RESUMO
BACKGROUND: This randomised phase II trial compared gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer. METHODS: Patients were randomly assigned to 4-week treatment with gemcitabine alone (1000, mg m(-2) gemcitabine by 30-min infusion on days 1, 8, and 15) or gemcitabine and S-1 combination therapy (1000, mg m(-2) gemcitabine by 30-min infusion on days 1 and 15 and 40 mg m(-2) S-1 orally twice daily on days 1-15). The primary end point was progression-free survival (PFS). RESULTS: Between July 2006 and February 2009, 106 patients were enrolled. The PFS in gemcitabine and S-1 combination arm was significantly longer than in gemcitabine arm (5.4 vs 3.6 months), with a hazard ratio of 0.64 (P=0.036). Overall survival (OS) for gemcitabine and S-1 combination was longer than that for gemcitabine monotherapy (13.5 vs 8.8 months), with a hazard ratio of 0.72 (P=0.104). Overall, grade 3 or 4 adverse events were similar in both arms. CONCLUSION: Gemcitabine and S-1 combination therapy demonstrated longer PFS in advanced pancreatic cancer. Improved OS duration of 4.7 months was found for gemcitabine and S-1 combination therapy, though this was not statistically significant.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Ácido Oxônico/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Tegafur/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , GencitabinaRESUMO
INTRODUCTION/OBJECTIVES: The American College of Veterinary Internal Medicine (ACVIM) guidelines suggest that pimobendan should be initiated in dogs which meet all criteria of stage B2 myxomatous mitral valve disease (MMVD): murmur intensity ≥ 3/6, left atrial-to-aortic ratio ≥ 1.6, normalized left ventricular internal diameter in diastole ≥ 1.7, and vertebral heart size > 10.5. Recently, a new radiographic index for left atrial enlargement, vertebral left atrial size (VLAS), was proposed. The objective of the present study was to evaluate whether VLAS is useful in staging MMVD and if it can distinguish between ACVIM stages B1 and B2. ANIMALS: Ninety-seven client-owned dogs with MMVD were evaluated and classified as ACVIM stage B1, B2, or C-D. MATERIALS AND METHODS: The echocardiographs and radiographs of all the dogs were retrospectively evaluated to obtain left atrial-to-aortic ratio, normalized left ventricular internal diameter in diastole, and VLAS values. The data were analyzed to assess the correlation between these measurements and VLAS, and the optimal cutoff value of VLAS was determined. RESULTS: A VLAS cutoff value of 2.6 provided the greatest diagnostic accuracy for identification of dogs with ACVIM stage B2 MMVD (area under the curve, 0.96; sensitivity, 95%; specificity, 84%). A VLAS ≥2.5 exhibited the highest sensitivity (sensitivity, 100%; specificity, 78%), and a VLAS ≥ 3.1 exhibited the highest specificity (sensitivity, 47%; specificity, 100%). CONCLUSIONS: VLAS is a helpful index for monitoring MMVD using radiography. A VLAS cutoff value of 2.5 could be used to identify dogs that may benefit from echocardiography to determine if they have reached ACVIM stage B2.
