RESUMEN
Inhibition of proliferative neointima formed by vascular smooth muscle cells is a potential target in preventing angioplasty-induced restenosis. We have created a potent antiproliferative by fusing the active regions of the p27 and p16 cell cycle inhibitors. Intravascular delivery of a replication-deficient adenoviral vector (AV) encoding this p27-p16 fusion protein, named W9, inhibited balloon injury-induced neointimal hyperplasia in rabbit carotid arteries. In a therapeutically more relevant model, AV-W9 was delivered to balloon-injured porcine coronary arteries in vivo using an infusion catheter. Of the three coronary arteries, two were injured with a 15-mm balloon catheter and either were left untreated or were treated with 10(12) viral particles of either AV-W9 or a control null virus. AV-W9 treatment significantly inhibited neointimal hyperplasia in this porcine arterial balloon injury model compared with untreated or control virus-treated vessels. The average intimal area of the AV-W9-treated group 10 days after balloon injury and treatment was 0.42+/-0.36 mm(2), whereas the AV-null group demonstrated an intimal area of 0.70+/-0.52 mm(2). At day 10 the average intimal thickness of the AV-W9-treated vessels was 9.1 microm (n=5, x 20 magnification) compared with 21.2 microm (n=5, x 20 magnification) in control virus-treated vessels. This trend was also observed at 28 days after balloon injury and gene transfer during which AV-W9-treated vessels demonstrated an average intimal thickness of 4.7 microm (n=8, x 20 magnification) compared with 13.3 microm (n=3, x 20 magnification) in control virus-treated vessels and 7.3 microm (n=5, x 20 magnification) in the sham-treated vessels. The AV-W9 treatment was safe and well tolerated. These data suggest that AV-W9 gene therapy may be useful in preventing angioplasty-induced intimal hyperplasia in the coronary artery.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Proteínas de Ciclo Celular/genética , Enfermedad Coronaria/prevención & control , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Terapia Genética/métodos , Hiperplasia/prevención & control , Proteínas Supresoras de Tumor , Adenoviridae/genética , Animales , Cateterismo Cardíaco , Células Cultivadas , Enfermedad Coronaria/etiología , Enfermedad Coronaria/patología , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Modelos Animales de Enfermedad , Femenino , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Humanos , Infusiones Intraarteriales , Masculino , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Conejos , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Porcinos , Transducción Genética/métodos , Resultado del Tratamiento , Túnica Íntima/patologíaRESUMEN
BACKGROUND: The purpose of this study was to determine the efficacy of stent-based delivery of sirolimus (SRL) alone or in combination with dexamethasone (DEX) to reduce in-stent neointimal hyperplasia. SRL is a potent immunosuppressive agent that inhibits SMC proliferation by blocking cell cycle progression. METHODS AND RESULTS: Stents were coated with a nonerodable polymer containing 185 microgram SRL, 350 microgram DEX, or 185 microgram SRL and 350 microgram DEX. Polymer biocompatibility studies in the porcine and canine models showed acceptable tissue response at 60 days. Forty-seven stents (metal, n=13; SRL, n=13; DEX, n=13; SRL and DEX, n=8) were implanted in the coronary arteries of 16 pigs. The tissue level of SRL was 97+/-13 ng/artery, with a stent content of 71+/-10 microgram at 3 days. At 7 days, proliferating cell nuclear antigen and retinoblastoma protein expression were reduced 60% and 50%, respectively, by the SRL stents. After 28 days, the mean neointimal area was 2.47+/-1.04 mm(2) for the SRL alone and 2.42+/-1.04 mm(2) for the combination of SRL and DEX compared with the metal (5.06+/-1.88 mm(2), P<0.0001) or DEX-coated stents (4.31+/-3.21 mm(2), P<0.001), resulting in a 50% reduction of percent in-stent stenosis. CONCLUSIONS: Stent-based delivery of SRL via a nonerodable polymer matrix is feasible and effectively reduces in-stent neointimal hyperplasia by inhibiting cellular proliferation.
