RESUMO
BACKGROUND AND PURPOSE: Arterial stiffness is reported to be able to cause axonal demyelination or degeneration. The present study aimed to use advanced MR imaging techniques to examine the effect of arterial stiffness on the WM microstructure among older adults. MATERIALS AND METHODS: Arterial stiffness was measured using the cardio-ankle vascular elasticity index (CAVI). The high-CAVI (mean CAVI ≥ 9 points) and the low-CAVI groups (mean CAVI < 9 points) were created. The neuronal fiber integrity of the WM was evaluated by neurite orientation dispersion and density imaging and magnetization transfer saturation imaging. Tract-Based Spatial Statistics and the tracts-of-interest analysis were performed. Specific WM regions (corpus callosum, internal capsule, anterior thalamic radiation, corona radiata, superior longitudinal fasciculus, forceps minor, and inferior fronto-occipital fasciculus) were selected in the tracts-of-interest analysis. RESULTS: In Tract-Based Spatial Statistics, the high-CAVI group showed a significantly lower myelin volume fraction value in the broad WM and significantly higher radial diffusivity and isotropic volume fraction values in the corpus callosum, forceps minor, inferior fronto-occipital fasciculus, internal capsule, corona radiata, and anterior thalamic radiation than the low-CAVI group. In tracts-of-interest analysis using multivariate linear regression, significant associations were found between the mean CAVI and radial diffusivity in the anterior thalamic radiation and the corona radiata; isotropic volume fraction in the anterior thalamic radiation and the corona radiata; and myelin volume fraction in the superior longitudinal fasciculus (P < .05). Additionally, partial correlation coefficients were observed for the significant associations of executive function with radial diffusivity and myelin volume fraction (P < .05). CONCLUSIONS: Arterial stiffness could be associated with demyelination rather than axonal degeneration.
Assuntos
Doenças Desmielinizantes , Rigidez Vascular , Substância Branca , Humanos , Idoso , Neuritos , Imagem de Tensor de Difusão/métodos , Imageamento por Ressonância Magnética/métodos , Substância Branca/diagnóstico por imagem , Encéfalo/diagnóstico por imagemRESUMO
A 76-year-old woman with recurrent ball-like thrombus in right atrium after primary repair of atrial septal defect (ASD) and tricuspid annuloplasty was successfully treated by surgical resection and strict management of anticoagulation and antiarrhythmics. A routine follow-up echocardiography, 27 months after initial operation, showed a swinging ball mass looks like a myxoma in the right atrium. Intra-operative findings showed the mass attached the free wall of right atrium with a 5 mm stalk, which was far from the ASD patch, initial suture lines, and the tricuspid annulus. Histological examination revealed the round and smooth mass was thrombus. She was successfully discharged 13 days after the 2nd operation without any complaint. A postoperative laboratory check demonstrated normal coagulability. Despite the patient was prescribed warfarin potassium and aspirin, the follow-up echocardiography at 3 months showed a recurrent thrombus in the right atrium. However the strict anticoagulation therapy with warfarin potassium and aspirin induced thrombolysis and prevent any embolic event, 1 month later. It is important to continue a strict anticoagulant therapy and prevent arrhythmia to avoid recurrence thrombus.
Assuntos
Cardiopatias/etiologia , Comunicação Interatrial/cirurgia , Trombose/etiologia , Idoso , Anticoagulantes/uso terapêutico , Feminino , Seguimentos , Átrios do Coração , Cardiopatias/tratamento farmacológico , Humanos , Complicações Pós-Operatórias , Recidiva , Trombose/tratamento farmacológicoRESUMO
We report here the temperature-dependent unoccupied molecular orbitals (MO's) of C60 molecules adsorbed on a Si(001)-(2 x 1) surface measured using near edge x-ray absorption fine structure (NEXAFS). At 300 K, the NEXAFS spectrum reveals that the interaction between a 1.0 monolayer (ML) C60 film and a Si(001) surface is mainly the van der Waals force. After annealing the samples at 500 K, we observe an increment in the full-width at half-maximum of unoccupied MO's, which indicates the change of the interaction. Moreover, the lowest unoccupied molecular orbital (LUMO) shifts to the higher photon energy side and the intensity of the LUMO+1 relative to that of the LUMO+3 decreases in the NEXAFS spectrum. These results suggest that the strong interaction induced at 500 K has a covalent character, to which the LUMO+1 contributes.