Assuntos
Doenças do Cão/diagnóstico por imagem , Átrios do Coração/diagnóstico por imagem , Insuficiência da Valva Mitral/veterinária , Animais , Cães , Feminino , Masculino , Insuficiência da Valva Mitral/diagnóstico por imagem , Radiografia Torácica/veterinária , Registros/veterinária , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
It is widely recognized that nitric oxide (NO) in mammalian tissues is produced from L-arginine via catalysis by NO synthase (NOS) isoforms such as neuronal NOS (nNOS) and endothelial NOS (eNOS) that are constitutively expressed mainly in the central and peripheral nervous system and vascular endothelial cells, respectively. This review concentrates only on these constitutive NOS (cNOS) isoforms while excluding information about iNOS, which is induced mainly in macrophages upon stimulation by cytokines and polysaccharides. The NO signaling pathway plays a crucial role in the functional regulation of mammalian tissues and organs. Evidence has also been accumulated for the role of NO in invertebrates and non-mammalian vertebrates. Expression of nNOS in the brain and peripheral nervous system is widely determined by staining with NADPH (reduced nicotinamide adenine dinucleotide phosphate) diaphorase or NOS immunoreactivity, and functional roles of NO formed by nNOS are evidenced in the early phylogenetic stages (invertebrates and fishes). On the other hand, the endothelium mainly produces vasodilating prostanoids rather than NO or does not liberate endothelium-derived relaxing factor (EDRF) (fishes), and the ability of endothelial cells to liberate NO is observed later in phylogenetic stages (amphibians). This review article summarizes various types of interesting information obtained from lower organisms (invertebrates, fishes, amphibians, reptiles, and birds) about the properties and distribution of nNOS and eNOS and also the roles of NO produced by the cNOS as an important intercellular signaling molecule.
Assuntos
Óxido Nítrico/biossíntese , Filogenia , Anfíbios/metabolismo , Animais , Aves/metabolismo , Peixes/metabolismo , Invertebrados/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Répteis/metabolismoRESUMO
PURPOSE: Gallbladder cancer (GBC) has a poor prognosis that is related to delayed diagnosis. The present study evaluated the efficacy of the transcystic ductal approach in diagnosing GBC. METHODS: A catheter was introduced into the gallbladder endoscopically via the cystic duct to obtain bile for cytology. Subsequently, cytology specimens were collected using a brush, and intraductal ultrasonography (IDUS) was performed using a miniature probe in patients suspected of having GBC. RESULTS: Bile cytology was performed successfully in 23 of 25 patients (92%). The sensitivity, specificity and accuracy of cytology were 44.4%, 100% and 78.3%, respectively. Brush cytology and IDUS were successful in six of eight (75%) and nine of 15 (60%) patients, respectively. Brush cytology was positive in two of five patients with GBC. In all four patients with invasive cancer, IDUS showed an irregularity or disruption of the outermost hyperechoic layer. CONCLUSIONS: The endoscopic transpapillary approach to the gallbladder was useful for the diagnosis of GBC. Brush cytology and IDUS may improve diagnostic efficacy and provide more useful information.
Assuntos
Ampola Hepatopancreática , Endoscopia do Sistema Digestório/métodos , Endossonografia/métodos , Neoplasias da Vesícula Biliar/diagnóstico , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
We have reported that a deficiency of tetrahydrobiopterin (BH(4)), an active cofactor of endothelial NO synthase (eNOS), contributes to the endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O(2)(-)) generation in the insulin-resistant state. To further confirm this hypothesis, we investigated the effects of dietary treatment with BH(4) on endothelium-dependent arterial relaxation and vascular oxidative stress in the aortas of insulin-resistant rats. Oral supplementation of BH(4) (10 mg. kg(-1). d(-1)) for 8 weeks significantly increased the BH(4) content in cardiovascular tissues of rats fed high levels of fructose (fructose-fed rats). Impairment of endothelium-dependent arterial relaxation in the aortic strips of the fructose-fed rats was reversed with BH(4) treatment. The BH(4) treatment was associated with a 2-fold increase in eNOS activity as well as a 70% reduction in endothelial O(2)(-) production compared with those in fructose-fed rats. The BH(4) treatment also partially improved the insulin sensitivity and blood pressure, as well as the serum triglyceride concentration, in the fructose-fed rats. Moreover, BH(4) treatment of the fructose-fed rats markedly reduced the lipid peroxide content of both aortic and cardiac tissues and inhibited the activation of 2 redox-sensitive transcription factors, nuclear factor-kappaB and activating protein-1, which were increased in fructose-fed rats. The BH(4) treatment of control rats did not have any significant effects on these parameters. These results indicate that BH(4) augmentation is essential for the restoration of eNOS function and the reduction of vascular oxidative stress in insulin-resistant rats.