Asunto(s)
Antibacterianos/farmacología , Enfermedad Coronaria/prevención & control , Sistemas de Liberación de Medicamentos/métodos , Sirolimus/farmacología , Stents , Túnica Íntima/efectos de los fármacos , Animales , Materiales Biocompatibles , Western Blotting , Quimiocina CCL2/análisis , Enfermedad Coronaria/metabolismo , Enfermedad Coronaria/terapia , Vasos Coronarios/química , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/patología , Dexametasona/farmacología , Modelos Animales de Enfermedad , Perros , Sinergismo Farmacológico , Femenino , Hiperplasia/prevención & control , Interleucina-6/análisis , Masculino , Polímeros , Antígeno Nuclear de Célula en Proliferación/análisis , Proteína de Retinoblastoma/análisis , Porcinos , Túnica Íntima/química , Túnica Íntima/patologíaRESUMEN
BACKGROUND: We have previously reported a virtual absence of neointimal hyperplasia 4 months after implantation of sirolimus-eluting stents. The aim of the present investigation was to determine whether these results are sustained over a period of 1 year. METHODS AND RESULTS: Forty-five patients with de novo coronary disease were successfully treated with the implantation of a single sirolimus-eluting Bx VELOCITY stent in São Paulo, Brazil (n=30, 15 fast release [group I, GI] and 15 slow release [GII]) and Rotterdam, The Netherlands (15 slow release, GIII). Angiographic and volumetric intravascular ultrasound (IVUS) follow-up was obtained at 4 and 12 months (GI and GII) and 6 months (GIII). In-stent minimal lumen diameter and percent diameter stenosis remained essentially unchanged in all groups (at 12 months, GI and GII; at 6 months, GIII). Follow-up in-lesion minimal lumen diameter was 2.28 mm (GIII), 2.32 mm (GI), and 2.48 mm (GII). No patient approached the >/=50% diameter stenosis at 1 year by angiography or IVUS assessment, and no edge restenosis was observed. Neointimal hyperplasia, as detected by IVUS, was virtually absent at 6 months (2+/-5% obstruction volume, GIII) and at 12 months (GI=2+/-5% and GII=2+/-3%). CONCLUSIONS: This study demonstrates a sustained suppression of neointimal proliferation by sirolimus-eluting Bx VELOCITY stents 1 year after implantation.
Asunto(s)
Implantación de Prótesis Vascular/instrumentación , Enfermedad Coronaria/cirugía , Oclusión de Injerto Vascular/prevención & control , Sirolimus/administración & dosificación , Stents , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/métodos , Brasil , Estudios de Cohortes , Angiografía Coronaria , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/tratamiento farmacológico , Preparaciones de Acción Retardada/administración & dosificación , Implantes de Medicamentos/administración & dosificación , Endosonografía , Femenino , Estudios de Seguimiento , Oclusión de Injerto Vascular/etiología , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Sirolimus/efectos adversos , Stents/efectos adversos , Tasa de Supervivencia , Resultado del Tratamiento , Túnica Íntima/efectos de los fármacos , Grado de Desobstrucción Vascular/efectos de los fármacosRESUMEN
A series of close analogues of the potent, long-acting cardiotonic bemoradan (2a) was synthesized and examined in both in vitro and in vivo test systems. Changing the oxygen heteroatom at the 1-position of the benzoxazine ring of bemoradan to sulfur gave 4a, a more potent enzyme inhibitor and in vivo cardiotonic compound by the iv route. Intraduodenal administration of bemoradan, however, showed a superior response compared to its sulfur analogue, possibly due to oxidation of sulfur followed by a facile Pummerer rearrangement. Model studies were performed to examine the effect of the oxidation state of sulfur. Lack of a heteroatom at the 1-position, 3a (Y-590), afforded a compound with activity and potency very similar to those of bemoradan while the 1-selena compound gave a much less potent analogue 5. Analogues having a methyl group on the 4-nitrogen (2b, 3b, and 4b) were less potent than the desmethyl compounds, but all of these compounds have potent PDE III inhibiting activity and the ability to increase cardiac force in an anesthetized dog preparation when given iv.
