired biomechanics. Both aspects influence the choice of the proper surgical therapeutic strategy. Osteolysis, deformity, fracture, prosthesis loosening or failure, heterotopic ossification, and foreign body-associated formation of granulation tissue are complications which can be detected on follow-up radiographs early on.
Assuntos
Artrite Reumatoide/cirurgia , Artroplastia de Substituição , Ossos do Carpo/cirurgia , Articulações dos Dedos/cirurgia , Articulação Metacarpofalângica/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Falha de Prótese , Articulação do Punho/cirurgia , Artrite Reumatoide/diagnóstico por imagem , Fenômenos Biomecânicos , Ossos do Carpo/diagnóstico por imagem , Articulações dos Dedos/diagnóstico por imagem , Seguimentos , Humanos , Prótese Articular , Articulação Metacarpofalângica/diagnóstico por imagem , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/cirurgia , Desenho de Prótese , Radiografia , Reoperação , Articulação do Punho/diagnóstico por imagemRESUMO
Multifocal leukoencephalopathy and sensory-motor polyneuropathy have not been reported as side-effects of long-lasting interferon alpha therapy in a single patient. In a 77-year-old man interferon alpha2b and interferon alpha2a were administered subsequently but continuously since 1984 for hairy cell leukemia. Since early 2000, left-sided hemi-hypesthesia occurred and the patient developed gait disturbance, proximal weakness of the lower limbs, bilateral stocking-type sensory disturbances, and restless leg syndrome. Repeated cerebral magnetic resonance images showed multifocal T2-hyperintense white matter lesions supratentorially. The nerve conduction velocity of the peroneal and sural nerve was reduced. After exclusion of various differential diagnoses of leukoencephalopathy and application of a screening program for polyneuropathy, central and peripheral nervous system abnormalities were attributed to the long-lasting interferon alpha therapy. In single patients abnormally long-lasting interferon alpha therapy may cause multifocal white matter lesions supratentorially and sensory-motor polyneuropathy.
Assuntos
Interferon-alfa/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Polineuropatias/induzido quimicamente , Idoso , Diagnóstico Diferencial , Humanos , Leucemia de Células Pilosas/complicações , Leucemia de Células Pilosas/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Fatores de TempoRESUMO
The TRAM-flap has become a well-established method for breast reconstruction. Even though the aesthetic result is superior to implant reconstruction, a main disadvantage is the potential risk to create weakness of the abdominal wall. For evaluation of abdominal wall function, an imaging method has to be used which is able to prove functional properties of the remaining muscle. This study was undertaken in order to verify if ultrasound imaging is a reasonable method to examine muscle movements after TRAM-flap procedures in addition to clinical examination. In 8 patients, a DIEP-flap, in 11 patients, a free TRAM-flap, and in 3 patients, a pedicled TRAM-flap were used for breast reconstruction. Patients were examined 10-72 months (mean, 32 months) after surgery. Ultrasound imaging of the abdominal wall was performed in longitudinal as well as cross sections (multifrequent, 13 Mhz; Siemens Elegra, Erlangen, Germany). The diameter of the remaining muscle was measured 2 cm below the rib bow, at the level of the umbilicus, and at the level of the skin scar. The operated side was compared to the nonoperated contralateral side. In order to evaluate the contractility of the remaining rectus muscle, patients were invited to perform sit-ups during ultrasound monitoring of muscle movement. Clinically the functional testing was performed by the method of Janda (Muskelfunktionsdiagnostik, 2nd ed. Berlin: Volk- und Gesundheit; 1986). The abdominal wall was inspected for bulging or hernia formation. Additionally, patients answered a six-scale self-designed questionnaire concerning the impairment of daily living and pain. Muscle contractility as well as muscle diameter were graded into four degrees from 0-3. The highest degree of 3 with normal muscle contractility and muscle diameter was found in 1 of 5 patients after DIEP-flap. Degree 2, with reduced muscle contractility and reduced muscle diameter, was found in 10 of 22 patients, especially after unilateral TRAM-flap. Degree 1, with no muscle contractility and remaining muscle, and degree 0, with scar tissue, were found in 11 patients. Impairment in daily-life activity was found in 10 patients, while 8 patients complained of pain. Muscle strength scored by the method of Janda (Muskelfunktionsdiagnostik, 2nd ed. Berlin: Volk- und Gesundheit; 1986) reached 4 and 5 in 19 patients after all kinds of flap harvesting; 3 patients reached Janda 2 and 3 after unilateral free TRAM or unilateral DIEP-flap. In one patient, a hernia was detected after unilateral DIEP-flap; 10 patients showed bulging of the abdominal wall. Functional testing of the abdominal wall by the method of Janda as well as CT-scans or MRI for evaluation of the remaining muscle is reported in the literature. As there is a need for cost reduction in medical treatment, we were looking for a more cost-effective evaluation method compared to CT-scan or MRI. Ultrasound imaging of the donor site after TRAM-flap harvesting in order to evaluate the remaining function of the rectus muscle is not yet reported in the literature. We consider ultrasound imaging to be superior to CT-scan or MRI in terms of functional evaluation and cost effectiveness.