Assuntos
Biopterinas/análogos & derivados , Biopterinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Resistência à Insulina , Administração Oral , Animais , Antioxidantes/farmacologia , Aorta/citologia , Endotélio Vascular/fisiologia , Humanos , Masculino , Relaxamento Muscular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Mismatch repair genes are the responsible genes for hereditary non-polyposis colon cancer, and mutation of these genes causes replication error (RER). In several RER-positive colon cancer cell lines, mutations of repetitive sequences of transforming growth factor beta (TGF-beta) type II receptor (RII) gene have been reported. Since TGF-beta inhibits cell proliferation, loss of response to TGF-beta is an important tumor progression step. In this study, the relationship between RER status and mutation of the RII gene was analyzed in 112 cases of various types of sporadic gastrointestinal and hepatobiliary cancer (41 with gastric, 49 with colorectal, 5 with gallbladder, and 17 with hepatic cancers). RER was found in 17 cases (4 with gastric, 12 with colorectal, and 1 with gallbladder cancer), and 10 of those (3 with gastric and 7 with colorectal cancer) showed mutations of the RII gene. Of interest was that in all seven cases with colorectal cancer, tumors were located at the cecum. These data indicate that mutation of the RII gene, presumably caused by abnormality of repair gene, play an important role in carcinogenesis of sporadic gastrointestinal cancer, especially at the cecum.
Assuntos
Neoplasias do Ceco/genética , Neoplasias Colorretais/genética , Replicação do DNA/genética , Mutação/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Neoplasias Gástricas/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases , Receptor do Fator de Crescimento Transformador beta Tipo IIRESUMO
We developed a sensitive enzyme-linked immunosorbent assay (ELISA) for detection of malondialdehyde-modified low-density lipoprotein (MDA-LDL) in human serum. A monoclonal antibody against MDA-LDL (ML25) used in our method recognized not only MDA-LDL but also other MDA-modified proteins. However, MDA-LDL was able to be detected specifically by using a combination of ML25 and an antibody specific for apolipoprotein B (apo B) (AB16), which was conjugated with beta-galactosidase. Using this method, measurable amounts of MDA-LDL were detected in the sera of 40 healthy individuals. MDA-LDL was observed to be mainly distributed in the human LDL fraction separated by density gradient ultracentrifugation, while in each lipoprotein subfraction the largest amount of MDA-LDL per protein was found at a subfraction between LDL and HDL. The particle size of LDL in this fraction was smaller than that of LDL in the main LDL fraction, as assessed by electrophoresis. In addition, LDL oxidized by Cu2+ was also detectable with this method. We conclude that our method is sensitive and specific for MDA-LDL and might be useful for investigating MDA-LDL in the human circulation.
Assuntos
Ensaio de Imunoadsorção Enzimática , Lipoproteínas LDL/sangue , Malondialdeído , Anticorpos Monoclonais , Apolipoproteínas B/imunologia , Centrifugação com Gradiente de Concentração , Humanos , Lipoproteínas LDL/imunologia , Lipoproteínas LDL/isolamento & purificação , Malondialdeído/química , Malondialdeído/imunologiaRESUMO
To investigate underlying mechanisms responsible for the impaired nitric oxide (NO)-dependent vascular relaxation in the insulin-resistant state, we examined production of both NO and superoxide anion radical (O2-) and those modulating factors in aortas obtained from normal (CTR), insulin-treated (INS), or high fructose-fed (FR) rats. FR rats showed insulin resistance with endogenous hyperinsulinemia, whereas INS rats showed normal insulin sensitivity. Only FR aortic strips with endothelium elicited impaired relaxation in response to either acetylcholine or calcium ionophore A23187. Endothelial NO synthase (eNOS) activity and its mRNA levels were increased only in vessels from INS rats (P < 0.001), whereas eNOS activity in FR rats was decreased by 58% (P < 0.05) when compared with CTR rats. NO production from aortic strips stimulated with A23187 was significantly lower in FR than CTR rats. In contrast, A23187-stimulated O2- production was higher (P < 0.01) in FR than CTR rats. These differences were abolished when aortic strips were preincubated in the media including (6R)-5,6,7,8-tetrahydrobiopterin (BH4), an active cofactor for eNOS. Furthermore, as compared with CTR rats, aortic BH4 contents in FR rats were decreased (P < 0.001), whereas the levels of 7,8-dihydrobiopterin, the oxidized form of BH4, were increased, with opposite results in INS rats. These results indicate that insulin resistance rather than hyperinsulinemia itself may be a pathogenic factor for decreased vascular relaxation through impaired eNOS activity and increased oxidative breakdown of NO due to enhanced formation of O2- (NO/O2- imbalance), which are caused by relative deficiency of BH4 in vascular endothelial cells.