Asunto(s)
Cardiotónicos/síntesis química , Oxazinas/química , Oxazinas/síntesis química , Piridazinas/química , Piridazinas/síntesis química , Animales , Benzoxazinas , Cardiotónicos/química , Cardiotónicos/farmacología , Perros , Corazón/efectos de los fármacos , Miocardio/enzimología , Oxazinas/farmacología , Piridazinas/farmacología , Relación Estructura-ActividadRESUMEN
A series of 6-benzoxazinylpyridazin-3-ones was prepared and evaluated for inhibition of cardiac phosphodiesterase (PDE) fraction III in vitro and for positive inotropic activity in vivo. 6-[3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl]-2,3,4,5-tetrahydro-5 - methylpyridazin-3-one (bemoradan) was found to be an extremely potent and selective inhibitor of canine PDE fraction III and a long-acting, potent, orally active inotropic vasodilator agent in various canine models. Additional benzoxazin-6-yl and -8-yl compounds were also prepared. Altering the pyridazinone substitution from the 6-position to the 7-position produced a 14-fold increase in the iv cardiotonic potency (ED50) from 77 to 5.4 micrograms/kg while substitution at the 8-position reduced potency. Methyl substitution at various sites in the molecule was also examined. Positive inotropic activity was maintained for between 8 and 24 h after a single oral dose (100 micrograms/kg) of bemoradan in dogs, thus making it one of the most potent and long-acting orally effective inotropes yet described. Bemoradan is currently under development as a cardiotonic agent for use in the management of congestive heart failure.
Asunto(s)
Cardiotónicos , Contracción Miocárdica/efectos de los fármacos , Oxazinas/farmacología , Piridazinas/farmacología , Vasodilatación/efectos de los fármacos , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Animales , Benzoxazinas , Fenómenos Químicos , Química , Perros , Estructura Molecular , Miocardio/enzimología , Oxazinas/síntesis química , Piridazinas/síntesis química , Estimulación Química , Relación Estructura-ActividadRESUMEN
A series of thieno[3,4-d]-, thieno[3,2-d]-, and thieno[2,3-d]pyrimidine-2,4-diones with (phenylpiperazinyl)alkyl substitution at N-3 have been synthesized and evaluated for antihypertensive effects in spontaneously hypertensive rats (SHR). These 49 compounds were compared to the vasodilator standards prazosin and the isosteric quinazoline-2,4-dione SGB 1534. Substitution at the 2-, 3-, or 4-position of the phenyl ring was examined, with that at the 2-position more potent than 4-substitution while the isomeric 3-substituted compounds were least potent. Neither alkylation nor acylation at the N-1 position improved the antihypertensive effects as compared to hydrogen. The three thienopyrimidine-2,4-diones (3-5) that contain a [(2-methoxyphenyl)piperazinyl]ethyl moiety at N-3 and hydrogen at N-1 were found to be potent oral antihypertensive agents in the SHR with doses (mg/kg, po) for reducing systolic blood pressure (SBP) by 50 mmHg (ED-50SBP) of 0.21, 0.19, and 1.0, respectively. The compounds 1-5 were further evaluated for alpha blocking potency by measuring the iv doses necessary to antagonize the phenylephrine pressor response by 50% (ED50) in the SHR. The ED50 values (micrograms/kg) are 10.4, 3.3, 1.7, 2.1, and 15.4, respectively. These results clearly show that all three thiophene systems have potent activity as antihypertensive agents and that 3 and 4 are more potent than 1 or 2 as alpha 1-antagonists in vivo.
Asunto(s)
Hipertensión/tratamiento farmacológico , Pirimidinas/uso terapéutico , Tiofenos/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Fenómenos Químicos , Química , Relación Dosis-Respuesta a Droga , Cinética , Fenilefrina/farmacología , Prazosina/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Ratas Endogámicas SHR , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos alfa/fisiología , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
A series of isoquinolin-3-ol derivatives (II) was prepared as analogues of the clinical cardiotonic agent bemarinone (ORF 16600, I). Although in many respects the structural requirements for the cardiotonic activity of II are similar to those of bemarinone, certain differences between the series were noted. Our structure-activity studies show that II is less sensitive to alkoxy-substitution effects than is I, and more significantly, 4-substitution of II by alkyl groups, halogen, or alkanecarboxylic acid derivatives enhances cardiotonic activity in II in contrast to I, wherein analogous substitution eliminated activity. A linear correlation between contractile force (CF) increase and cyclic nucleotide phosphodiesterase fraction III (PDE-III) inhibition by the title compounds was determined. The isoquinoline derivatives were characteristically short-acting cardiotonic agents with good potency and selectivity.
