Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, A. Pawińskiego 5, 02-106, Warsaw, Poland.
Laboratory of Experimental Hypertension, Institute of Physiology, Czech Academy of Sciences, Czech Republic.
Eur J Pharmacol. 2021 Nov 5;910:174445. doi: 10.1016/j.ejphar.2021.174445. Epub 2021 Sep 4.
Endothelin 1 (ET-1) seems essential in salt-dependent hypertension, and activation of ETA receptors causes renal vasoconstriction. However, the response in the renal medulla and the role of tissue NO availability has never been adequately explored in vivo. We examined effects of ETA and ETB receptor blockade (atrasentan and BQ788) on blood pressure (MAP), medullary blood flow (MBF) and medullary tissue NO. Effects of systemic and intramedullary blocker application were compared in anesthetized normotensive ET-1-pretreated Sprague-Dawley rats (S-D), in salt-dependent hypertension (HS/UNX) and in spontaneously hypertensive rats (SHR). Total renal blood flow (RBF) was measured using a Transonic renal artery probe, MBF as laser-Doppler flux, and tissue NO signal using selective electrodes. In normotensive rats ET-1 significantly increased MAP, decreased RBF (-20%) and renal medullary NO. In HS/UNX rats atrasentan decreased MAP and increased medullary NO, earlier and more profoundly with intravenous infusion. In SHR atrasentan decreased MAP, more effectively with intravenous infusion; the increase in tissue NO (∼10%) was similar with both routes; however, only intramedullary atrasentan increased MBF. No consistent responses to BQ788 were seen. We confirmed dominant role of ETA receptors in regulation of blood pressure and renal hemodynamics in normotensive and hypertensive rats and provided novel evidence for the role of ETA in control of intrarenal NO bioavailability in salt-dependent and spontaneous hypertension. Under conditions of activation of the endothelin system ETB stimulation preserved medullary perfusion.
内皮素 1（ET-1）似乎在盐依赖性高血压中至关重要，ETA 受体的激活会导致肾血管收缩。然而，在体内，肾髓质的反应和组织中一氧化氮（NO）可用性的作用从未得到充分探索。我们研究了 ETA 和 ETB 受体阻滞剂（atrasentan 和 BQ788）对血压（MAP）、髓质血流（MBF）和髓质组织 NO 的影响。在麻醉的正常血压 ET-1 预处理的 Sprague-Dawley 大鼠（S-D）、盐依赖性高血压（HS/UNX）和自发性高血压大鼠（SHR）中，比较了全身和髓内阻滞剂应用的效果。使用 Transonic 肾动脉探头测量总肾血流量（RBF），激光多普勒通量测量 MBF，选择性电极测量组织 NO 信号。在正常血压大鼠中，ET-1 显著增加 MAP，减少 RBF（-20%）和肾髓质 NO。在 HS/UNX 大鼠中，atrasentan 降低 MAP，并更早和更显著地增加髓质 NO，静脉输注时效果更明显。在 SHR 中，atrasentan 降低 MAP，静脉输注时效果更显著；组织 NO 的增加（约 10%）与两种途径相似；然而，只有髓内 atrasentan 增加 MBF。对 BQ788 没有一致的反应。我们证实了 ETA 受体在正常血压和高血压大鼠血压和肾血液动力学调节中的主导作用，并为 ETB 在盐依赖性和自发性高血压中控制肾内 NO 生物利用度的作用提供了新的证据。在内皮素系统激活的情况下，ETB 刺激可维持髓质灌注。