Assuntos
Aorta Torácica/fisiologia , Biopterinas/metabolismo , Endotélio Vascular/fisiologia , Frutose/farmacologia , Resistência à Insulina/fisiologia , Insulina/farmacologia , Contração Isométrica/fisiologia , Músculo Liso Vascular/fisiologia , Óxido Nítrico/fisiologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Ácido Ascórbico/farmacologia , Biopterinas/análogos & derivados , Biopterinas/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Calcimicina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hiperinsulinismo/fisiopatologia , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Masculino , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiopatologia , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Nitroprussiato/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , Transcrição Gênica , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Endogenous cerebral vasoconstrictor mediators regulate vascular resistance and blood flow in the brain as a whole and in various regions and participate in the pathogenesis of cerebral circulatory disturbances. Vasoconstrictors are effective in the treatment of diseases associated with cerebral vasodilatation. There are variations in the response of cerebral arteries from primate and subprimate mammals; therefore, information as to similarities and differences in their response is quite important in evaluating the physiological role, involvement in pathogenesis and therapeutic usefulness of the mediators in healthy men and patients. In this review we described characteristics of the action of vasoconstrictors (amines, peptides, prostanoids, and others) on isolated cerebral arteries from mammals, including humans and monkeys.
Assuntos
Circulação Cerebrovascular/fisiologia , Vasoconstrição/fisiologia , Vasoconstritores/farmacologia , Animais , Circulação Cerebrovascular/efeitos dos fármacos , Humanos , Vasoconstrição/efeitos dos fármacosRESUMO
Transmembrane potentials were recorded from single cells of the sino-atrial (S-A) node and right atrium isolated from rabbits of different ages (2 to 360 days old). In neonatal rabbit atria, the shape of pacemaker action potentials recorded from same S-A nodal cells were not regular, and action potentials showing a slow depolarisation during diastole were frequently recorded from the right atrium close to the crista terminalis. The atrial rate decreased, the maximal diastolic potential or resting potential and the size of the overshoot increased, and action potential durations were prolonged with age. Such alterations in the membrane potential related to age were not associated with changes in the atrial rate. The maximum rate of rise did not significantly differ in S-A nodes and right atria from rabbits of different ages. It may be concluded that the membrane permeability for K+ is increased and/or the permeability for Na+ is decreased during early postnatal period, resulting in alterations in the automaticity and parameters of the membrane potential. The relationship between maximum rate of rise and maximal diastolic potential or resting potential appears to be altered with age.