RESUMO
YM471, (Z)-4'-[4,4-difluoro-5-[2-(4-dimethylaminopiperidino)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl]-2-phenylbenzanilide monohydrochloride, is a newly synthesized potent vasopressin (AVP) receptor antagonist. Its effects on binding to and signal transduction by cloned human AVP receptors (V(1A), V(1B) and V(2)) stably expressed in Chinese hamster ovary (CHO) cells, and oxytocin receptors in human uterine smooth muscle cells (USMC) were studied. YM471 potently inhibited specific [(3)H]-AVP binding to V(1A) and V(2) receptors with K(i) values of 0.62 nM and 1.19 nM, respectively. In contrast, YM471 exhibited much lower affinity for V(1B) and oxytocin receptors with K(i) values of 16.4 microM and 31.6 nM, respectively. In CHO cells expressing V(1A) receptors, YM471 potently inhibited AVP-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) increase, exhibiting an IC(50) value of 0.56 nM. However, in human USMC expressing oxytocin receptors, YM471 exhibited much lower potency in inhibiting oxytocin-induced [Ca(2+)](i) increase (IC(50)=193 nM), and did not affect AVP-induced [Ca(2+)](i) increase in CHO cells expressing V(1B) receptors. Furthermore, in CHO cells expressing V(2) receptors, YM471 potently inhibited the production of cyclic AMP stimulated by AVP with an IC(50) value of 1.88 nM. In all assays, YM471 showed no agonistic activity. These results demonstrate that YM471 is a potent, nonpeptide human V(1A) and V(2) receptor antagonist which will be a valuable tool in defining the physiologic and pharmacologic actions of AVP.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Azepinas/farmacologia , Músculo Liso/efeitos dos fármacos , Piperidinas/farmacologia , Receptores de Ocitocina/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Arginina Vasopressina/metabolismo , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cricetinae , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Indóis/farmacologia , Morfolinas/farmacologia , Músculo Liso/citologia , Músculo Liso/metabolismo , Ocitocina/metabolismo , Pirrolidinas/farmacologia , Ensaio Radioligante , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/metabolismo , Compostos de Espiro/farmacologia , Trítio , Útero/metabolismoRESUMO
OBJECTIVE: To assess age-related changes in bladder function using the contractile responses to ATP of detrusor strips from rats of various ages. Materials and methods Urinary bladders were obtained from male Wistar rats aged 9 weeks (young), 24 weeks (adult) and 24 months (aged). Contractions of urinary bladder muscle strips to ATP were measured isometrically. The size of the initial phasic response and the secondary contractile response that developed after washing out ATP (postwashout contraction) were measured. The magnitudes of the ATP-induced phasic and postwashout contraction were compared among the age groups. During the contractions, prostanoid concentrations in the organ-bath medium were measured using an enzyme immunoassay. RESULTS: The ATP-induced postwashout contraction did not occur after stimulation with KCl or acetylcholine, but was induced by alpha,beta-methylene ATP. Both the phasic and postwashout contractions were concentration-dependent. Although the phasic contraction did not change progressively with age, the magnitude and duration of the postwashout contraction increased substantially with age. Nicardipine (a calcium antagonist) slightly inhibited both contractions. Suramin (a nonselective P2-receptor antagonist) did not significantly inhibit the phasic contraction, but reduced the postwashout contraction. PPADS (a selective P2X receptor antagonist) did not inhibit either contraction. Indomethacin (a prostaglandin synthesis inhibitor) had no effect on the phasic contraction but almost completely blocked the postwashout contraction when added before ATP stimulation, but was less effective when added after ATP. The prostaglandin E2 concentration in the organ bath increased during the postwashout contraction. CONCLUSIONS: These findings suggest that the ATP-induced postwashout contraction is not directly mediated by P2x purinoceptors, but results from the synthesis of prostaglandins, especially E2, which is a sensory autacoid. The age-linked increase in postwashout contraction may be involved in the changes in sensory and voiding mechanisms seen in the aged urinary bladder.