Assuntos
Músculos Abdominais/diagnóstico por imagem , Músculos Abdominais/transplante , Mamoplastia/métodos , Ultrassonografia Doppler , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Mamoplastia/efeitos adversos , Pessoa de Meia-Idade , Contração Muscular/fisiologia , Probabilidade , Valores de Referência , Medição de Risco , Estudos de Amostragem , Retalhos Cirúrgicos , Coleta de Tecidos e Órgãos , Cicatrização/fisiologiaRESUMO
UNLABELLED: Enhanced platelet activity and platelet endothelial interaction are hallmarks of different vascular and metabolic diseases with subsequent thrombus formation. In atherosclerosis, coronary artery disease, congestive heart failure, nitrate tolerance, chronic inflammation, or diabetic states, platelet activation may in part be due to a stimulation of the renin-angiotensin-aldosteron system, which also contributes to enhanced oxidant stress in these conditions. AIMS: We examined the putative role of the angiotensin receptor (AT1) and of phospholipase A2 (PLA2) in mediating platelet activation under defined in vitro conditions using the AT1 receptor antagonists losartan, EXP 3174, candesartan, and the PLA2 inhibitor arachidonyltrifluoromethyl ketone (AACOCF3), respectively. RESULTS: In washed human or canine platelet suspensions, losartan (10(-4)-10(-6) mol/L) dose-dependently suppressed thrombin-induced calcium transients as well as thromboxane (TxA2) release. In both species, aggregation of washed platelets in response to thrombin or ADP was substantially diminished by different doses of losartan. This inhibition of platelet aggregation was even maintained in ADP-stimulated platelet-rich plasma. While the PLA2 inhibitor AACOCF3 effectively inhibited thrombin-induced TxA2 release from washed human or canine platelets (similar to the effects observed with losartan), the AT1 agonist angiotensin II elicited platelet TxA2 release only at high supra-physiological doses (e.g., at 10(-4) mol/L). The AT1 specific antagonist candesartan did not diminish stimulated platelet aggregation, TxA2 formation, or calcium transients. By contrast, the active losartan metabolite EXP 3174 dose-dependently inhibited stimulated platelet calcium transients as well as TxA2 release at 1-100 micromol/L. CONCLUSIONS: Losartan significantly counteracts ex vivo platelet activation, probably via the blockade of TxA2 receptor-dependent signaling (e.g. implying activation of phospholipase A2) rather than acting at the AT1 receptor itself. This implies that the TxA2 signaling pathway plays a significant role during platelet activation, which may be successfully antagonized in vivo under different pathological states with enhanced thrombus formation or platelet-endothelium interactions.