Assuntos
Envelhecimento , Coração/fisiologia , Nó Sinoatrial/fisiologia , Potenciais de Ação , Animais , Função Atrial , Feminino , Coração/crescimento & desenvolvimento , Técnicas In Vitro , Masculino , Potenciais da Membrana , CoelhosRESUMO
OBJECTIVE: The aim was to analyse and compare mechanisms of histamine or acetylcholine action in mesenteric venous and arterial strips obtained from Japanese monkeys. METHODS: Monkey mesenteric arterial and venous strips were suspended for isometric tension recording in modified Ringer-Locke solutions, and responses of the strips precontracted with prostaglandin F2 alpha to histamine or acetylcholine were compared. RESULTS: Histamine (2 x 10(-8) M-10(-5) M) produced a concentration related relaxation in the arteries and veins. The arterial relaxation was slightly but significantly attenuated by endothelial denudation [57.1(SEM 11.2)% inhibition at 10(-7) M, n = 14, p < 0.05] and treatment with 10(-6) M chlorpheniramine [26.7(6.7)% inhibition at 10(-7) M, n = 10, p < 0.05] or 10(-5) M methylene blue [31.5(11.2)% inhibition at 10(-7) M, n = 9, p < 0.05], and markedly suppressed by 10(-5) M cimetidine [96.8(1.2)% inhibition at 10(-7) M, n = 13, p < 0.001]. Indomethacin (10(-6) M) was without effect. On the other hand, relaxant responses to histamine of the venous strips were not influenced by endothelial denudation and treatment with chlorpheniramine or indomethacin but were abolished by treatment with cimetidine. Removal of the endothelium did not alter the venous relaxation caused by acetylcholine (10(-8) M-10(-4) M) but almost abolished the response to Ca2+ ionophore A23187 (10(-7) M) and substance P (10(-7) M). The acetylcholine induced relaxation was reversed to a contraction by indomethacin. CONCLUSIONS: Histamine-induced relaxations of monkey mesenteric arteries seem to be associated mainly with activation of the H2 receptor subtype in smooth muscle and partially mediated by relaxing factor liberated by stimulation of the H1 subtype in the endothelium, whereas the mesenteric venous relaxation seems to be due exclusively to a mediation of H2 receptors. Acetylcholine-induced relaxations of venous strips appear to be caused by vasodilator prostanoids, possibly prostaglandin I2, liberated from subendocardial tissues.
Assuntos
Acetilcolina/farmacologia , Histamina/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Animais , Clorfeniramina/farmacologia , Cimetidina/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Feminino , Técnicas In Vitro , Macaca , Masculino , Azul de Metileno/farmacologia , Receptores Histamínicos/efeitos dos fármacosRESUMO
OBJECTIVES: The present study was designed to determine whether tonic nitric oxide (NO)-mediated vasodilator innervation participates in basilar arterial dilatation in the anesthetized Japanese monkey. METHODS: The basilar arterial diameter was angiographically measured, and NG-nitro-L-arginine (L-NNA), a nitric oxide synthase inhibitor, was intracisternally applied. RESULTS: The injection of L-NNA produced a sustained constriction of the basilar artery, the effect being reversed by the cisternal injection of L-arginine. The vasoconstriction tended to be accelerated by treatment with phentolamine. Under alpha-adrenoceptor blockade, hexamethonium significantly attenuated the vasoconstrictor response to L-NNA. Intracisternal injections of this inhibitor did not alter the systemic blood pressure and heart rate. CONCLUSIONS: These findings suggest that construction by the NO synthase inhibitor of the monkey basilar artery is associated with suppression of synthesis of NO in vasodilator nerves receiving tonic impulses from the central nervous system. The basilar arterial tone appears to be regulated by nitroxidergic and adrenergic nerves and by NO derived from the endothelium in anesthetized monkeys.
Assuntos
Arginina/análogos & derivados , Artéria Basilar/efeitos dos fármacos , Óxido Nítrico Sintase/antagonistas & inibidores , Vasoconstrição , Angiografia Digital , Animais , Arginina/farmacologia , Artéria Basilar/diagnóstico por imagem , Feminino , Bloqueadores Ganglionares/farmacologia , Hexametônio/farmacologia , Macaca , Masculino , Nitroarginina , Fentolamina/farmacologiaRESUMO
Dopamine contracted isolated canine coronary arteries at initial concentrations of 5 times 10(-6) mol/l. In the presence of phentolamine or phenoxybenzamine and after contraction of the arteries with K+ or prostaglandin F2alpha, dopamine caused dose-related relaxation at initial concentrations of 5 times 10(-6) mol/l and 10(-6) mol/l. Propranolol, 10(-6) mol/l, and haloperidol, 10(-5) mol/l, did not antagonize the relaxation.