Assuntos
Trifosfato de Adenosina/farmacologia , Envelhecimento/fisiologia , Bexiga Urinária/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Relação Dose-Resposta a Droga , Ácido Egtázico/farmacologia , Masculino , Contração Muscular/efeitos dos fármacos , Nicardipino/farmacologia , Antagonistas Purinérgicos , Ratos , Ratos WistarRESUMO
A retrospective study on medically compromised patients was made using 1,000 outpatients who visited the Clinic for Oral Implant, University Hospital, Faculty of Dentistry, Tokyo Medical and Dental University between April 1995 and June 1998. The results were as follows: 1. 35.3% (353 patients: 140 males and 213 females) of the outpatients were medically compromised. 2. The greatest number of medically compromised patients was in the 50-59 age group (118 cases), followed by those in the 40-49 and 60-69 age groups. 3. The highest ratio of medically compromised patients was in the 60-69 age group (48.2%), followed by those in the 70-79 and 50-59 age groups. 4. Among the 353 patients, 96 (27.2%) underwent surgical treatment such as insertion of implant (68 cases), removal of implant, extraction of tooth, and free gingival graft. 5. Among the 68 patients who underwent insertion of implant, in a classification by type of disease, the patients with cardiovascular diseases were the most numerous (33.9%), followed by metabolic and digestive tract diseases. 6. All surgical treatments of implant insertion were performed under local anesthesia, while monitoring cardiac and respiratory function, and SpO2. Among the 68 patients, 9 underwent operation under intravenous sedation and 2 under nitrous oxide inhalation sedation. All 11 patients had hypertension. The results suggested that identification of preoperative risk factors, precise recognition of general condition, and establishment of control system are important to manage medically compromised patients for dental implant treatment.
Assuntos
Implantes Dentários/estatística & dados numéricos , Adulto , Idoso , Asma/complicações , Doenças Cardiovasculares/complicações , Feminino , Hepatite/complicações , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The effects of the angiotensin II type 1 receptor antagonist YM358 on blood pressure were compared to those of the angiotensin converting enzyme inhibitor enalapril in one-kidney, one-clip renal hypertensive rats (1K1C RHR), two-kidney, one-clip renal hypertensive rats (2K1C RHR) and normotensive rats (NTR). Additionally, the local drug actions in peripheral tissues were investigated using isolated mesenteric arteries from these rats. In 2K1C RHR, YM358 and enalapril produced a long-lasting hypotensive effect in a dose-dependent manner. In 1K1C RHR, YM358 (30 mg/kg) also produced an antihypertensive effect, whereas enalapril (30 mg/kg) had no effect. Administration of YM358, but not enalapril, to 1K1C RHR, 2K1C RHR and NTR did not affect heart rate. In isolated mesenteric arteries from 1K1C RHR and 2K1C RHR, angiotensin II (Ang II), angiotensin I (Ang I) and tetradecapeptide (TDP), a physiologically active renin substrate, produced concentration-dependent vasoconstriction. YM358 (10(-7) M) inhibited the vasoconstricting responses to Ang II, Ang I and TDP in isolated mesenteric arteries. In contrast, enalaprilat (10(-7) M), an active metabolite of enalapril, did not completely inhibit the response to Ang I and TDP. These results indicate that YM358 has higher efficacy than enalapril for the treatment of hypertension.
