RESUMEN
We investigated whether gender differences in renal damage in DOCA-salt hypertension are associated with effects of ovarian hormones and/or endothelin-1 (ET-1). Renal injuries and renal pre-pro-ET-1 mRNA expression were enhanced in male and female ovariectomized (OVX) DOCA rats versus female DOCA rats. Treatment with estrogen plus progesterone or progesterone, but not estrogen alone, attenuated renal damage and pre-pro-ET-1 mRNA expression in OVX DOCA rats. The ETA antagonist BMS182874 greatly ameliorated renal damage in male and OVX DOCA rats. In conclusion, the ovarian hormones have a protective role on the renal structural alterations in female DOCA rats by modulating effects of ET-1, via ETA receptors.
Asunto(s)
Endotelina-1/farmacología , Enfermedades Renales/prevención & control , Riñón/efectos de los fármacos , Caracteres Sexuales , Animales , Compuestos de Dansilo/farmacología , Desoxicorticosterona/antagonistas & inhibidores , Desoxicorticosterona/química , Modelos Animales de Enfermedad , Endotelina-1/genética , Estrógenos/farmacología , Femenino , Hidralazina/farmacología , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Hipertensión/prevención & control , Riñón/química , Riñón/fisiopatología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/fisiopatología , Masculino , Ovariectomía/métodos , Progesterona/farmacología , ARN Mensajero/genética , Ratas , Ratas Wistar , Receptor de Endotelina A/efectos de los fármacos , Cloruro de SodioRESUMEN
The contribution of endothelial factors and mechanisms underlying decreased acetylcholine-induced relaxation and endothelial inhibitory action on phenylephrine-induced contraction were evaluated in aortas of two-kidney, one-clip hypertensive (2K-1C) and normotensive (2K) rats. Relaxation induced by acetylcholine in 2K-1C precontracted by phenylephrine was lower [Maximum Effect (ME): 71.33+/-3.36%; pD(2): 7.050+/-0.03] than in 2K (ME: 95.26+/-1.59%; pD(2): 7.31+/-0.07). This response was abolished by N(G)-nitro-L-arginine (L-NNA) in 2K-1C, but was only reduced in 2K (ME: 29.21+/-9.28%). Indomethacin had no effect in 2K-1C, and slightly attenuated acetylcholine-induced relaxation in 2K. The combination of L-NNA and indomethacin almost abolished acetylcholine-induced relaxation in 2K-1C, while in 2K, the inhibition (ME: 56.61+/-8.95%) was lower than the effect of L-NNA alone. During the KCl-induced precontraction, 2K and 2K-1C aortas showed similar acetylcholine-induced relaxation (43.50+/-5.64% vs. 41.60+/-4.36%), which was abolished by L-NNA. The levels of cGMP produced in response to acetylcholine were not different between 2K and 2K-1C. The sensitivity to sodium nitroprusside was lower in phenylephrine-precontracted aortas from 2K-1C than 2K, as showed by the pD(2) values (7.72+/-0.20 vs. 8.59+/-0.17), and this difference was abolished in aortas precontracted by KCl. The membrane potential was less negative in 2K-1C than in 2K (-41.57+/-1.19 vs. -51.00+/-1.13 mV) and hyperpolarization induced by acetylcholine was lower in 2K-1C than in 2K aortas (6.00+/-0.66 vs. 13.27+/-1.61 mV). Phenylephrine-induced contraction in aortas with endothelium was similar in both groups, and increased by the endothelium removal. This increase was lower in 2K-1C (from 1.32+/-0.06 to 1.90+/-0.21 g) than 2K (from 1.49+/-0.07 to 2.83+/-0.18 g). L-NNA and the endothelium removal had similar effect in 2K-1C (1.85+/-0.18 g) and were lower in 2K (2.18+/-0.20 g). Indomethacin decreased phenylephrine-induced contraction only in 2K. In conclusion, our major finding was a selective defect in smooth muscle membrane hyperpolarization, which could explain the decreased relaxation to acetylcholine and the attenuated inhibitory effect of endothelium on the contractile function in 2K-1C aortas.
Asunto(s)
Acetilcolina/farmacología , Aorta/efectos de los fármacos , Hipertensión Renovascular/fisiopatología , Relajación Muscular/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Factores Biológicos/fisiología , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Endotelio Vascular/efectos de los fármacos , Hipertensión Renal/fisiopatología , Indometacina/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso Vascular/efectos de los fármacos , Fenilefrina/farmacología , Ratas , Ratas Wistar , Estimulación QuímicaRESUMEN
This study examined whether alterations in intracellular or extracellular Ca2+ mobilization were related to differences in caffeine and phenylephrine (PHE)-induced contractions between two-kidney. one-clip hypertensive (2K-1C) and normotensive (2K) rat aortas. After depletion and reloading of intracellular Ca2+ stores, caffeine and PHE-induced contractions in Ca2+-free solution were increased in 2K-1C. Thapsigargin reduced the contraction to caffeine in 2K-1C and 2K with similar sensitivity. PHE-induced contraction in 1.6-mM Ca2+ solution was decreased in 2K-1C, and nifedipine was less effective in lowering this response. The responsiveness to extracellular Ca2+ was decreased in 2K-1C hypertensive rat aortas. Our results indicate an increased intracellular Ca2+ stores that are not related to alteration in Ca2+-ATPase function and a lower contribution of L-type channels to the contraction of 2K-1C aortas.