Assuntos
Antagonistas de Receptores de Angiotensina , Losartan/farmacologia , Fosfolipases A/antagonistas & inibidores , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tromboxano A2/fisiologia , Animais , Ácidos Araquidônicos/farmacologia , Benzimidazóis/farmacologia , Compostos de Bifenilo , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/farmacologia , Fosfolipases A/fisiologia , Fosfolipases A2 , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Agregação Plaquetária/fisiologia , Receptor Tipo 1 de Angiotensina , Receptores de Angiotensina/fisiologia , Receptores de Tromboxanos/efeitos dos fármacos , Sistema Renina-Angiotensina , Transdução de Sinais , Tetrazóis/farmacologiaRESUMO
Myocardial ischemia-reperfusion is associated with bursts of reactive oxygen species (ROS) such as superoxide radicals (O(2)(-).). Membrane-associated NADH oxidase (NADHox) activity is a hypothetical source of O(2)(-)., implying the NADH concentration-to-NAD(+) concentration ratio ([NADH]/[NAD(+)]) as a determinant of ROS. To test this hypothesis, cardiac NADHox and ROS formation were measured as influenced by pyruvate or L-lactate. Pre- and postischemic Langendorff guinea pig hearts were perfused at different pyruvate/L-lactate concentrations to alter cytosolic [NADH]/[NAD(+)]. NADHox and ROS were measured with the use of lucigenin chemiluminescence and electron spin resonance, respectively. In myocardial homogenates, pyruvate (0.05, 0.5 mM) and the NADHox blocker hydralazine markedly inhibited NADHox (16 +/- 2%, 58 +/- 9%). In postischemic hearts, pyruvate (0.1-5.0 mM) dose dependently inhibited ROS up to 80%. However, L-lactate (1.0-15.0 mM) stimulated both basal and postischemic ROS severalfold. Furthermore, L-lactate-induced basal ROS was dose dependently inhibited by pyruvate (0.1-5.0 mM) and not the xanthine oxidase inhibitor oxypurinol. Pyruvate did not inhibit ROS from xanthine oxidase. The data suggest a substantial influence of cytosolic NADH on cardiac O(2)(-). formation that can be inhibited by submillimolar pyruvate. Thus cytotoxicities due to cardiac ischemia-reperfusion ROS may be alleviated by redox reactants such as pyruvate.
Assuntos
Antioxidantes/metabolismo , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Ácido Pirúvico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/farmacologia , Ácidos Cumáricos/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Cobaias , Hidralazina/farmacologia , Técnicas In Vitro , Ácido Láctico/metabolismo , Ácido Láctico/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Complexos Multienzimáticos/antagonistas & inibidores , NADH NADPH Oxirredutases/antagonistas & inibidores , Oxirredução/efeitos dos fármacos , Ácido Pirúvico/farmacologia , Coelhos , Xantina Oxidase/antagonistas & inibidoresRESUMO
To compare contrast-enhanced power Doppler (PD) harmonic imaging (CHI) with contrast-enhanced power Doppler fundamental imaging (CPD) in the depiction of renal cortical vessels, 20 healthy volunteers were subjected to PD imaging and HI assessment of the kidney after bolus injection of Levovist(R) (SH U 508A). System settings were standardized and the pulse-repetition frequencies (PRF) systematically toggled from 750 to 500 and 250. Videotapes were independently reviewed by three readers with regard to the presence of artefacts, the degree of Doppler signal enhancement, demarcation of vessels and the extent of visualization. The assessments were graded separately for each PRF in accordance with a multistage scoring system. In comparison to contrast-enhanced PD, artefacts were significantly lower with CHI for all PRF (p = 0.0001). Vessels were better visualized (p = 0.002) and less blurred (p = 0.006) with CHI than with CPD. There was no significant difference in the extent of Doppler signal increase between CPD and the contrast-enhanced harmonic mode. Combination of the contrast-enhanced harmonic method and PD allows the PRF to be lowered and, by balancing the greater susceptibility of PD to interference from clutter, increases the likelihood of detection of flow in small vessels.