Assuntos
Vasos Coronários/efeitos dos fármacos , Dopamina/farmacologia , Animais , Artérias/efeitos dos fármacos , Cães , Antagonistas de Dopamina , Relação Dose-Resposta a Droga , Feminino , Haloperidol/farmacologia , Técnicas In Vitro , Isoproterenol/antagonistas & inibidores , Isoproterenol/farmacologia , Masculino , Norepinefrina/antagonistas & inibidores , Norepinefrina/farmacologia , Fenoxibenzamina/farmacologia , Fentolamina/farmacologia , Potássio/farmacologia , Propranolol/farmacologia , Prostaglandinas F/farmacologiaRESUMO
Helically-cut strips of dog cerebral, coronary, mesenteric, renal and femoral arteries contracted with prostaglandin (PG) F2 alpha or K+ responded to amrinone (10(-5) to 10(-4) mol X litre-1) with relaxation, which was not influenced by treatment with propranolol, atropine, cimetidine, aminophylline or aspirin. The contractile response of mesenteric arteries to transmural electrical stimulation (2, 5 and 20 Hz) and noradrenaline was attenuated by amrinone (3 X 10(-5) and 10(-4) mol X litre-1); the attenuation of the response to nerve stimulation and noradrenaline did not significantly differ. Ca2+-induced contractions in mesenteric arteries exposed to Ca2+-free media and depolarised by excess K+ were inhibited by amrinone, and the inhibition could not be reversed by the addition of excess Ca2+. Treatment with amrinone potentiated the relaxant responses of mesenteric arteries to adenosine but did not alter the response to isoprenaline. Amrinone in concentrations sufficient to produce moderate and marked relaxation did not significantly alter the content of cyclic AMP in mesenteric arteries. Attenuation by amrinone of the contractile response to transmural stimulation, noradrenaline and Ca2+ and the relaxation of a variety of arteries induced by amrinone may not be due to interference with the transmembrane influx of Ca2+ and intracellular accumulation of cyclic AMP but to a nonspecific action on arterial smooth muscle. Amrinone appears to increase the metabolic vasodilatation by potentiating the vasodilator action of adenosine.
Assuntos
Aminopiridinas/farmacologia , Artérias/efeitos dos fármacos , Cardiotônicos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Adenosina/farmacologia , Amrinona , Animais , Cálcio/antagonistas & inibidores , Dinoprosta , Cães , Relação Dose-Resposta a Droga , Estimulação Elétrica , Feminino , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Norepinefrina/antagonistas & inibidores , Potássio/antagonistas & inibidores , Prostaglandinas F/antagonistas & inibidoresRESUMO
Contractile responses to 30 mmol . litre-1 K+ of helical strips of coronary arteries from human cadavers did not change within 5 h after death; however, they were suppressed 8 h after death. In coronary arteries from monkey cadavers, the K+-induced contractions did not significantly differ within the first 5 h, but were suppressed 12 h after death. On the other hand, K+-induced contractions were retained without deterioration in cerebral artery strips from human cadavers 20 to 24 h after death and those from monkey cadavers 8 to 16 h. Acetylcholine caused contractions of human coronary arteries, but caused only a relaxation of monkey coronaries which was abolished by rubbing off the endothelium. These responses were attenuated by no more than K+-induced contractions up to 12 h after death. Maximum contractions induced by noradrenaline, histamine and serotonin remained the same in human coronary arteries for 3 to 5 h after death. Similar magnitudes of contraction were elicited by noradrenaline in human cerebral arteries up to 20 h after death. It appears that the reactivity of human coronary arteries to K+ and other vasoconstrictor agents used is normally retained for at least 6 h after death and that of human cerebral arteries up to 24 h.
