RESUMEN
The distribution of atherosclerotic lesions within the rabbit vasculature, particularly within the descending thoracic aorta, has been mapped in numerous studies. The patchy nature of such lesions has been attributed to local variation in the pattern of blood flow. However, there have been few attempts to model and characterize the flow. In this study, a high-order continuous Galerkin finite-element method was used to simulate blood flow within a realistic representation of the rabbit aortic arch and descending thoracic aorta. The geometry, which was obtained from computed tomography of a resin corrosion cast, included all vessels originating from the aortic arch (followed to at least their second generation) and five pairs of intercostal arteries originating from the proximal descending thoracic aorta. The simulations showed that small geometrical undulations associated with the ductus arteriosus scar cause significant deviations in wall shear stress (WSS). This finding highlights the importance of geometrical accuracy when analysing WSS or related metrics. It was also observed that two Dean-type vortices form in the aortic arch and propagate down the descending thoracic aorta (along with an associated skewed axial velocity profile). This leads to the occurrence of axial streaks in WSS, similar in nature to the axial streaks of lipid deposition found in the descending aorta of cholesterol-fed rabbits. Finally, it was observed that WSS patterns within the vicinity of intercostal branch ostia depend not only on local flow features caused by the branches themselves, but also on larger-scale flow features within the descending aorta, which vary between branches at different locations. This result implies that disease and WSS patterns in the vicinity of intercostal ostia are best compared on a branch-by-branch basis.
Asunto(s)
Aorta Torácica/fisiología , Velocidad del Flujo Sanguíneo/fisiología , Animales , Aterosclerosis/fisiopatología , Biofisica/métodos , Análisis de Elementos Finitos , Hemodinámica , Lípidos/química , Masculino , Modelos Anatómicos , Modelos Teóricos , Conejos , Resistencia al Corte , Estrés Mecánico , Tomografía Computarizada por Rayos X/métodosRESUMEN
The purpose of this study was to investigate the pharmacological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration-dependently inhibited radioligand binding in membranes containing rat and human 5-HT3 receptors with estimated pKi values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5-HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycardia (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of approximately 3.0 at 1.0 microg kg-1, = 3-5). Alosetron administered via the duodenum also inhibited this reflex, with duration of action that was significantly longer than that seen with ondansetron (120-60 min, respectively, n = 6). Alosetron had no significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5-HT3 antagonist which normalizes perturbed small intestinal propulsion. Previous clinical data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.
Asunto(s)
Carbolinas/uso terapéutico , Ayuno , Tránsito Gastrointestinal/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Antagonistas de la Serotonina/uso terapéutico , Agonistas alfa-Adrenérgicos/farmacología , Animales , Clonidina/análogos & derivados , Clonidina/farmacología , Evaluación Preclínica de Medicamentos , Ondansetrón/farmacología , Ovalbúmina/farmacología , Ensayo de Unión Radioligante , Ratas , Valores de Referencia , Reflejo/efectos de los fármacos , Nervio Vago/efectos de los fármacosRESUMEN
The cardioprotective effects of the selective adenosine A1-receptor agonist, GR79236 (N-[(1S, trans)-2-hydroxycyclopentyl]adenosine), were examined in a porcine model of myocardial ischaemia-reperfusion injury. When pigs were subjected to a 50-min coronary artery occlusion followed by 3-h reperfusion, GR79236 (10 nmol/kg, i.v.) significantly reduced infarct size whether given 10 min before the onset of ischaemia or reperfusion. This effect was independent of the bradycardia induced by GR79236, as it was also observed in animals in which heart rate was maintained by electrical pacing. However, GR79236 administered 10 min after reperfusion did not reduce infarct size. GR79236 had no effect on the incidence or outcome of ventricular dysrhythmias in this pig model of infarction. Similarly, ischaemic preconditioning (IPC, 2 x 10-min ischaemia and 10-min reperfusion) significantly reduced infarct size. The selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 3.3 micromol/kg, i.v.), abolished the haemodynamic and cardioprotective effects of GR79236 and the cardioprotective effects of IPC in anaesthetised pigs. In conclusion, GR79236 exerted a marked cardioprotective effect in a porcine model of myocardial ischaemia-reperfusion injury, provided that it was administered before reperfusion. This suggests that GR79236 may have clinical utility in the treatment of various aspects of ischaemic heart disease.