Assuntos
Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Azóis/farmacologia , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Enalapril/farmacologia , Hipertensão Renovascular/fisiopatologia , Vasoconstrição/efeitos dos fármacos , Angiotensina I/farmacologia , Angiotensina II/farmacologia , Animais , Frequência Cardíaca/efeitos dos fármacos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Renina/sangue , Renina/fisiologia , Circulação EsplâncnicaRESUMO
[(3)H]-oxytocin was used to characterize the oxytocin receptor found in human uterine smooth muscle cells (USMC). Specific binding of [(3)H]-oxytocin to USMC plasma membranes was dependent upon time, temperature and membrane protein concentration. Scatchard plot analysis of equilibrium binding data revealed the existence of a single class of high-affinity binding sites with an apparent equilibrium dissociation constant (K(d)) of 0.76 nM and a maximum receptor density (B(max)) of 153 fmol mg(-1) protein. The Hill coefficient (n(H)) did not differ significantly from unity, suggesting binding to homogenous, non-interacting receptor populations. Competitive inhibition of [(3)H]-oxytocin binding showed that oxytocin and vasopressin (AVP) receptor agonists and antagonists displaced [(3)H]-oxytocin in a concentration-dependent manner. The order of potencies for peptide agonists and antagonists was: oxytocin>[Asu(1,6)]-oxytocin>AVP= atosiban>d(CH(2))(5)Tyr(Me)AVP>[Thr(4),Gly(7)]-oxytocin>dDAVP, and for nonpeptide antagonists was: L-371257>YM087>SR 49059>OPC-21268>SR 121463A>OPC-31260. Oxytocin significantly induced concentration-dependent increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) and hyperplasia in USMC. The oxytocin receptor antagonists, atosiban and L-371257, potently and concentration-dependently inhibited oxytocin-induced [Ca(2+)](i) increase and hyperplasia. In contrast, the V(1A) receptor selective antagonist, SR 49059, and the V(2) receptor selective antagonist, SR 121463A, did not potently inhibit oxytocin-induced [Ca(2+)](i) increase and hyperplasia. The potency order of antagonists in inhibiting oxytocin-induced [Ca(2+)](i) increase and hyperplasia was similar to that observed in radioligand binding assays. In conclusion, these data provide evidence that the high-affinity [(3)H]-oxytocin binding site found in human USMC is a functional oxytocin receptor coupled to [Ca(2+)](i) increase and cell growth. Thus human USMC may prove to be a valuable tool in further investigation of the physiologic and pathophysiologic roles of oxytocin in the uterus. British Journal of Pharmacology (2000) 129, 131 - 139
Assuntos
Músculo Liso/efeitos dos fármacos , Receptores de Ocitocina/efeitos dos fármacos , Útero/efeitos dos fármacos , Antagonistas dos Receptores de Hormônios Antidiuréticos , Arginina Vasopressina/farmacologia , Ligação Competitiva/efeitos dos fármacos , Cálcio/metabolismo , Contagem de Células , Divisão Celular/efeitos dos fármacos , Feminino , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Técnicas In Vitro , Cinética , Ligantes , Músculo Liso/citologia , Ocitocina/análogos & derivados , Ocitocina/farmacologia , Receptores de Ocitocina/agonistas , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Vasopressinas/agonistas , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Útero/citologia , Vasoconstritores/farmacologiaRESUMO
Effects of extracellular anions were studied in electrophysiological experiments on freshly isolated rat ventricular myocytes. Under current-clamp, action potential duration (APD) was prolonged by reducing the extracellular Cl(-) concentration and shortened by replacement of extracellular Cl(-) with I(-). Under voltage-clamp, membrane potential steps or ramps evoked an anionic background current (I(AB)) carried by either Cl(-), Br(-), I(-) or NO(3)(-). Activation of I(AB) was Ca(2+)- and cyclic AMP-independent, and was unaffected by cell shrinkage. I(AB) was insensitive to stilbene and fenamate anion transport blockers at concentrations that inhibit Ca(2+)-, cyclic AMP- and swelling-activated Cl(-) currents in ventricular cells of other mammals. These results suggest that I(AB) may be carried by a novel class of Cl(-) channel. Correlation of anion substitution experiments on membrane current and action potentials revealed that I(AB) could play a major role in controlling rat ventricular APD. These findings have important implications for those studying cardiac Cl(-) channels as potential targets for novel antiarrythmic agents.