Asunto(s)
Isoquinolinas/síntesis química , Contracción Miocárdica/efectos de los fármacos , Quinazolinas/síntesis química , Animales , Presión Sanguínea/efectos de los fármacos , Fenómenos Químicos , Química , Perros , Frecuencia Cardíaca/efectos de los fármacos , Isoquinolinas/farmacología , Cinética , Inhibidores de Fosfodiesterasa/farmacología , Quinazolinas/farmacología , Estimulación Química , Relación Estructura-Actividad , Vasodilatación/efectos de los fármacosRESUMEN
The synthesis and cardiovascular evaluation of a series of isoquinolin-3-ol derivatives bearing a variety of nitrogen substituents (amino, acylamino, carbamate, and ureido) at C-4 are described. Certain of these compounds have a selective renal vasodilating profile and have minimal effects on arterial blood pressure or heart rate when administered intravenously in the instrumented anesthetized dog. The most potent renal vasodilator in the series is 4-(allylureido)-6,7-dimethoxyisoquinolin-3-ol (38), which at a dose of 1.2 mg/kg iv produces a 97% maximal increase in renal blood flow without significant hypotensive or chronotropic effects. Structure-activity observations on the nature of the 4-substituent and the alkoxy substitution pattern in the aromatic ring of the isoquinolinol nucleus are discussed.
Asunto(s)
Isoquinolinas/farmacología , Circulación Renal/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Perros , Frecuencia Cardíaca/efectos de los fármacos , Relación Estructura-Actividad , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/síntesis químicaRESUMEN
The synthesis and biological activity of novel thiazole-based heterocycles as inhibitors of thrombin-induced human platelet aggregation are described. Further evaluation of selected compounds show they inhibit platelet aggregation as stimulated by a variety of agonists. The more active compounds also were found to inhibit fibrinogen binding to platelets. To further delineate the mechanism of action of these compounds, direct binding studies with the purified glycoprotein (GP) IIb/IIIa receptor were performed. Flow cytometry analyses of 24 and 32 indicate that these compounds block the activation process of the GPIIb/IIIa receptor without denaturing the integrin receptor. On the basis of these studies, 32 exhibited the best profile as a novel nonpeptide inhibitor of fibrinogen-mediated platelet aggregation.
Asunto(s)
Fibrinógeno/fisiología , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Fibrinógeno/metabolismo , Citometría de Flujo , Humanos , Radioisótopos de Yodo , Cinética , Agregación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/fisiología , Relación Estructura-Actividad , Trombina/antagonistas & inhibidores , Trombina/farmacologíaRESUMEN
The synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxy-5,5-dimethylthieno[3,2-b]pyrans and related compounds are described. The compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats (SHR) and selected compounds were evaluated in vitro for increases in 86Rb efflux in rabbit isolated mesenteric arteries. The effects on activity in SHR of lactam ring size, the presence of heteroatoms in the lactam ring, the relative stereochemistry at C-6 and C-7, and the substituents on the thiophene ring are examined. The best racemic compound in this series is 32, trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-5H- thieno[3,2-b]pyran, which is 10-fold more potent than cromakalim with an ED30 = 0.015 mg/kg in SHR. Compound 32 could be resolved and the antihypertensive activity determined to reside primarily in the (6S,7S)-(-)-enantiomer 41. Surprisingly, the elimination of water to give the enamides 50-52, thiophene isosteres of bimakalim, diminishes activity significantly.
Asunto(s)
Antihipertensivos/síntesis química , Canales de Potasio/efectos de los fármacos , Piranos/síntesis química , Tiofenos/síntesis química , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Piranos/química , Piranos/farmacología , Conejos , Ratas , Ratas Endogámicas SHR , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
A series of purine derivatives was prepared and examined for selective inotropic activity in vitro and in vivo. Thioether-linked derivatives were superior to their oxygen and nitrogen isosteres. Substitution of electron-withdrawing groups on the benzhydryl moiety of these agents increased potency. The best compound of the study, 17 (carsatrin), was examined further and demonstrated selective oral activity as a positive inotrope. These compounds are presumed to act by affecting the kinetics of the cardiac sodium channel by analogy to the prototypic agent DPI 201106 (1). Their high selectivity for increasing contractile force and dP/dt without affecting blood pressure or heart rate is consistent with this mechanism. Carsatrin (17) was selected as a potential development candidate.