Assuntos
Meios de Contraste/administração & dosagem , Rim/irrigação sanguínea , Rim/diagnóstico por imagem , Polissacarídeos/administração & dosagem , Ultrassonografia Doppler/métodos , Adulto , Humanos , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Gravação de VideoteipeRESUMO
In hypercholesterolemia in the presence or absence of atherosclerosis, cardiovascular dysfunction and altered signaling of angiotensin, nitric oxide, or prostanoids are closely related to enhanced oxidant stress. We analyzed the potentially beneficial effects of the specific angiotensin-converting enzyme inhibitor enalapril and the specific angiotensin receptor blocker losartan on cardiac performance, eicosanoid metabolism, and parameters of oxidant stress in hypercholesterolemic animals. Guinea pigs were fed a 1% cholesterol diet for 8 weeks (Chol) with or without equieffective doses of either enalapril (1.5 mg/kg/d; Ena) or losartan (3 mg/kg/d; Los). Hemodynamics were analyzed in Langendorff hearts. Detection of eicosanoids was by enzyme immunoassay. Estimation of plasma xanthine oxidase (XO) activity was determined by spectrophotometry. In hypercholesterolemic guinea pigs, enhanced oxidant stress (e.g., increased plasma XO activities) was associated with profound myocardial and coronary (e.g., endothelial) dysfunction. Both enalapril and losartan lowered plasma cholesterol levels slightly, but only the angiotensin receptor antagonist effectively suppressed the increased plasma XO activities (from 11.4 +/- 0.7 to 7.6 +/- 2.2 U/L), and at the same time decreased the augmented coronary flow (from 26.0 +/- 1.0 to 23.0 +/- 1.0 mL/min/g tissue) observed in hypercholesterolemic animals. Assessment of left ventricular pressure and contractility (e.g., dp/dtmax) as well as the diastolic relaxation parameter (tau) revealed substantial myocardial dysfunction (systolic and diastolic) in Chol that was more substantially (and comparably) improved during administration of losartan (Los) than during enalapril (Ena). Surprisingly, angiotensin signaling blockade by either antagonist further suppressed the diminished coronary dilator responses to bradykinin (BK; not significant for enalapril) or adenosine (Ado) was demonstrated in Chol Langendorff hearts [delta CPPBK/Ado: from 5.0 +/- 0.5/0.9 +/- 0.1 to 4.4 +/- 1.5/0.4 +/- 0.1 (Ena) or to 1.9 +/- 0.5/0.4 +/- 0.1 (Los) cm2 (area under the curve), respectively]. Finally, as expected from control studies using heart preparations from normocholesterolemic guinea pigs, enhanced cardiac release of eicosanoids, prostacyclin, and thromboxane in Chol (0.48 +/- 0.03 and 0.6 +/- 0.1 ng/min/g) was augmented even further by treatment with enalapril (Ena: 1.6 +/- 0.4 and 1.0 +/- 0.1 ng/min/g), but was significantly reduced to or below control levels in losartan-treated animals (Los: 0.4 +/- 0.1 and 0.2 +/- 0.1 ng/min/g). Blockade of angiotensin signaling via angiotensin-converting enzyme inhibition or receptor antagonism--although differentially acting on enhanced cardiac prostanoid metabolism and oxidant stress--efficiently restored proper systolic and diastolic myocardial performance (losartan was more beneficial than enalapril), probably by counterbalancing altered angiotensin II-->angiotensin receptor signaling in the cardiovascular system of hypercholesterolemic animals. Impaired coronary vasodilator capacity seems to be irreversible after 8 weeks of a high-cholesterol diet, as shown by the unexpected lack of a dilator effect with both enalapril and losartan.
Assuntos
Angiotensinas/fisiologia , Eicosanoides/metabolismo , Coração/efeitos dos fármacos , Hipercolesterolemia/fisiopatologia , Miocárdio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Colesterol na Dieta/farmacologia , Circulação Coronária/efeitos dos fármacos , Eicosanoides/biossíntese , Cobaias , Hipercolesterolemia/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Proteínas/metabolismoRESUMO
BACKGROUND: In hypercholesterolemia with or without atherosclerosis cardiovascular dysfunction and altered signalling of angiotensin (Ang II), nitric oxide (NO), or prostanoids are intimately related to enhanced oxidant stress and concomitant changes in gene expression. We analyzed cardiac angiotensin receptor (AT1) expression and metabolism of Ang II, eicosanoids, and NO in hypercholesterolemic animals. METHODS: Guinea pigs were fed a 1% cholesterol diet for 8 weeks (Chol). Hemodynamics were analyzed in Langendorff hearts. Spectrophotometric determination of plasma lipids and radioimmunological detection of eicosanoids/cyclic guanosine monophosphate (cGMP). Activities of NO synthase III (NOS-III) or angiotensin