Assuntos
Canais de Cloreto/fisiologia , Coração/fisiologia , Miocárdio/citologia , Miocárdio/metabolismo , Ácido 4,4'-Di-Isotiocianoestilbeno-2,2'-Dissulfônico/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Cálcio/metabolismo , Tamanho Celular/efeitos dos fármacos , Canais de Cloreto/efeitos dos fármacos , Estimulação Elétrica , Eletrofisiologia , Coração/efeitos dos fármacos , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Técnicas In Vitro , Ácido Niflúmico/farmacologia , Técnicas de Patch-Clamp , Ratos , Função VentricularRESUMO
We examined the change in cardiac sympathetic function in the hibernating heart. To induce hibernating hearts in dogs, we placed a nylon tube via the carotid artery in the left circumflex artery (LCx) and obstructed the LCx flow. The plasma norepinephrine (NE) and epinephrine (E) concentrations in the coronary sinus and the aorta were measured before and 1 week after the tube placement to evaluate the catecholamine release from the heart. The wall motion was followed by echocardiography and. 1 week after the tube placement, regional myocardial blood flow (RBF) was measured using colored microspheres. Also. the restorability of myocardial dysfunction was examined in other dogs by extracting the LCx tube 1 week after the placement. Finally, the heart was removed for pathological observation and dogs showing myocardial infarction were excluded. One week after placing the tube, wall thickening was reduced in the LCx area, but was not in the left anterior descending (LAD) area. Compared with the LAD area, RBF in the LCx area was decreased in the endocardium (p < 0.05), but was not in the epicardium. In other dogs, the reduced wall thickening in the LCx area was restored to normal levels 1 or 2 weeks after the tube extraction. Thereby, our dogs with the tube placed were considered to be models of myocardial hibernation. The plasma NE and E concentrations were not significantly changed by placing the tube, but NE release from the heart was increased after the tube placement (p < 0.05). E uptake from the heart did not differ. Therefore, it is suggested that NE release is increased in the hibernating heart and may contribute to its mechanism.
Assuntos
Modelos Animais de Doenças , Miocárdio Atordoado/metabolismo , Miocárdio/metabolismo , Norepinefrina/metabolismo , Animais , Doença Crônica , Circulação Coronária , Cães , Miocárdio/patologiaRESUMO
BACKGROUND: We describe a simple method using membrane potential ramps for rapidly determining the ion-channel selectivity of drugs that affect action-potential duration in isolated cardiac myocytes. The method allows the simultaneous assay of compounds on a number of ionic currents in a single cardiac cell. METHODS: Trains of membrane potential ramps were applied from -90 to +70 mV at 0.33 Hz to obtain a consistent "signature current," in which the major individual currents involved in the cardiac action potential could be easily identified. Confirmatory experiments were performed using known inhibitors of these currents. RESULTS: The identities of the currents in the signature were established by varying the concentrations of extracellular cations and by adding known ion channel blockers to superfusion solutions. Inhibition of each current had a characteristic and reproducible effect on the overall signature current. CONCLUSIONS: The consistent current signature in the presence and absence of blockers suggests that this method could be used for tertiary electrophysiological evaluation of compounds, eg, in a drug discovery program focusing on antiarrhythmic agents. The ability to assay for secondary effects of novel compounds against multiple currents in the target cell type is convenient and avoids the artefacts associated with using artificial expression systems.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Coração/efeitos dos fármacos , Canais Iônicos/antagonistas & inibidores , Potenciais de Ação/fisiologia , Animais , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Técnicas de Patch-Clamp/métodos , Ratos , Ratos WistarRESUMO
Radioligand binding studies with [3H]vasopressin (AVP) were used to determine the affinities of AVP receptor agonists and antagonists for mouse liver and kidney plasma membrane preparations. Both membrane preparations exhibited one class of high-affinity binding site. AVP ligand binding inhibition studies confirmed that mouse liver binding sites belong to the V1A subtype while kidney binding sites belong to the V2 receptor subtype. The affinity of each ligand for mouse V1A receptors was very similar to that for rat V1A receptors, showing differences in Ki values of less than 3-fold. In contrast, several peptide (d(CH2)5Tyr(Me)AVP) and nonpeptide (OPC-21268 and SR 49059) ligands had different affinities for mouse and rat kidney V2 receptors, with differences in Ki values ranging from 14- to 17-fold. These results indicate that mouse and rat kidney V2 receptors show significant pharmacologic differences.