Asunto(s)
Cardiotónicos/síntesis química , Cardiotónicos/farmacología , Mercaptopurina/análogos & derivados , Contracción Miocárdica/efectos de los fármacos , Piperazinas/síntesis química , Purinas/síntesis química , Purinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Perros , Hurones , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Mercaptopurina/síntesis química , Mercaptopurina/farmacología , Estructura Molecular , Músculos Papilares/efectos de los fármacos , Músculos Papilares/fisiología , Piperazinas/farmacología , Canales de Sodio/efectos de los fármacos , Canales de Sodio/fisiología , Estimulación Química , Relación Estructura-ActividadRESUMEN
It is unknown whether the addition of aspirin might increase both the efficacy and the potency of clopidogrel, a potent and selective ADP blocker. For that purpose, the efficacy of clopidogrel (1-20 mg/kg, p.o.) administered orally to rabbits alone or in combination with aspirin (0.1-10 mg/kg, p.o.) was determined in several experimental models. A potent synergistic effect of the clopidogrel/aspirin association was demonstrated with regard to collagen-induced platelet aggregation measured ex vivo. Similarly, aspirin potentiated the antithrombotic activity of clopidogrel measured with regard to experimental thrombosis induced by a silk thread or on stents placed in an arteriovenous shunt, thrombus formation following electrical stimulation of the rabbit carotid artery and with regard to 111In-labeled platelet deposition on a stent implanted in an arteriovenous shunt or on the subendothelium following air drying injury of the rabbit carotid artery. A similar potentiating effect of aspirin was obtained with regard to myointimal proliferation (restenosis) in the femoral arteries of atherosclerotic rabbits which occurred as a consequence of stent placement. The clopidogrel/aspirin combination showed only additive-type effects on bleeding time prolongation induced by ear transection in the rabbit, therefore showing that combined inhibition of cyclooxygenase and ADP's effects provide a marked enhanced antithrombotic efficacy. Such a combination may provide substantial protection against platelet aggregation leading to thrombotic occlusion at sites of endothelial injuries and coronary artery stenosis in humans.
Asunto(s)
Aspirina/farmacología , Arteria Femoral/patología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Trombosis/tratamiento farmacológico , Ticlopidina/análogos & derivados , Animales , Aspirina/uso terapéutico , Clopidogrel , Constricción Patológica/tratamiento farmacológico , Sinergismo Farmacológico , Fibrinolíticos/farmacología , Fibrinolíticos/uso terapéutico , Masculino , Inhibidores de Agregación Plaquetaria/uso terapéutico , Conejos , Ticlopidina/farmacología , Ticlopidina/uso terapéuticoRESUMEN
Rabbit platelet cyclic AMP phosphodiesterase is inhibited by the three calcium channel blockers nifedipine, diltiazem, and verapamil with IC50's of 100 microM, 100 microM and 420 microM, respectively. Also, platelet aggregation induced by 4 microM ADP is inhibited by those compounds. Verapamil is the most potent aggregation inhibitor with an IC50 of 260 microM while diltiazem and nifedipine have IC50's of 630 microM and 840 microM, respectively. All three compounds display a maximum inhibition of 80-85%. Diltiazem and PGD2 potentiate the antiaggregatory activity of each other in that the inhibitions occurring in the presence of the combination of the two (at varying concentrations) exceed the calculated sums of the inhibitions produced by each alone. On the other hand, the antiaggregatory activities of verapamil or nifedipine, are additive with that of PGD2 in that no significant differences exist between the observed inhibitions produced by the combinations and the calculated summed values of the individual inhibitions. Our data suggest, therefore, that in addition to lowering intracellular calcium ions, which are required for platelet aggregation, the three calcium channel blockers inhibit the breakdown of cyclic AMP thereby promoting antiaggregation.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/sangre , Plaquetas/enzimología , Bloqueadores de los Canales de Calcio/farmacología , Agregación Plaquetaria/efectos de los fármacos , 1-Metil-3-Isobutilxantina/farmacología , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Adenosina Difosfato/farmacología , Animales , Citosol/enzimología , Diltiazem/farmacología , Cinética , Nifedipino/farmacología , Conejos , Relación Estructura-Actividad , Verapamilo/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Chronic proliferative responses of different vascular cell types have been involved in the pathogenesis of atherosclerosis. However, their functional role remains to be established. Sirolimus reduces neointimal proliferation after balloon angioplasty and chronic graft vessel disease. These studies were undertaken to investigate the effects of this anti-proliferative drug on atherogenesis. EXPERIMENTAL APPROACH: Low-density lipoprotein receptor-deficient (LDL r-KO) mice on a cholesterol-rich diet were randomized to receive placebo or sirolimus (0.1; 0.3; or 1 mg.kg(-1)) in their diet for 8 or 16 weeks. RESULTS: In both studies, plasma levels of the drug increased in a dose-dependent fashion, animals gained weight normally and, among groups, plasma lipids levels did not differ significantly. Compared with placebo, plasma levels of interleukin-6, monocyte chemoattractant protein-1, interferon gamma, tumour necrosis factor alpha and CD40, and their mRNA levels in aortic tissue were significantly reduced in sirolimus-treated mice. This effect resulted in a significant and dose-dependent reduction in atherosclerotic lesions, in both the root and aortic tree. Also these lesions contained less monocyte/macrophages and smooth muscle cells, but more collagen. CONCLUSIONS AND IMPLICATIONS: The present results demonstrated that at low doses, sirolimus was an effective and safe anti-atherogenic agent in the LDL r-KO mice. It attenuated the progression of atherosclerosis and modulated the plaque phenotype by reducing the pro-inflammatory vascular responses typical of the disease.