converting enzyme (ACE) were determined by enzymatic assays. AT1 receptor density was assessed by radioligand binding assay. NOS-III mRNAs were quantitated by reverse transcription polymerase chain reaction. RESULTS: Hypercholesterolemia was associated with fatty degeneration of the liver and profound myocardial and coronary (e.g., endothelial) dysfunction. In Chol Langendorff hearts we observed significant increases in coronary flow (26.0 +/- 1.0 vs. 17.5 +/- 0.5 mL/min/g tissue) but diminished coronary responses to bradykinin (Bk, 250 ng bolus) or adenosine (Ado, 250 micrograms bolus) (delta CPPBk/Ado: 5 +/- 0.5 vs. 7.2 +/- 1/0.9 +/- 0.1 vs. 1.9 +/- 0.3 cm2 (area under the curve)). AT1 receptor expression was significantly increased in Chol hearts (72 +/- 6.8 vs. 45 +/- 5.6 fmol/mg protein), whereas marked suppression of cardiac activities of ACE (1.96 +/- 0.34 vs. 4.90 +/- 0.20 nmol/min/mg tissue) and of the entire cardiac nitric oxide-cGMP axis (e.g., NOS-III activity: 1.9 +/- 0.4 vs. 3.1 +/- 0.1 pmol/min/mg tissue; NOS-III mRNA: 0.82 +/- 0.16 vs. 1.20 +/- 0.12 arbitrary units; cGMP release: 0.41 +/- 0.02 vs. 0.54 +/- 0.04 pmol/min/g tissue) were shown in Chol. Finally, cardiac release of eicosanoids prostacyclin (PGI2) and thromboxane (TxA2) were significantly enhanced (0.48 +/- 0.05 vs. 0.38 +/- 0.05 and 0.60 +/- 0.10 vs. 0.24 +/- 0.10 ng/min/g tissue, respectively). Enhanced cardiac PGI2 release and suppression of cGMP synthesis in Chol were even more pronounced on stimulation with Bk (38.2 +/- 3.0 vs. 28.2 +/- 2.0 ng/min/g tissue and 1.9 +/- 0.3 vs. 3.0 +/- 0.3 pmol/min/g tissue, respectively). CONCLUSIONS: Altered angiotensin-mediated signal transduction probably related to augmented eicosanoid formation does not compensate for the limited endogenous NO production and for cardiovascular dysfunction in hypercholesterolemic guinea pigs. In this context, changes in redox-sensitive regulation of gene expression (AT1 receptor, NOS-III--caused by enhanced oxidant stress--could play a pivotal role.
Assuntos
Eicosanoides/biossíntese , Hemodinâmica , Hipercolesterolemia/fisiopatologia , Receptores de Angiotensina/biossíntese , Animais , Regulação da Expressão Gênica , Guanilato Ciclase/metabolismo , Cobaias , Masculino , Complexos Multienzimáticos/metabolismo , Miocárdio/metabolismo , NADH NADPH Oxirredutases/metabolismo , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/análise , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de AngiotensinaRESUMO
BACKGROUND: Anti-ischemic therapy with organic nitrates as nitric oxide (NO) donors is complicated by the induction of tolerance. When nitrates are metabolized to release NO, there is a considerable coproduction of reactive oxygen species (superoxide radical and peroxynitrite) in vessels leading to inactivation of NO, to diminished cyclic quanosine monophosphate production in smooth muscle cells (SMC), to impaired vasomotor responses to the endothelium-derived relaxation factor (EDRF), and to formation of nitrotyrosine as a marker of glyceryltrinitrate (GTN)-induced formation of peroxynitrite. The aim of the study was to analyze in vitro the formation of superoxide radicals and of peroxynitrite in GTN-treated endothelial and smooth muscle cells and in washed ex vivo platelets using electron spin resonance and spin-trapping techniques. METHODS AND RESULTS: Using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap, it was shown that in platelets, smooth muscle, and endothelial cells incubated acutely for 15 minutes with 0.5 mM GTN, the rate of generation of reactive oxygen species (ROS) was twice as high as under control conditions. Using the new spin-trap 2H-imidazole-1-oxide (TMIO), a GTN-induced peroxynitrite formation was detected in SMC and in platelets incubated with 0.5 mM GTN for 15 minutes. Spin-trap 1-hydroxy-3-carboxy-pyrrolidine (CP-H) was used to estimate the rate of ROS formation in platelets incubated for 15 minutes with 0.5 mM GTN; the rate amounted to 14.6 +/- 1.1 nM/min/mg protein compared with 4.0 +/- 0.4 nM/min/mg protein in controls. The rate of ROS formation in SMCs was substantially increased (240 +/- 16%) after initiation of GTN tolerance by treatment of the cells in culture with 100 µM GTN for 24 hours. CONCLUSIONS: GTN increases the formation of superoxide radicals in endothelial cells, SMCs, and platelets. Peroxynitrite is formed during GTN metabolism in vascular cells and may contribute to the development of tolerance. A decrease in the nitrate-induced inhibition of platelet aggregation during GTN tolerance is associated with oxidative actions of ROS formed in platelets during GTN metabolism.