Asunto(s)
Adenosina/análogos & derivados , Presión Sanguínea/efectos de los fármacos , Infarto del Miocardio/patología , Agonistas del Receptor Purinérgico P1 , Daño por Reperfusión/prevención & control , Disfunción Ventricular/patología , Adenosina/farmacología , Anestesia , Animales , Enfermedad Coronaria/patología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Estructura Molecular , Porcinos , Factores de Tiempo , Xantinas/farmacologíaRESUMEN
1. The antagonist activity of the angiotensin AT1 receptor antagonist, GR138950, and its haemodynamic effects have been investigated in beagle dogs. 2. In four anaesthetized dogs, GR138950 (0.1, 1 and 10 mg kg-1 i.v.), displaced dose-response curves to angiotensin II (AngII) rightwards, in a parallel manner; GR138950, at 1 mg kg-1 i.v., produced a 15-fold displacement of the AngII dose-response curve. In four conscious dogs, GR138950 (1 mg kg-1 i.v. or p.o.) antagonized AngII, and produced rightward and parallel displacements of the AngII dose-pressor response curves. Maximum displacements of approximately 33- and 16-fold occurred at 1 h after intravenous and 5 h after oral administration, respectively. The inhibitory effect of GR138950 was long lasting; AngII dose-pressor response curves were still displaced by 10-fold from control values, 24 h after intravenous or oral administration of GR138950. 3. In comparison with its vehicle, GR138950 (0.1-10 mg kg-1) caused a significant decrease in resting blood pressure as a consequence of a significant decrease in total peripheral resistance in anaesthetized dogs. Effects on cardiac output, stroke volume and heart rate were not significantly different between GR138950- or vehicle-treated dogs. 4. Compared with vehicle, GR138950 administration did not significantly affect blood flow to the mesenteric and femoral vascular beds but did significantly increase blood flow to the renal vascular bed. Vascular resistance of the femoral bed was unaffected but that of the mesenteric and renal vascular beds was significantly reduced by GR138950, compared with the changes produced by vehicle treatment. 5. Compared with vehicle, left ventricular end diastolic pressure was significantly reduced by GR138950, but GR138950 had no significant effect on indices of cardiac contractility (+dP/dtmax and +dP/dt@40) or cardiac relaxation during early diastole (-dP/dt). 6. In conclusion, GR138950 acts as a competitive, surmountable antagonist at vascular angiotensin II receptors in beagle dogs. GR138950 reduced arterial blood pressure by reducing total peripheral resistance, attributable partly to reduction in resistance in the mesenteric and renal vascular beds. GR138950 reduced left ventricular end diastolic pressure whilst having no direct effect on cardiac contractility or relaxation.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/farmacología , Benzofuranos/farmacología , Hemodinámica/efectos de los fármacos , Administración Oral , Angiotensina II/antagonistas & inhibidores , Angiotensina II/farmacología , Animales , Antihipertensivos/administración & dosificación , Benzofuranos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Arteria Femoral/efectos de los fármacos , Arteria Femoral/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos , Arteria Renal/efectos de los fármacos , Arteria Renal/fisiología , Volumen Sistólico/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
The antagonist activity of GR138950 (1-[[3-bromo-2-[2-[[(trifluoromethyl)sulphonyl]amino]phenyl]-5- benzofuranyl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxamide) was investigated at angiotensin AT1 receptors and AT2 receptors in vitro and on blood pressure in conscious rats. GR138950 suppressed and displaced angiotensin II (AII) concentration-effect curves in the rabbit isolated aorta (pKb approximately 9.0-9.7) but had no effect against phenylephrine or serotonin induced-contractions. GR138950 competed with [3H]-AII for angiotensin AT1 receptors in rat liver membranes (pKi = 9.09). GR138950 had no apparent affinity for angiotensin AT2 receptors (bovine cerebellum; pKi < 6.0). GR138950 (1 mg/kg i.a. and p.o.) inhibited pressor responses to AII, but not phenylephrine, in conscious normotensive rats. Parallel displacements in AII dose-response curves occurred without any reduction in the maximum response to AII. The antagonist activity of GR138950 lasted for up to 24 h. GR138950 (> 0.03 mg/kg i.a., > 0.3 mg/kg p.o.) significantly reduced diastolic blood pressure (DBP) in renal artery ligated hypertensive rats. DBP was reduced maximally, 5 to 7 h after administration and the antihypertensive effect of GR138950 lasted for up to 48 h. Daily administration (5 days) of GR138950 to renal artery ligated hypertensive rats produced a sustained reduction in DBP. Acute administration of GR138950 (1 mg/kg i.a.) also significantly reduced DBP in spontaneously hypertensive rats but not in normotensive rats. Heart rate was little changed in renal artery ligated hypertensive rats, normotensive rats and spontaneously hypertensive rats. These experiments demonstrate that GR138950 is a potent, selective and specific angiotensin AT1 receptor antagonist that is orally active and reduces DBP in conscious hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Antagonistas de Receptores de Angiotensina , Antihipertensivos/farmacología , Benzofuranos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Masculino , Conejos , Ratas , Ratas Wistar , Vasoconstricción/efectos de los fármacosRESUMEN