Assuntos
Rim/metabolismo , Fígado/metabolismo , Receptores de Vasopressinas/metabolismo , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Arginina Vasopressina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ligação Proteica , Ensaio Radioligante , Ratos , Especificidade da EspécieRESUMO
Several studies indicate that oxytocin and vasopressin receptors in the human uterus are heterogeneous. We have investigated whether oxytocin and vasopressin bind to separate receptors or one class of receptors in human uterine smooth muscle cells. [3H]d(CH2)5Tyr(Me)AVP, the vasopressin V1A receptor selective radioligand, was used for comparison of vasopressin binding sites in human uterine and vascular smooth muscle cell membranes. Both membrane preparations exhibited one class of high-affinity binding sites with Kd values of 6.44 and 0.47 nM, Bmax values of 166 and 34.8 fmol/mg protein for uterine and vascular smooth muscle cells, respectively. In vascular preparations, the selective vasopressin V1A receptor antagonist, SR 49059 ((2S) 1-[(2R 3S)-(5-chloro-3-(2-chlorophenyl)- -(3.4-dimethoxybenzenesulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2- carbonyl]-pyrrolidine-2-carboxamide), showed high affinity with Ki value of 0.98 nM, confirming that these receptors belong to the vasopressin V1A receptor subtype. On the contrary, in uterine preparations, binding of [3H]d(CH2)5Tyr(Me)AVP was more effectively displaced by oxytocin and the oxytocin receptor selective antagonist, L-371257, (1-[1-[4-[ N-Acetyl-4-piperidinyl)oxy]2-methoxybenzoyl]piperidin-4-yl]- 4H-3,1-benzoxazin-2(1H)-one), than vasopressin and SR 49059, suggesting that binding may be due to cross-reaction with the oxytocin receptors. These results suggest that human uterine smooth muscle cells express only a high density of oxytocin receptors.
Assuntos
Músculo Liso Vascular/metabolismo , Miométrio/metabolismo , Receptores de Vasopressinas/metabolismo , Vasopressinas/metabolismo , Sítios de Ligação , Feminino , Humanos , Músculo Liso Vascular/citologia , Ensaio Radioligante , TrítioRESUMO
The systemic hemodynamic and renal responses to conivaptan hydrochloride (YM087; 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine -6-carbonyl)-2-phenylbenzanilide monohydrochloride), a vasopressin V1A and V2 receptor antagonist, were determined in pentobarbital-anesthetized dogs after 2 to 3 weeks of rapid right ventricular pacing. Congestive heart failure, characterized by decreases in first derivative of left ventricular pressure (left ventricular d P/dt(max)) and cardiac output, and increases in left ventricular end-diastolic pressure and total peripheral vascular resistance, was induced by chronic rapid right ventricular pacing at 260-280 beats/min. Intravenous administration of conivaptan (0.1 mg/kg) significantly increased left ventricular dP/dt(max) and cardiac output and significantly decreased left ventricular end-diastolic pressure and total peripheral vascular resistance. Conivaptan also increased urine flow and reduced urine osmolality by markedly increasing free water clearance. These results indicate that conivaptan produced hemodynamic improvement and marked aquaresis in dogs with congestive heart failure. Therefore, conivaptan may find clinical use in treating patients with congestive heart failure.
Assuntos
Benzazepinas/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Diurese/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Receptores de Vasopressinas/uso terapêutico , Fármacos Renais/uso terapêutico , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/urina , Estimulação Cardíaca Artificial , Fármacos Cardiovasculares/urina , Cães , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Masculino , Fármacos Renais/urinaRESUMO
The present study was undertaken to examine whether the ATP-sensitive potassium channel opener, YM934, would be effective in reducing infarct size in a model of myocardial infarction in anesthetized dogs. For this purpose the effects of nifedipine, a calcium channel blocker, and hydralazine, a vasodilator with unknown mechanisms, were also investigated for comparison. Severe, irreversible myocardial injury was produced by a 90-min occlusion of the proximal left anterior descending coronary artery followed by 5 h of reperfusion. Infusion of YM934 (0.1 microg/kg/min i.c.) during the last 15 min of pre-ischemia reduced the myocardial infarct size and attenuated the release of creatine kinase MB eluted from the hearts without alteration in hemodynamic parameters including regional myocardial blood flow. In contrast, the other vasodilators, hydralazine and nifedipine, did not reduce myocardial infarct size under the same coronary vasodilatory conditions. These observations indicate that intracoronary YM934 is cardioprotective and that this effect is independent of alterations in regional myocardial blood flow.
