RESUMEN
Surge hyperemia and mechanical damage to the cerebrovascular endothelium may serve to exacerbate the neuropathological outcome in animal models of focal cerebral ischemia. We have modified an existing model of endothelin-1-induced middle cerebral artery (MCA) occlusion to enable controlled reperfusion without damage to the cerebral vasculature. Endothelin-1 (ET-1) and endothelin-3 (ET-3) were injected via a double-injection cannula into brain parenchyma adjacent to the MCA of anesthetized rats to produce focal cerebral ischemia. ET-1 and ET-3 produced large ischemic lesions that were restricted to those cortical and subcortical structures supplied by the MCA. The volume of ischemic damage produced by 100 pmol of ET-1 and ET-3 was similar. The endothelin-A (ET(A)) receptor antagonist FR139317 (3 or 30 nmol) injected 10 min after ET-1 did not significantly alter the volume of damage. By contrast, the lesion produced by ET-3 was completely inhibited by FR139317 at the 10 min time-point. FR139317 partially attenuated the ET-3-induced lesion when administered 30 min post-occlusion, but injection 90 min following ET-3 produced a lesion not different to that produced by ET-3 alone. These findings were supported by laser Doppler flowmetry which determined FR139317 induces reperfusion when injected 10 or 90 min following ET-3. ET-3-induced MCA occlusion is therefore amenable to reversal by the ET(A) receptor antagonist FR139317, and this model may offer a means to investigate the neuropathology of reperfusion without the procedure-related artifacts associated with some reperfusion models.
Asunto(s)
Encéfalo/fisiopatología , Endotelina-1/toxicidad , Endotelina-3/toxicidad , Ataque Isquémico Transitorio/fisiopatología , Reperfusión , Animales , Azepinas/farmacología , Glucemia/metabolismo , Presión Sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/patología , Dióxido de Carbono/sangre , Circulación Cerebrovascular , Antagonistas de los Receptores de Endotelina , Endotelina-1/administración & dosificación , Endotelina-3/administración & dosificación , Indoles/farmacología , Ataque Isquémico Transitorio/inducido químicamente , Ataque Isquémico Transitorio/patología , Masculino , Microinyecciones , Arteria Cerebral Media , Oxígeno/sangre , Ratas , Ratas Sprague-Dawley , Receptor de Endotelina ARESUMEN
Endothelins have potent biological effect in vivo which may, in part, be mediated by stimulation of cyclooxygenase metabolism of arachidonic acid. We administered endothelins (ETs) intravenously to chronically instrumented awake sheep with and without pretreatment with meclofenamate (n = 8). 30 micrograms doses of ET-1, ET-2, and ET-3 caused similar degrees of acute elevation of pulmonary artery pressure (PPA), reduction of the dynamic compliance of the lungs (Cdyn), and increases in lung lymph flow. Pretreatment with meclofenamate inhibited the rise in PPA and reduction in Cdyn, but had no effect on lung lymph flow. We conclude that the biological effects of the endothelins on PPA and Cdyn, but not lung fluid balance, are mediated in part by cyclooxygenase products of arachidonic acid metabolism.
Asunto(s)
Inhibidores de la Ciclooxigenasa/uso terapéutico , Endotelinas/toxicidad , Hipertensión Pulmonar/inducido químicamente , Pulmón/efectos de los fármacos , Ácido Meclofenámico/uso terapéutico , Animales , Presión Sanguínea , Endotelina-1/toxicidad , Endotelina-2/toxicidad , Endotelina-3/toxicidad , Femenino , Hipertensión Pulmonar/fisiopatología , Pulmón/fisiopatología , Rendimiento Pulmonar , Linfa/fisiología , Masculino , OvinosRESUMEN
The effects of an endothelin (ET)-receptor B-specific antagonist, RES-701-1, on ET-induced contraction of guinea-pig trachea and on ET-induced bronchoconstriction in anaesthetized guinea-pigs were investigated. In the epithelium-removed tracheal preparation, 1 x 10(-5) M RES-701-1 inhibited contractions induced by the ETB-specific agonist sarafotoxin S6c (pKB = 6.10). In the epithelium-intact tracheal preparation, RES-701-1 (1 x 10(-5) M)inhibited the ET-3-induced contraction (pKB = 5.27), but enhanced the ET-1-induced contraction significantly and shifted the concentration-response curve to the left. The maximal responses of ET-1- and ET-3-induced contraction were augmented by epithelium removal by 1.5 and 1.8-fold, respectively. Against ET-3-induced contraction in the tracheal preparation without epithelium, RES-701-1 (0.3-10 x 10(-6)M) antagonized the contraction in a concentration-dependent manner (pA2 = 5.9). On the other hand, RES-701-1 (1 x 10(-5)M) did not affect ET-1-evoked responses in the trachea without epithelium. The intravenous administration of ET-1 (1.5 nmol/kg-1) or ET-3 (1.5 nmol/kg-1) evoked a biphasic, fast and sustained bronchoconstriction in anaesthetized guinea-pigs pretreated with propranolol (1.0 mg/kg-1). when administered intravenously, RES-701-1 (0.3 or 1.0 mg/kg-1) showed significant reduction in both phases of bronchoconstriction induced by ET-3. As in the case of ET-1-induced bronchoconstriction, rES-701-1 augmented the sustained phase although a significant reduction of the fast phase was observed. These results indicate that RES-701-1 can inhibit the ET-3 induced airway responses not only in-vitro but also in-vivo.