Assuntos
Artérias Cerebrais/patologia , Vasos Coronários/patologia , Mudanças Depois da Morte , Adolescente , Adulto , Idoso , Animais , Artérias Cerebrais/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Feminino , Histamina/farmacologia , Humanos , Macaca , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Norepinefrina/farmacologia , Serotonina/farmacologia , Fatores de TempoRESUMO
Physiological importance in vasodilator innervation alleviating noradrenergic neurogenic vasoconstriction has not been clarified. Isolated monkey mesenteric artery strips denuded of the endothelium responded to nerve stimulation by electrical pulses or nicotine with a contraction, which was potentiated by Ng-nitro-L-arginine, a nitric oxide synthesis inhibitor, but not by the D-enantiomer. The potentiation was abolished by L-arginine. NG-Nitro-L-arginine did not potentiate the response to exogenous norepinephrine nor did it increase the release of [3H]norepinephrine from adrenergic nerves electrically stimulated. The contraction was reversed by treatment with phentolamine and guanethidine to a relaxation, which was abolished by NG-nitro-L-arginine. The inhibition was reversed by L- but not D-arginine. The relaxant response was not influenced by atropine, timolol, or indomethacin. These findings strongly suggest the importance of reciprocal nitric oxide-related (nitroxidergic) vasodilator and noradrenergic vasoconstrictor innervation in the regulation of monkey arterial tone.
Assuntos
Artérias Mesentéricas/fisiologia , Fenômenos Fisiológicos do Sistema Nervoso , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Estimulação Elétrica , Feminino , Macaca , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/inervação , Nicotina/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Nitroarginina , Concentração OsmolarRESUMO
This study aimed to determine the mechanism of hypertension associated with nitric oxide synthase inhibition. Intravenous injections of NG-nitro-L-arginine, a nitric oxide synthase inhibitor, produced a sustained increase in systemic blood pressure and a decrease in heart rate in anesthetized dogs, whereas NG-nitro-D-arginine had no effect. L-Arginine reversed the pressor response. NG-Nitro-L-arginine-induced hypertension was markedly attenuated or abolished by treatment with hexamethonium; this inhibition was still observed when the blood pressure fall caused by the ganglionic blocking agent was compensated by continuous infusion of angiotensin II. In dogs treated with phentolamine in a dose sufficient to lower blood pressure to the level similar to that elicited by hexamethonium and to suppress the pressor response to norepinephrine, the hypertensive effect of NG-nitro-L-arginine was not attenuated. We conclude that hypertension caused by the nitric oxide synthase inhibitor is associated with an elimination of nitroxidergic neural function rather than an impairment of the basal release of nitric oxide from the endothelium.
Assuntos
Aminoácido Oxirredutases/antagonistas & inibidores , Arginina/análogos & derivados , Hipertensão/fisiopatologia , Animais , Arginina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hexametônio , Compostos de Hexametônio/farmacologia , Masculino , Óxido Nítrico Sintase , Nitroarginina , Fentolamina/farmacologiaRESUMO
We analyzed mechanisms underlying neurogenic vasodilatation in dog and Japanese monkey renal arteries. Isometric mechanical responses of the arterial strip to nerve stimulation by nicotine were recorded. Nicotine-induced contractions were abolished by hexamethonium and potentiated by NG-nitro-L-arginine, a nitric oxide synthase inhibitor. The potentiating effect was reversed by L-arginine. NG-Nitro-L-arginine did not potentiate the contraction caused by norepinephrine. The nicotine-induced contraction was reversed to a relaxation by prazosin. The relaxation was not influenced by indomethacin, timolol, or atropine but was abolished by NG-nitro-L-arginine, methylene blue (a guanylate cyclase inhibitor), oxyhemoglobin (a nitric oxide scavenger), and hexamethonium. In the strips treated with NG-nitro-L-arginine, the nicotine-induced relaxation was restored by L-arginine. Histochemical study demonstrated perivascular nerves containing NADPH diaphorase and nitric oxide synthase immunoreactivity in dog and monkey arteries. We conclude that renal arteries are innervated by nitric oxide-mediated vasodilator and adrenergic vasoconstrictor nerves, and depression of the vasodilator nerve function by nitric oxide synthase inhibition potentiates the contraction caused by adrenergic nerve excitation.