Assuntos
Óxidos N-Cíclicos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Oxazinas/uso terapêutico , Canais de Potássio/uso terapêutico , Animais , Benzoxazinas , Bloqueadores dos Canais de Cálcio/uso terapêutico , Vasos Coronários/efeitos dos fármacos , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Hemodinâmica/efeitos dos fármacos , Hidralazina/uso terapêutico , Masculino , Infarto do Miocárdio/patologia , Nifedipino/uso terapêutico , Vasodilatadores/uso terapêuticoRESUMO
1. YM087 is a newly synthesized non-peptide arginine vasopressin (AVP) antagonist that shows high affinity for both V1A and V2 receptors. In the present study, the V1A and V2 receptor antagonist effects of orally administered YM087 were assessed in conscious rats. 2. In conscious rats, orally administered YM087 (0.1, 0.3 and 1.0 mg/kg) did not affect basal blood pressure, but YM087 dose-dependently inhibited 30 mU/kg, i.v., AVP-induced pressor responses. This inhibition lasted for over 8 h following the oral administration of the highest dose of YM087 (1 mg/kg). 3. In rats deprived of water and food for 16-18 h, oral administration of YM087 (0.1, 0.3, 1 and 3 mg/kg) dose-dependently increased urine volume and reduced urine osmolality, with associated increases in urinary sodium and potassium excretion. However, these increases in electrolyte excretion were lower than those seen at comparable diuretic doses of furosemide (3, 10, 30 and 100 mg/kg, p.o.). 4. Oral administration of YM087 (0.3, 1 and 3 mg/kg) produced a dose-dependent increase in urine volume in rats allowed free access to water, with the diuretic effect peaking 2-4 h post-dosing at all dose levels. The diuretic effect of YM087 was sustained 8-10 h after a dose of 3 mg/kg; this is in contrast with the transient diuresis seen after furosemide (100 mg/kg, p.o.) dosing. 5. The present results demonstrate that YM087 is an orally active AVP antagonist with potent and long-lasting effects. YM087 suppressed V1A receptor-mediated pressor responses to AVP with minimal effects on basal haemodynamics and exerted a diuretic effect without increased electrolyte excretion by inhibiting V2 receptor-mediated water reabsorption.
Assuntos
Benzazepinas/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Urinário/efeitos dos fármacos , Vasopressinas/antagonistas & inibidores , Administração Oral , Animais , Arginina Vasopressina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Fatores de Tempo , Micção/efeitos dos fármacosRESUMO
The effects of YM934 [2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl) pyridine N-oxide], an adenosine triphosphate (ATP)-sensitive potassium channel opener, on stunned myocardium were examined. Forty eight anesthetized dogs were subjected to 15 min of left anterior descending (LAD) coronary artery occlusion followed by 3 hours of reperfusion. To elucidate the possible contribution of the cardioprotective property of YM934 to stunned myocardium, a nonhypotensive dose of YM934 was directly injected into the LAD coronary artery before the ischemic insults. Intracoronary artery infusion (i.c.) of YM934 (0.1 microg/kg/min) produced a marked improvement in post-ischemic regional contractile dysfunction. The effects were not associated with improvement of hemodynamics, including regional myocardial blood flow during ischemia, heart rate and mean arterial blood pressure. The anatomic areas at risk expressed as a percentage of the left ventricle and regional myocardial blood flow were not significantly different between groups. The cardioprotective effect of YM934 was completely blocked by pretreatment with an ATP-sensitive potassium channel blocker, glibenclamide (1.0 mg/kg i.v. bolus). These results suggest that YM934 exerts cardioprotective effect on stunned myocardium through opening myocardial ATP-sensitive potassium channels.