Asunto(s)
Aorta/efectos de los fármacos , Aterosclerosis/prevención & control , Receptores de LDL/genética , Sirolimus/farmacología , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/orina , Animales , Aorta/inmunología , Aorta/patología , Aterosclerosis/inmunología , Aterosclerosis/patología , Colesterol/sangre , Colágeno/metabolismo , Creatinina/orina , Citocinas/orina , Dieta Aterogénica , Relación Dosis-Respuesta a Droga , Inflamación/inmunología , Inflamación/patología , Inflamación/prevención & control , Isoprostanos/orina , Masculino , Ratones , Ratones Noqueados , Distribución Aleatoria , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Tromboxano B2/análogos & derivados , Tromboxano B2/orina , Factores de Tiempo , Triglicéridos/sangreRESUMEN
A comparison was made of the effect of prostaglandin synthesis inhibitors (PGSI) on systemic blood pressure and hindlimb muscle vascular resistance of anesthetized dogs under different experimental conditions. When muscle blood flow was monitored using an extracorporeal or noncannulating electromagnetic blood flow probe, indomethacin (5 mg/kg i.v.) increased blood pressure slightly, but did not change vascular resistance. Administration of PGSI (indomethacin, meclofenamate, or naproxen, 5 mg/kg i.v.) after 2 hr of pump perfusion of the hindlimb caused a 22% increase in blood pressure, and 39% increase in vascular resistance 30 min afterwards. When administered immediately after instituting pump perfusion, indomethacin caused no significant change in blood pressure or vascular resistance at the 30 min interval, but at 60 min vascular resistance was increased. A similar vasoconstrictor response to indomethacin was obtained when it was infused in a lower dose intraarterially to the hindlimb, or when given i.v. after ligation of the renal pedicles. The results indicate that pump perfusion results in elaboration of a nonrenal prostaglandin(s) which maintains a vasodilator influence on the skeletal muscle vascular bed.
Asunto(s)
Inhibidores de la Ciclooxigenasa , Músculos/irrigación sanguínea , Vasoconstricción/efectos de los fármacos , Animales , Perros , Femenino , Miembro Posterior/irrigación sanguínea , Técnicas In Vitro , Indometacina/farmacología , Masculino , Ácido Meclofenámico/farmacología , Naproxeno/farmacología , Perfusión , Flujo Sanguíneo Regional/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
Several calcium entry blockers and alpha 2-adrenergic receptor antagonists were evaluated for inhibition of pressor responses induced by the selective alpha 2 agonist B-HT 920 in pentobarbital-anesthetized dogs pretreated with prazosin (0.5 mg/kg, i.v.), propranolol (0.5 mg/kg, i.v.), and hexamethonium (10 mg/kg i.v.). In this preparation, autonomic blockade (alpha 1, beta, and ganglionic block) persists for approximately 4 hr. The B-HT 920 administered intravenously causes dose-related increases in mean arterial blood pressure (ED50 = 4.90 micrograms/kg, i.v., dose causing a 50 mm Hg rise in mean arterial blood pressure). Maximum increases in mean arterial pressure approximate 80 mm Hg at 100 micrograms/kg, i.v. Repeated bolus administration of B-HT 920 over a 4-hr period shows no significant reduction in the pressor response, suggesting good stability of this experimental model and no rapidly developing tolerance. Calcium entry blockers (nifedipine, D-600, and diltiazem) and alpha 2-adrenergic receptor antagonists (yohimbine and idazoxan) inhibit the B-HT 920-induced pressor response in a dose-related manner. The ED50 values (dose of antagonist that causes a 50% inhibition of B-HT 920-induced pressor response) were calculated. Idazoxan and yohimbine have ED50 values (mg/kg, i.v.) of 0.086 and 0.063, respectively, whereas D-600, nifedipine, and diltiazem have values of 0.074, 0.111, and 0.542, respectively. The data show that calcium entry blockers and alpha 2-adrenergic blockers are potent inhibitors of B-HT 920 pressor responses in the autonomically blocked dog. This experimental model is appropriate for the evaluation of calcium entry blockers and/or alpha 2-adrenergic antagonists in vivo.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Sistema Nervioso Autónomo/efectos de los fármacos , Azepinas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Yoduro de Dimetilfenilpiperazina/farmacología , Perros , Femenino , Galopamilo/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Isoproterenol/farmacología , Masculino , Nifedipino/farmacología , Yohimbina/farmacologíaRESUMEN