Assuntos
Óxido Nítrico/fisiologia , Artéria Renal/inervação , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Cães , Feminino , Técnicas In Vitro , Macaca , Masculino , Nicotina/farmacologia , Nitroarginina , Artéria Renal/fisiologia , Vasoconstrição/efeitos dos fármacosRESUMO
Intravenous injection of NG-nitro-L-arginine (L-NA), a nitric oxide synthase inhibitor, elevated mean blood pressure by 29.0 +/- 4.9 mm Hg and decreased heart rate by 40.7 +/- 5.6 beats per minute in anesthetized Japanese monkeys (n = 6), whereas NG-nitro-D-arginine was without effect. After pretreatment with pentolinium, the magnitude of the pressure elevation by L-NA was significantly less than that after pretreatment with phentol-amine. The reduced blood pressure by either of the pretreatment drugs was compensated to control levels by a continuous infusion of angiotensin II before L-NA administration. Isolated monkey distal mesenteric arteries (150 to 200 microns OD) without endothelium responded to nerve stimulation by nicotine with a contraction, which was abolished by prazosin alone or in combination with alpha, beta-methylene ATP. In the strips thus treated and contracted with prostaglandin F2 alpha, nicotine caused a relaxation that L-NA abolished. L-NA but not NG-nitro-D-arginine reversed the inhibition. Histochemical staining of NADPH diaphorase, considered to be identical to nitric oxide synthase in neuronal tissues, demonstrated that positively stained nerve fibers were consistently present in the adventitia of monkey distal mesenteric arteries and arterioles. These results strongly suggest that nitroxidergic vasodilator nerves innervate peripheral small arteries and arterioles in the monkey and that these nerves participate in the regulation of systemic blood pressure. High blood pressure caused by nitric oxide synthase inhibitors is associated with an elimination of nitroxidergic nerve function together with an impairment of the basal release of nitric oxide from the endothelium.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/farmacologia , Animais , Artérias/inervação , Feminino , Histocitoquímica , Técnicas In Vitro , Macaca , Masculino , NADPH Desidrogenase/metabolismo , Fibras Nervosas/enzimologia , Nicotina/farmacologia , Estimulação Química , VasoconstriçãoRESUMO
The possible role of the renin-angiotensin system in the maintenance of hypertension in two-kidney, one clip hypertensive rats was studied. Plasma renin activity rose rapidly and markedly in association with the elevation of blood pressure and then decreased gradually, although blood pressure remained high. Renin activity in the lung, aorta, and mesenteric artery also increased with the development of hypertension and then decreased in a way similar to that of plasma renin activity at the chronic stage of hypertension. Plasma angiotensin converting enzyme activity did not change significantly until 16 weeks after unilateral renal artery clipping, whereas vascular angiotensin converting enzyme activity significantly increased at the chronic, but not the acute, stage of hypertension. In chronically renal hypertensive rats, 1-sarcosine, 8-isoleucine angiotensin II or enalapril, an angiotensin converting enzyme inhibitor, lowered the blood pressure and enalapril also lowered the angiotensin converting enzyme activity of vascular tissues. The constrictor effect of angiotensin I was greater in isolated arteries from chronically hypertensive rats than in those from age-matched normotensive rats. These results suggest that the vascular renin-angiotensin system plays an important role in the maintenance of two-kidney, one clip hypertension. Elevated vascular angiotensin converting enzyme activity appears to increase local production of angiotensin II, which results in vasoconstriction by acting directly and indirectly through adrenergic nerves on vascular smooth muscle.