1. The effect of GR117289, an angiotensin AT1 receptor antagonist, on diastolic blood pressure (DBP) was determined in angiotensin-dependent and angiotensin-independent models of hypertension in rats. In addition, the antagonist profile of GR117289 at angiotensin AT1 receptors was determined in conscious renal hypertensive rats and conscious normotensive rats, dogs and marmosets. 2. Intra-arterial and oral administration of GR117289 (0.3-3 mg kg-1, i.a.; 1-10 mg kg-1, p.o.) to 6-day left renal artery ligated hypertensive (RALH) rats (DBP > 140 mmHg) produced significant, dose-related reductions in DBP with little apparent effect on heart rate (< 15%). The antihypertensive effect of GR117289 developed progressively over several hours and with some doses persisted for 24-48 h after administration. 3. Administration of GR117289 (1 mg kg-1, i.a.) on 5 consecutive days to RALH rats reduced DBP on each day. The antihypertensive effect of GR117289 was not cumulative as DBP had almost returned to base-line values, 24 h after administration of each dose. 4. A dose of GR117289 (3 mg kg-1, i.a.), which produced a substantial reduction in DBP (about 70 mmHg) in RALH rats, was administered to rats in which blood pressure was elevated either by unilateral renal artery clipping, sustained infusion of angiotensin II (AII), DOCA-salt administration or genetic inbreeding. GR117289 reduced DBP in rats in which the renin-angiotensin system was activated by renal artery clipping or AII infusion but had little effect in normotensive rats, DOCA-salt rats and SHR. 5. Systemic administration of All to RALH rats and to normotensive rats, dogs and marmosets elicited reproducible pressor responses in all species. Systemic or oral administration of GR1 17289 (3 mg kg-1)inhibited the pressor responses produced by All, resulting in parallel, rightward displacements of All dose-response curves.6. Maximal displacements of All dose-response curves occurred 1 h and 1-7 h after systemic and oral administration, respectively. GR1 17289 produced a 32-246 fold displacement after systemic administration and a 4-12 fold displacement after oral administration. The effect in dogs was short lasting after systemic administration but the effect of GRI17289 lasted for up to 24 h in rats and marmosets and for up to 24 h after oral administration in all species. The antagonist activity appeared specific for angiotensin receptors as GRi17289 did not inhibit pressor responses to phenylephrine or vasopressin.7. These experiments demonstrate that GRI 17289 reduces blood pressure in conscious hypertensive rats after both systemic and oral administration, and is an effective antagonist at angiotensin AT1 receptors in conscious rats, dogs and marmosets.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Ácidos Nicotínicos/farmacología , Tetrazoles/farmacología , Administración Oral , Angiotensina II/farmacología , Animales , Callithrix , Perros , Relación Dosis-Respuesta a Droga , Hipertensión/fisiopatología , Hipertensión Renovascular/tratamiento farmacológico , Hipertensión Renovascular/fisiopatología , Inyecciones Intraarteriales , Masculino , Ácidos Nicotínicos/administración & dosificación , Ácidos Nicotínicos/uso terapéutico , Ratas , Ratas Endogámicas SHR , Tetrazoles/administración & dosificación , Tetrazoles/uso terapéuticoAsunto(s)
Clonidina/farmacología , Hipotensión/inducido químicamente , Receptores Adrenérgicos alfa/fisiología , Receptores Adrenérgicos/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Gatos , Clonidina/antagonistas & inhibidores , Femenino , Prazosina/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Yohimbina/farmacologíaRESUMEN
When infused into the third ventricle of the brain of the conscious cat, the phosphodiesterase inhibitors, papaverine and aminophylline, increased blood pressure and heart rate whilst the phosphodiesterase stimulator, imidazole-4'-acetic acid, decreased blood pressure. Administered intravenously, these compounds caused the opposite effects indicating that the responses after third-ventricular administration were centrally mediated. Infused of dibutyryl cyclic 3',5'-AMP into the third ventricle increased blood pressure and heart rate, whereas dibutyryl cyclic 3',5'-GMP had little effect and antagonised and pressor response to dibutyryl cyclic 3',5'-AMP. ATP, 5'-AMP and adenosine induced similar changes to dibutyryl cyclic 3',5'-AMP, although the pressor responses to these compounds were of different onset and/or duration. When administered into the third ventricle both alpha- and beta-adrenoceptor blocking agents reduced the pressor response caused caused by the phosphodiesterase inhibitor, papaverine, given by the same route. These results demonstrate a central effect of adenosine and adenosine nucleotides to raise blood pressure. The possibility of a specific role for cyclic 3',5'-AMP in the central control of blood pressure is discussed.