The effects of trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-7H- thieno[3,2-b]pyran (RWJ 26629) were compared with those of the standard potassium channel opener cromakalim and several standard calcium channel blockers. RWJ 26629 lowered the mean arterial blood pressure in conscious spontaneously hypertensive (ED30 = 10 micrograms/kg p.o. or 8 micrograms/kg i.v.) and renal hypertensive (15 micrograms/kg p.o.) rats, conscious renal hypertensive (ED20 = 4 micrograms/kg p.o.) and normotensive (ED20 = 5 micrograms/kg p.o. or 2 micrograms/kg i.v.) dogs and anesthetized rhesus monkeys (ED20 = 6 micrograms/kg i.v.). RWJ 26629 was more potent than cromakalim and had a maximal activity greater than the calcium channel blockers. At antihypertensive doses, RWJ 26629 had no significant effect on cardiac force, cardiac output, stroke volume or stroke work in dogs and had little or no effect on renal, carotid or femoral blood flow or vascular resistance. RWJ 26629 was also selective for antihypertensive activity in rats compared with its ability to inhibit intestinal motility. However, RWJ 26629 did relax contracted pulmonary smooth muscle in vivo at antihypertensive doses. All compounds tested caused reflex tachycardia in conscious dogs, although this effect was lowest for RWJ 26629. Most importantly, RWJ 26629 potently and selectively increased coronary blood flow with a potency and duration of action greater than that of cromakalim or nifedipine without affecting contractile force. In vitro, RWJ 26629 selectively relaxed precontracted coronary arteries compared with its effect on femoral arteries.(ABSTRACT TRUNCATED AT 250 WORDS)
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Antihipertensivos/farmacología , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Piranos/farmacología , Tiofenos/farmacología , Angina de Pecho/tratamiento farmacológico , Animales , Benzopiranos/farmacología , Broncoconstricción/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Cromakalim , Perros , Relación Dosis-Respuesta a Droga , Femenino , Hurones , Motilidad Gastrointestinal/efectos de los fármacos , Cobayas , Atrios Cardíacos/efectos de los fármacos , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos , Músculo Liso Vascular/fisiología , Nitrendipino/metabolismo , Músculos Papilares/efectos de los fármacos , Pilocarpina/farmacología , Pirroles/farmacología , Conejos , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Rubidio/farmacocinética , Radioisótopos de Rubidio , Vasodilatadores/farmacologíaRESUMEN
This study was designed to determine the relationship between the hemodynamic responses to bemoradan, a novel cardiotonic agent, and its plasma levels after single administration of an oral dose or a 15 minute i.v. infusion to mongrel dogs, and to demonstrate that the clinical capsule formulation of bemoradan elicits a pharmacological response in the dog. Four conscious, instrumented mongrel dogs received each of four bemoradan treatments (30 micrograms kg-1 i.v., 100 micrograms kg-1 i.v., 100 micrograms kg-1 suspension p.o., or 1 mg capsule p.o.) in a Latin square cross-over design. Plasma levels of bemoradan up to 24 h post-dosing were determined by HPLC. Cardiac contractility (dP/dt), heart rate, and arterial blood pressure were continuously monitored for 8 h and again at 24 h. Results of the study indicate that there was a significant correlation between bemoradan plasma levels and dP/dt. The 1 mg clinical capsule formulation was well absorbed when compared to an oral suspension and an i.v. dose. Peak increases in dP/dt of 64 per cent at 15 min for the suspension and 53 per cent at 1 h for the capsule were observed.
