Silldorff E P, Yang S, Pallone T L
Department of Medicine, Pennsylvania State University, Hershey Medical Center, Hershey 17033, USA.
J Clin Invest. 1995 Jun;95(6):2734-40. doi: 10.1172/JCI117976.
Endothelins (ET) and prostaglandin E2 are synthesized in the inner medulla by collecting duct epithelium and interstitial cells, respectively. All ascending vasa recta (AVR) blood returns from the inner medulla to the cortex in outer medullary vascular bundles. We reasoned that hormones might influence medullary blood flow by diffusing across AVR fenestrations to modulate vasoconstriction of outer medullary descending vasa recta (OMDVR). To investigate this possibility, OMDVR dissected from vascular bundles were exposed to ET-1, 2, or 3. Each endothelin isoform induced stable vasoconstriction with potency, ET-1 > ET-2 > ET-3 (EC50, 1.8 x 10(-15), 5.9 x 10(-12), and 8.8 x 10(-10) M, respectively). The ETA receptor antagonist BQ-123 and BQ-610 (10(-6) M), as well as an ETA and ETB receptor antagonist combination, attenuated vasoconstriction due to ET-1 (10(-12) M). BQ-123 had no effect on the response to ET-3 (10(-8) M). The ETB receptor antagonist BQ-788 (10(-6) M) attenuated the response to ET-3 (10(-10) M), but not that to ET-1 (10(-12) M). Finally, PGE2 (10(-6) M) reversibly dilated OMDVR preconstricted with ET-1 (10(-12) M) or ET-3 (10(-8) M) but not ET-1 (10(-10) M). We conclude that ET-1,2, and 3 are potent constrictors of OMDVR and the response to ET-1 is mainly ETA receptor subtype mediated, while ET-3 acts via the ETB. PGE2 modulates ET induced constriction. These findings are consistent with interactive feedback and control of medullary perfusion by locally synthesized hormones.
内皮素（ET）和前列腺素E2分别由集合管上皮细胞和间质细胞在内髓质中合成。所有直小血管升支（AVR）的血液都通过外髓质血管束从内髓质回流到皮质。我们推测，激素可能通过扩散穿过AVR的窗孔来调节外髓质直小血管降支（OMDVR）的血管收缩，从而影响髓质血流。为了研究这种可能性，从血管束中分离出的OMDVR被暴露于ET-1、ET-2或ET-3。每种内皮素同工型均能诱导稳定的血管收缩，其效力为ET-1>ET-2>ET-3（EC50分别为1.8×10⁻¹⁵、5.9×10⁻¹²和8.8×10⁻¹⁰ M）。ETA受体拮抗剂BQ-123和BQ-610（10⁻⁶ M）以及ETA和ETB受体拮抗剂组合可减弱ET-1（10⁻¹² M）引起的血管收缩。BQ-123对ET-3（10⁻⁸ M）的反应无影响。ETB受体拮抗剂BQ-788（10⁻⁶ M）可减弱对ET-3（10⁻¹⁰ M）的反应，但对ET-1（10⁻¹² M）的反应无影响。最后，前列腺素E2（10⁻⁶ M）可使预先用ET-1（10⁻¹² M）或ET-3（10⁻⁸ M）预收缩的OMDVR可逆性舒张，但对ET-1（10⁻¹⁰ M）无效。我们得出结论，ET-1、2和3是OMDVR的强效收缩剂，对ET-1的反应主要由ETA受体亚型介导，而ET-3通过ETB起作用。前列腺素E2调节ET诱导的收缩。这些发现与局部合成激素对髓质灌注的相互反馈和控制一致。