RESUMO
OBJECTIVE: The aim was to test the effects of nicorandil on coronary arterial conductance and on a possible development of tolerance or cross tolerance with glyceryl trinitrate during a 5 d continuous intravenous infusion of this hybrid molecule (consisting of a combination of potassium channel activation and simultaneous nitro-ester induced soluble guanylyl-cyclase activation). METHODS: Continuous intravenous infusions of nicorandil at 2.5 micrograms.kg-1.min-1 and 10 micrograms.kg-1.min-1 into conscious chronically instrumented dogs were carried out for 5 d using a special portable infusion system. Employing additional short term infusions, dose-response curves were obtained by giving nicorandil or glyceryl trinitrate at increasing dosages both in the preinfusion control state and 4 h after terminating the nicorandil infusion. RESULTS: The 5 d infusion of 2.5 or 10.0 micrograms.kg-1.min-1 nicorandil resulted in a significant increase in large coronary artery diameter by 4.21 (SEM 0.14)% or 9.20(0.28)%, respectively. At the lower dose no significant tolerance or cross tolerance with glyceryl trinitrate was observed. However, at the higher dose there was a shift of the dose-response curve of both nicorandil and glyceryl trinitrate to the right, indicating some tolerance. The smaller dose did not induce hypotension or reflex increase in heart rate, whereas the larger resulted in a 42(2.5)% increase in heart rate. CONCLUSIONS: A dose regimen of 2.5 micrograms.kg-1.min-1 continuously administered for 5 d is capable of inducing a significant increase in coronary arterial conductance which was well maintained over the whole infusion period. Thus nicorandil can exert a selective large coronary artery dilatation and may bring about a well maintained increase in epicardial coronary conductance, especially when applied as a low dose slow release preparation which circumvents hypotension and increase in heart rate.
Assuntos
Vasos Coronários/efeitos dos fármacos , Niacinamida/análogos & derivados , Vasodilatadores/farmacologia , Animais , Vasos Coronários/anatomia & histologia , Cães , Relação Dose-Resposta a Droga , Esquema de Medicação , Sistemas de Liberação de Medicamentos , Feminino , Masculino , Niacinamida/farmacologia , Nicorandil , Nitroglicerina/farmacologia , Fatores de TempoRESUMO
We analyzed the effect of enalapril (0.1 mg/kg p.o. twice daily) on plasma electrolytes, urea, and creatinine in low cardiac output failure. In 14 male dogs implanted with chronic instrumentation, tachycardia was induced by ventricular pacing (265 impulses/min., 10-14 days). In 7 untreated dogs, pacing progressively lowered aortic flow by 44% and induced hyponatremia and elevations of plasma urea, creatinine, and potassium. Treatment with enalapril (n = 7) during pacing reduced the decrease in aortic flow by 33% and prevented changes in plasma urea, potassium, and sodium. We conclude that this is due to enalapril-induced retardation of heart failure progression.
Assuntos
Baixo Débito Cardíaco/sangue , Enalapril/farmacologia , Hiponatremia/etiologia , Modelos Biológicos , Administração Oral , Animais , Baixo Débito Cardíaco/etiologia , Baixo Débito Cardíaco/prevenção & controle , Estimulação Cardíaca Artificial , Creatinina/sangue , Cães , Enalapril/administração & dosagem , Masculino , Potássio/sangue , Sódio/sangue , Taquicardia/etiologia , Ureia/sangueRESUMO
The feedback control of neuroendocrine activity by cardiopulmonary blood volume is disturbed in congestive heart failure. By analyzing plasma catecholamine kinetics, we tested in 11 chronically instrumented conscious dogs whether attenuations in the sympathoadrenal inhibition induced by atrial natriuretic peptide (ANP) contributed to this disturbance. Low-output failure was brought about by continuous ventricular pacing at 265 beats/min for 2 weeks. This resulted in a decline in aortic flow by 37 +/- 5% (SEM), an increase in peripheral vascular resistance by 48 +/- 4%, a 13 +/- 3-fold elevation in plasma ANP, a 9 +/- 3-fold elevation in plasma renin activity, and an augmentation of the norepinephrine-release rate into plasma by 132 +/- 17%. During ANP infusion, the epinephrine-release rate declined by 26 +/- 5% per 10-fold elevation in plasma ANP before pacing and by 31 +/- 7% (not significantly different) after 2 weeks of pacing. Before pacing, ANP attenuated plasma renin activity and caused hypotension without a rise in norepinephrine-release rate. After 2 weeks of pacing, ANP lowered norepinephrine release (by 16 +/- 6%) without affecting blood pressure or plasma renin activity, and vascular nonresponsiveness to ANP was verified under autonomic blockade. These data indicate that, during the development of heart failure, an inhibitory action of ANP on norepinephrine release is unmasked by an ANP-specific vascular desensitization, whereas the inhibition of epinephrine release is observed throughout. It is concluded that ANP-induced sympathoadrenal inhibition is not attenuated and, therefore, does not contribute to the disturbed regulation observed early in the development of failure.
