RESUMEN
The purpose of this study was to investigate the effects of endothelins (ET) 1, 2 and 3 on isolated isthmic segments of the human oviduct at the luteal phase of menstrual cycle. Fallopian tubes were taken from 21 patients and the isthmic segments were mounted in an organ bath longitudinally. Tension of the isolated preparations was recorded with an isometric transducer. ET-1 and ET-2 triggered concentration-dependent tonic contractions of the isolated isthmic segment and inhibited rhythmic activity, while ET-3 caused no effect. Furthermore, the selective ET(A) antagonist BQ-123 and the selective ET(B) antagonist BQ-788 inhibited the ET-1 effects on both tone and spontaneous rhythmic contractions. These results suggested that during the luteal phase of the menstrual cycle, both ET(A) and ET(B) receptors participate in contractile effects of endothelins on isthmic segment of fallopian tubes, probably regulating the length of time the oocyte remains in the oviduct ampulla.
Asunto(s)
Fase Luteínica/fisiología , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Adulto , Relación Dosis-Respuesta a Droga , Endotelina-1/administración & dosificación , Endotelina-1/metabolismo , Endotelina-1/farmacología , Endotelina-2/administración & dosificación , Endotelina-2/metabolismo , Endotelina-2/farmacología , Endotelina-3/administración & dosificación , Endotelina-3/metabolismo , Endotelina-3/farmacología , Trompas Uterinas/efectos de los fármacos , Trompas Uterinas/fisiología , Femenino , Humanos , Técnicas In Vitro , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Oocitos/metabolismo , Factores de TiempoRESUMEN
The aims of the present study were to determine (1) the hypotensive and regional circulatory effects of centrally administered endothelin (ET) ETA and ETB agonists, and (2) the role of the sympathetic nervous system in the mediation of hypotensive effects due to centrally administered ET-1. The systemic haemodynamics and regional blood circulation in urethane anaesthetized rats following intracerebroventricular (i.c.v.) administration of ET-1, ET-2, SRT6b, ET-3 and SRT6c (10, 30 and 90 ng) were determined by a radioactive microsphere technique. The effect of centrally administered ET-1 on sympathetic nerve activity was also analysed. Systemic haemodynamics and regional blood circulation were determined before (baseline) and 30 min after administration of ET agonists. Cumulative administration of three doses of saline (5 microliters, i.c.v. at 30 min intervals) did not produce any significant cardiovascular effects. ET-1, ET-2 and SRT6b produced a decrease in blood pressure (51%, 47% and 41%, respectively) along with a decrease in cardiac output (58%, 60% and 45%, respectively) and stroke volume. Heart rate and total peripheral resistance were not affected. ET-1, ET-2 and SRT6b also produced a significant reduction in blood flow to the brain, kidneys, heart, portal, mesentery and pancreas, gastrointestinal tract (GIT) and musculoskeletal system. The effect of ET-2 on the cardiovascular system was less intense in comparison with ET-1 and SRT6b. Centrally administered specific ETB receptor agonists ET-3 and SRT6c did not produce any change in systemic haemodynamics and regional blood flow. Centrally administered ET-1 (90 ng) produced a significant decrease (61%) in sympathetic nerve activity 30 min after drug administration, along with a fall in blood pressure. It is concluded that centrally administered ETA agonists produce significant cardiovascular effects mediating through the sympathetic nervous system.
Asunto(s)
Circulación Sanguínea/efectos de los fármacos , Endotelinas/administración & dosificación , Endotelinas/agonistas , Sistema Nervioso Simpático/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Endotelina-1/administración & dosificación , Endotelina-2/administración & dosificación , Endotelina-3/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Azul de Metileno , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Venenos de Víboras/farmacologíaRESUMEN
The three endothlins 1, 2 and 3 (ET-1, ET-2 and ET-3) are 21-amino-acid peptides which in a previous study in the rabbit have been shown to increase both mucociliary activity in the maxillary sinus in vivo and ciliary beat frequency (CBF) in sinus and tracheal samples in vitro. We have also demonstrated positive immunohistochemical staining for endothelin in the epithelium of samples from both maxillary sinus and trachea. The aims of the present investigation were to study the effects of the three endothlins on mucosal blood flow in the maxillary sinus of rabbits and the nasal mucosa of humans. ET-1, ET-2 and ET-3 decreased mucosal blood flow in the maxillary sinus of rabbits measured in vivo with laser Doppler flowmetry (LDF). Significant dose-response relationships were established for all endothelins. A comparison of the regression lines of the dose-response relationships for ET-1 and ET-2 did not show any difference, whereas the regression line of the dose-response relationships for ET-3 differed significantly. Maximum effect was seen at 50.0 pmol/kg ET-1, which reduced blood flow by -74.4 +/- 7.0%. Vasoconstriction became evident 30 s after administration of the endothelins, reached its maximum after 1 min and lasted 10 to 20 min. ET-1 induced stronger vasconstriction than ET-2 and ET-3 at equal dosage, except at 100.0 pmol/kg, where ET-2 had the same effect as ET-1. No tachyphylaxis was observed after repeated 10.0 pmol/kg-dose of ET-1. Similarly, there was no tachyphylactic effect on mucociliary activity in vivo in the maxillary sinus of rabbits after repeated challenges with ET-1 at 10.0 pmol/kg. Pretreatment with the cyclooxygenase inhibitors diclofenac had no inhibitory effect on the vasoconstriction induced by ET-1 at 10.0 and 50.0 pmol/kg. In 6 human volunteers the peak blood flow in the nasal septum decreased by -41.8 +/- 11.6% (p < 0.05) and AUC (area under curve) values decreased by -612.0 +/- 322.4% (p < 0.05) after challenge with 0.1 nmol ET-1, delivered in aerosol form into the nose. The effects of the endothelins on the blood flow in the upper airways of rabbit and man indicate that they have a functional role in the regulation of the mucosal vasculature of the upper airways.