Assuntos
Trifosfato de Adenosina/fisiologia , Óxidos N-Cíclicos/farmacologia , Miocárdio Atordoado/prevenção & controle , Oxazinas/farmacologia , Canais de Potássio/farmacologia , Anestesia , Animais , Benzoxazinas , Circulação Coronária/efeitos dos fármacos , Cães , Feminino , Glibureto/farmacologia , Hemodinâmica/efeitos dos fármacos , Hidrazinas/farmacologia , Hipoglicemiantes/farmacologia , Masculino , Miocárdio Atordoado/patologia , Miocárdio Atordoado/fisiopatologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Vascular endothelial growth factor (VEGF) is a potent and specific mitogen of vascular endothelial cells which promotes neovascularization in vitro. To determine whether vasopressin induces VEGF secretion in human vascular smooth muscle cells, we performed enzyme-linked immunosorbent assays. Vasopressin potently induced a time-dependent and concentration-dependent (maximal, 10(-7) M) increase in VEGF secretion by human vascular smooth muscle cells that was maximal after 24 h. Furthermore, vasopressin also concentration-dependently caused mitogenic effect, as reflected by total protein content of cells per culture well. These vasopressin-induced VEGF secretion increase and mitogenic effect of these cells were potently inhibited by vasopressin V1A receptor antagonists, confirming this is a vasopressin V1A receptor-mediated event. These results indicate that vasopressin increases VEGF secretion in human vascular smooth muscle cells, the magnitude of VEGF secretion being temporally related to the mitogenic effect of vascular smooth muscle cells and the potency of the growth-promoting stimulus. Vasopressin-induced VEGF secretion by proliferating vascular smooth muscle cells could act as a paracrine hormone to powerfully influence the permeability and growth of the overlying vascular endothelium, vasopressin play a more fundamental role in the regulation of vascular function than has previously been recognized.
Assuntos
Fatores de Crescimento Endotelial/farmacologia , Linfocinas/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasopressinas/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Fatores de Crescimento Endotelial/metabolismo , Humanos , Indóis/farmacologia , Linfocinas/metabolismo , Morfolinas/farmacologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Pirrolidinas/farmacologia , Compostos de Espiro/farmacologia , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Arginine vasopressin (AVP) induces cell proliferation and hypertrophy; however, the human receptor subtype and the intracellular signaling pathways responsible for this mitogenic activity remain unclear. Experiments were conducted to determine which AVP receptor is linked to mitogen-activated protein (MAP) kinase activation and the mitogenic effect seen in Chinese hamster ovary (CHO) cells expressing human V1A or V1B receptors. Adding AVP to CHO cells transfected with human V1A or V1B cDNA significantly and concentration-dependently induced activation of MAP kinase and increased DNA synthesis, as measured by [3H]thymidine incorporation. These effects were inhibited by AVP receptor antagonists and the potency order of antagonists in vitro was similar to that observed in radioligand binding assays. These results suggest that AVP induces the MAP kinase cascade leading to cell proliferation through either human V1A or V1B receptors, and that these cloned, expressed AVP receptors may prove an invaluable tool for probing the physiologic and pathophysiologic effects of AVP.
Assuntos
Arginina Vasopressina/farmacologia , Mitógenos/farmacologia , Receptores de Vasopressinas/biossíntese , Animais , Células CHO , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Clonagem Molecular , Cricetinae , Humanos , Timidina/metabolismoRESUMO
1. The effects of (-)-(S)-4-(3,4-dihydroxyphenyl)- 1,2,3,4-tetrahydroisoquinoline-7,8-diol monohydrochloride monohydrate (YM435), a dopamine DA1 receptor agonist, were evaluated in a canine model of ischemic acute renal failure (ARF). 2. ARF was induced by clamping the left renal artery for 1 hr and subsequent reperfusion of the left kidney in anesthetized uninephrectomized dogs. 3. After 1-hr complete renal artery occlusion, an intravenous infusion of either YM435 (0.3 microg/kg/ min) or 0.9% saline (vehicle) was begun and continued for 1 hr. 4. In the vehicle group, renal ischemia markedly decreased glomerular filtration rate, urine flow and urinary sodium excretion. The YM435 group was characterized by significant recoveries in glomerular filtration rate, urine flow, and urinary sodium excretion as compared with the vehicle group. 5. These results indicate that YM435 can facilitate recovery in glomerular filtration rate, urine flow, and urinary sodium excretion in a canine model of ARF induced by ischemia. YM435 may be useful in the preservation of renal function in ischemia-induced ARF.