Assuntos
Fator Natriurético Atrial/farmacologia , Insuficiência Cardíaca/fisiopatologia , Sistema Nervoso Simpático/fisiologia , Medula Suprarrenal/fisiologia , Animais , Baixo Débito Cardíaco/fisiopatologia , Estimulação Cardíaca Artificial , Cães , Epinefrina/metabolismo , Retroalimentação/fisiologia , Feminino , Insuficiência Cardíaca/etiologia , Masculino , Norepinefrina/metabolismoRESUMO
A 5 days group therapy (2 hours daily) for smoking cessation is presented. Based on the examination of 221 participants the efficiency of this group therapy was between 70 and 80% at the end of the treatment. The long-term follow-up efficiency was about 40%. Therefore this kind of therapy is effective for smoking cessation.
Assuntos
Terapia Comportamental , Psicoterapia de Grupo , Fumar/terapia , Adulto , Feminino , Seguimentos , Humanos , MasculinoRESUMO
In six conscious, trained dogs, maintained on a normal sodium intake of 2 to 4 mEq/kg/day, sympathetic activity was assessed as the release rate of norepinephrine and epinephrine during 15-minute i.v. infusions of human alpha-atrial natriuretic factor. Mean arterial pressure (as a percentage of control +/- SEM) during randomized infusions of 0.03, 0.1, 0.3, or 1.0 microgram/kg/min was 99 +/- 1, 95 +/- 1 (p less than 0.05), 93 +/- 1 (p less than 0.01), or 79 +/- 6% (p less than 0.001), respectively, but no tachycardia and no augmentation of the norepinephrine release rate (up to 0.3 microgram/kg/min) were observed, which is in contrast to comparable hypotension induced by hydralazine or nitroglycerin. The release rate of epinephrine (control, 6.7 +/- 0.6 ng/kg/min) declined immediately during infusions of atrial natriuretic factor to a minimum of 49 +/- 5% of control (p less than 0.001) during 0.1 microgram/kg/min and to 63 +/- 5% (0.1 greater than p greater than 0.05) or 95 +/- 13% (not significant) during 0.3 or 1.0 microgram/kg/min. Steady state arterial plasma concentrations of atrial natriuretic factor were 39 +/- 10 pg/ml (n = 6) during infusions of saline and 284 +/- 24 pg/ml (n = 6) and 1520 +/- 300 pg/ml (n = 9) during 0.03 and 0.1 microgram/kg/min infusions of the factor.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Fator Natriurético Atrial/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Epinefrina/sangue , Norepinefrina/sangue , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Cães , Pressorreceptores/efeitos dos fármacosRESUMO
Vasodilators may provoke myocardial ischemia in patients with coronary heart disease. Therefore, we analyzed in conscious dogs the effect of angiotensin-converting enzyme (ACE) inhibition by enalaprilat on parameters potentially important to provocation of myocardial ischemia, such as sympathetic activity, myocardial oxygen consumption, and vascular tone in coronary conduit and resistance vessels. Under normal sodium intake (2-4 mEq/kg/day), enalaprilat (0.03 and 0.3 mg/kg i.v. during 5-min infusion with 30-min intervals, n = 8) did not modify the norepinephrine release rate into plasma (a parameter of overall sympathetic activity). The higher dosage reduced myocardial oxygen consumption (to 87 +/- 2% of control), mean arterial pressure (MAP) (to 90 +/- 1%) and coronary conduit artery tone (normalized delta diameter: +3.2 +/- 0.7%) without dilating coronary resistance vessels. Following renin-angiotensin activation by sodium deprivation (3 X 1 mg/kg furosemide plus 7 days sodium intake less than 0.2 mEq/day), enalaprilat similarly lowered myocardial oxygen consumption and reduced vascular tone both in coronary conduit (normalized delta diameter: +4.0 +/- 0.9%) and resistance vessels (delta coronary flow: +45 +/- 12%). Although MAP declined to 76 +/- 6%, heart rate and norepinephrine release rate were not modified significantly. We propose that the dilation of epicardial arteries results from a direct intramural action. Enalaprilat seems unlikely to provoke myocardial ischemia even in states with a strongly activated renin-angiotensin system.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Enalapril/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Catecolaminas/sangue , Dieta Hipossódica , Cães , Feminino , Hemodinâmica/efeitos dos fármacos , Masculino , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