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Cardiotónicos/farmacología , Cardiotónicos/farmacocinética , Hemodinámica/efectos de los fármacos , Oxazinas/farmacología , Oxazinas/farmacocinética , Piridazinas/farmacología , Piridazinas/farmacocinética , Administración Oral , Animales , Benzoxazinas , Presión Sanguínea/efectos de los fármacos , Cápsulas , Cardiotónicos/sangre , Química Farmacéutica , Perros , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Infusiones Intravenosas , Masculino , Monitoreo Fisiológico , Contracción Miocárdica/efectos de los fármacos , Oxazinas/sangre , Piridazinas/sangreRESUMEN
The blood pressure-lowering potency and activity of BRL 34915, a new vasodilator and putative stimulator of potassium efflux from vascular smooth muscle, was investigated in conscious spontaneously hypertensive rats (SHR) and normotensive rats (NTR) after intravenous administration and compared with that of the calcium channel blocker, nifedipine. In SHR, BRL 34915 (3-100 micrograms/kg) or nifedipine (10-3000 micrograms/kg) produced similar reductions in mean arterial pressure of 58 +/- 3% and 55 +/- 3%, respectively. BRL 34915 (ED30% = 13.8 micrograms/kg) was 15.3 times more potent than nifedipine (ED30% = 207 micrograms/kg) in SHR. In contrast, only a 1.7-fold difference in potency was observed in NTR between BRL 34915 (ED30% = 123 micrograms/kg) and nifedipine (ED30% = 182 micrograms/kg). The potency ratio (ED30% NTR/ED30% SHR) for BRL 34915 was 8.83 whereas nifedipine had a ratio of 0.88, reflecting the greater responsiveness of the SHR to BRL 34915. Systemic hemodynamics were monitored in anesthetized SHR and NTR to determine the basis for the reductions in blood pressure. BRL 34915 (3-100 micrograms/kg iv) lowered mean arterial pressure in both groups solely by decreasing total peripheral vascular resistance, since no changes in cardiac output were observed. Relaxation responses were also obtained in phenylephrine-contracted isolated aortic strips from both strains of rat to ascertain whether differences in responsiveness existed at this level of the vasculature. No significant difference in the potency of BRL 34915 (3-10 microM) as a vasodilator was found in aortas from SHR or NTR. These results indicate that, unlike nifedipine, BRL 34915 is a more potent vasodepressor agent in SHR than in NTR and suggests that the potassium efflux stimulator may preferentially relax resistance vessels in the hypertensive rat.
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Benzopiranos/farmacología , Hipertensión/fisiopatología , Nifedipino/farmacología , Pirroles/farmacología , Vasodilatación/efectos de los fármacos , Animales , Antihipertensivos , Aorta , Presión Sanguínea/efectos de los fármacos , Cromakalim , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiopatología , Fenilefrina/farmacología , Ratas , Ratas Endogámicas SHR , Resistencia Vascular/efectos de los fármacosRESUMEN
Thrombin's cellular actions are mediated by a novel G-protein coupled transmembrane receptor. We infused SFLLRN, a peptide that directly activates thrombin receptors, into the left circumflex coronary artery (CFX) of anesthetized dogs to evaluate the cardiovascular effects of thrombin receptor activation in vivo. Intracoronary SFLLRN, 0.9, 9 and 90 nmol/min, produced transient, dose-related increases in CFX blood flow, followed by sustained decreases in CFX and left anterior descending (LAD) blood flow. SFLLRN also decreased positive and negative dP/dtmax, arterial pressure, cardiac output and heart rate. Peripheral vascular resistance transiently decreased and then increased. SFLLRN decreased systolic wall thickening (WT) and increased ST segment level within the CFX perfusion area. In contrast, WT was increased, and ST segment was unchanged in the LAD perfusion area. CFX flow, but not LAD flow, increased transiently above control after SFLLRN infusion. FSLLRN, a peptide that does not activate thrombin receptors, had no effect at 90 nmol/min. The response to intravenous SFLLRN was greatly attenuated when compared with intracoronary infusion, and regional changes in coronary flow and function were absent. Decreases in arterial pressure, heart rate, coronary blood flow, and positive and negative dP/dtmax, were inhibited after bilateral vagotomy. Moreover, arterial pressure and peripheral resistance increased in response to SFLLRN after vagotomy. Initial CFX flow increase, regional dysfunction, ST level changes and hyperemic response were comparable but attenuated after vagotomy. Ex vivo platelet function was not affected by SFLLRN up to 100 microM. We conclude that regional myocardial ischemia and cardiac dysfunction result from thrombin receptor-mediated local coronary vasoconstriction. Thus, thrombin generation at a site of vascular injury or thrombus may significantly affect vascular tone and myocardial perfusion.