Hoffman A, Abassi Z A, Brodsky S, Ramadan R, Winaver J
Department of Vascular Surgery, Rambam Medical Center, Haifa, Israel.
Hypertension. 2000 Mar;35(3):732-9. doi: 10.1161/01.hyp.35.3.732.
Endothelin-1 (ET-1) at high concentrations has marked antidiuretic and antinatriuretic activities, whereas its precursor, big endothelin-1 (big ET-1), has surprisingly potent diuretic and natriuretic actions. The mechanisms underlying the excretory effects of big ET-1 have not been fully elucidated. To explore these mechanisms, we examined the effects of a highly selective ET(B) antagonist (A-192621.1), a calcium channel blocker (verapamil), a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]), and a cyclooxygenase inhibitor (indomethacin) on the systemic and renal actions of big ET-1 in anesthetized rats. An intravenous bolus injection of incremental doses of big ET-1 (0.3, 1. 0, and 3.0 nmol/kg) produced a significant hypertensive effect that was dose dependent and prolonged (from 113+/-7 mm Hg to a maximum of 148+/-6 mm Hg). The administration of big ET-1 induced marked diuretic and natriuretic responses (urinary flow rate increased from 8.5+/-1 to 110+/-14 microL/min, and fractional excretion of sodium increased from 0.38+/-0.13% to 7.51+/-1.24%). Glomerular filtration rate and renal plasma flow significantly decreased only at the highest dose of big ET-1. Pretreatment with A-192621.1 (3 mg/kg plus 3 mg. kg(-1). h(-1)) significantly abolished the diuretic (17+/-5 microL/min to a maximum of 19+/-3 microL/min) and natriuretic (0. 29+/-0.1% to a maximum of 1.93+/-0.37%) responses induced by big ET-1. Moreover, A-192621.1 potentiated the decline in glomerular filtration rate and renal plasma flow and the increase in mean arterial blood pressure produced by the low doses of big ET-1. Similar to A-192621.1, pretreatment with a nitric oxide synthase inhibitor (L-NAME, 10 mg/kg plus 5 mg. kg(-1). h(-1)) significantly and comparably reduced the diuretic and natriuretic actions of big ET-1 and augmented the hypoperfusion/hypofiltration and systemic vasoconstriction induced by high doses of the peptide. Pretreatment with verapamil (2 mg. kg(-1). h(-1)) slightly inhibited the diuretic/natriuretic effects of the high-dose big ET-1 and completely prevented the increase in mean arterial blood pressure provoked by the peptide. Unlike verapamil and L-NAME, only indomethacin administration was associated with significant natriuretic/diuretic responses and did not influence the pressor effect and renal actions of big ET-1. Taken together, these results suggest that big ET-1-induced diuretic and natriuretic responses are mediated mainly by stimulation of nitric oxide production coupled to ET(B) receptor subtype activation.
高浓度的内皮素 -1（ET -1）具有显著的抗利尿和抗利钠活性，而其前体大内皮素 -1（big ET -1）却具有惊人的强效利尿和利钠作用。big ET -1排泄作用的潜在机制尚未完全阐明。为探究这些机制，我们在麻醉大鼠中研究了一种高选择性ET(B)拮抗剂（A -192621.1）、一种钙通道阻滞剂（维拉帕米）、一种一氧化氮合酶抑制剂（N -硝基 -L -精氨酸甲酯 [L -NAME]）和一种环氧化酶抑制剂（吲哚美辛）对big ET -1全身和肾脏作用的影响。静脉推注递增剂量的big ET -1（0.3、1.0和3.0 nmol/kg）产生了显著的高血压效应，该效应呈剂量依赖性且持续时间长（从113±7 mmHg升至最高148±6 mmHg）。big ET -1的给药诱导了显著的利尿和利钠反应（尿流率从8.5±1微升/分钟增加到110±14微升/分钟，钠分数排泄从0.38±0.13%增加到7.51±1.24%）。仅在big ET -1的最高剂量时，肾小球滤过率和肾血浆流量显著降低。用A -192621.1（3 mg/kg加3 mg·kg⁻¹·h⁻¹）预处理可显著消除big ET -1诱导的利尿（从17±5微升/分钟降至最高19±3微升/分钟）和利钠（从0.29±0.1%降至最高1.93±0.37%）反应。此外，A -192621.1增强了低剂量big ET -1引起的肾小球滤过率和肾血浆流量的下降以及平均动脉血压的升高。与A -192621.1类似，用一氧化氮合酶抑制剂（L -NAME，10 mg/kg加5 mg·kg⁻¹·h⁻¹）预处理可显著且同等程度地降低big ET -1的利尿和利钠作用，并增强高剂量该肽诱导的低灌注/低滤过和全身血管收缩。用维拉帕米（2 mg·kg⁻¹·h⁻¹）预处理可轻微抑制高剂量big ET -1的利尿/利钠作用，并完全阻止该肽引起的平均动脉血压升高。与维拉帕米和L -NAME不同，仅给予吲哚美辛会产生显著的利钠/利尿反应，且不影响big ET -1的升压作用和肾脏作用。综上所述，这些结果表明big ET -1诱导的利尿和利钠反应主要通过刺激一氧化氮生成并与ET(B)受体亚型激活相关联来介导。