The involvement of postsynaptic alpha 2-adrenergic receptors in the adrenergic constriction of the capacitance vessels was studied in anesthetized, spontaneously breathing dogs under ganglionic blockade (hexamethonium, 10 mg/kg + 10 mg/kg/hr; methylatropine, 0.5 mg/kg). Effective vascular compliance was measured as an indicator of venous tone (blood volume was varied by +/- 4 ml/kg in an 11-minute cycle of infusion, withdrawal, withdrawal, and reinfusion) and was calculated from the correlation between the observed changes in central venous pressure and the changes in blood volume. Sympathetic activity and central venous pressure were lower and effective vascular compliance was higher than values in untreated conscious dogs. The alpha 2-agonist UK 14,304 (5-bromo-6-[imidazolin-2-ylamino]-quinoxaline; 0.04 and 0.12 micrograms/kg/min; n = 6) dose-dependently lowered compliance and increased central venous pressure to levels found in conscious dogs, as did the alpha 1-agonist methoxamine (10 and 30 micrograms/kg; n = 6). Rauwolscine (alpha 2-antagonist), 0.3 mg/kg, significantly attenuated the effects of UK 14,304, but not those of methoxamine, while prazosin (alpha 1-antagonist), 0.12 mg/kg, attenuated the effects of methoxamine, but not those of UK 14,304 (n = 6 each). Under beta-blockade (nadolol, 2 mg/kg; n = 12) venous tone was increased to about physiological levels by norepinephrine, 0.15 micrograms/kg/min i.v., or by neuronal norepinephrine release induced by tyramine, 10 micrograms/kg/min i.v. These increases were significantly attenuated by prazosin as well as by rauwolscine and were abolished by a combination of both. These results indicate that postsynaptic alpha 2-adrenergic receptors (in addition to alpha 1-adrenergic receptors) are functional in the venous system in vivo and contribute substantially to adrenergic sympathetic and humoral regulation of venous tone.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Volume Sanguíneo , Receptores Adrenérgicos alfa/fisiologia , Vasoconstrição , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Volume Sanguíneo/efeitos dos fármacos , Tartarato de Brimonidina , Complacência (Medida de Distensibilidade) , Cães , Feminino , Masculino , Metoxamina/farmacologia , Norepinefrina/sangue , Norepinefrina/farmacologia , Prazosina/farmacologia , Quinoxalinas/farmacologia , Circulação Esplâncnica , Esplenectomia , Tiramina/farmacologia , Vasoconstrição/efeitos dos fármacos , Ioimbina/farmacologiaRESUMO
The study of venodilator tolerance to nitroglycerin has been complicated by reflex compensation and by problems in analyzing venous tone in the presence of multiple determinants of venous pressure. We assessed venous tone as total effective vascular compliance (TEVC) under autonomic blockade in six dogs, in the nontolerant state, and during a 5 day infusion of nitroglycerin (1.5 micrograms/kg/min). Under long-term treatment, baseline TEVC was unaffected and the nitroglycerin dose-response relationship for TEVC was shifted to greater than 10-fold higher doses, whereas baseline mean arterial pressure (MAP) was lowered by 17 +/- 3 mm Hg without any shift in nitroglycerin responsiveness. This lowering of MAP was observed only after autonomic blockade. In six additional dogs instrumented with aortic flow probes, nitroglycerin (1.5 micrograms/kg/min) induced a 15 +/- 1% decline in peripheral vascular resistance (PVR) under autonomic blockade, but with reflexes intact these dogs showed no change in PVR and a 21 +/- 10% increase in norepinephrine release rate. We conclude that modest long-term exposure to nitroglycerin results in tolerance to its venodilating effects, whereas arteriolar action is maintained. This tolerance-induced shift in action from venous toward arteriolar dilation is normally masked by compensatory reflexes.