Greven J, Gabriëls G
Institute of Pharmacology and Toxicology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
Arzneimittelforschung. 2000 Nov;50(11):973-9. doi: 10.1055/s-0031-1300320.
Nebivolol (CAS 99200-09-6) is a novel beta 1-selective adrenoceptor antagonist which possesses vasodilating properties and lowers systemic vascular resistance in dogs and humans, presumably by a nitric oxide-related mechanism. In the present study, clearance techniques were applied to anaesthetized male Sprague Dawley rats, and the effects of nebivolol on renal hemodynamics (glomerular filtration rate and renal plasma flow), on urinary excretion of sodium, chloride and potassium, on renal NO-excretion, and on plasma renin activity were studied. Nebivolol doses ranging from 0.1 to 2 mg/kg i.v. were tested. The results revealed that nebivolol dose-dependently increased glomerular filtration rate, urine flow and urinary excretion of sodium and chloride. Potassium excretion was only inconsistently increased and showed no dose dependency. At a dose of 1 mg/kg, the drug also significantly increased renal plasma flow measured as 3H-PAH (p-aminohippurate) clearance. The effect of nebivolol on the glomerular filtration rate could be abolished by L-NMMA (N6-monomethyl-L-arginine) (1 mg/kg), a non-selective inhibitor of NO-synthase and by iminoethyllysine (1 mg/kg), a relatively selective inhibitor of the inducible NO-synthase, but not by 7-nitroindazole (1 mg/kg), a relatively selective inhibitor of the neuronal NO-synthase isoform. The saluretic effect of nebivolol was diminished by all of the three NO-synthase inhibitors, but could not be completely reversed. At a dose of 2 mg/kg, nebivolol increased renal NO-excretion by 70.7%. This effect could be completely abolished by L-NMMA (1 mg/kg). Plasma renin activity was lowered by nebivolol (2 mg/kg) from 14.6 +/- 1.49 to 6.5 +/- 1.66 ng angiotensin I/ml/h (p < 0.01). The results demonstrate that, in anaesthetized rats, nebivolol exerts significant renal vasodilating effects and increases urinary excretion of fluid and solutes. The actions of nebivolol on renal hemodynamics are assumed to be mediated by a stimulation of the NO-synthase, probably the inducible isoform. Since none of the NO-synthase inhibitors could completely abolish the saluretic effect of nebivolol, an additional mechanism, not related to NO, may be involved in the tubular action of this drug.
奈必洛尔（CAS 99200-09-6）是一种新型的β1选择性肾上腺素能受体拮抗剂，具有血管舒张特性，可降低犬类和人类的全身血管阻力，推测其作用机制与一氧化氮相关。在本研究中，采用清除技术对麻醉的雄性斯普拉格-道利大鼠进行实验，研究了奈必洛尔对肾血流动力学（肾小球滤过率和肾血浆流量）、钠、氯和钾的尿排泄、肾一氧化氮排泄以及血浆肾素活性的影响。静脉注射剂量范围为0.1至2mg/kg的奈必洛尔进行了测试。结果显示，奈必洛尔剂量依赖性地增加肾小球滤过率、尿流量以及钠和氯的尿排泄。钾排泄仅偶尔增加，且无剂量依赖性。在1mg/kg的剂量下，该药物还显著增加了以3H-对氨基马尿酸（PAH）清除率衡量的肾血浆流量。奈必洛尔对肾小球滤过率的影响可被L-NMMA（N6-单甲基-L-精氨酸）（1mg/kg，一种一氧化氮合酶的非选择性抑制剂）和亚氨基乙基赖氨酸（1mg/kg，一种诱导型一氧化氮合酶的相对选择性抑制剂）消除，但不能被7-硝基吲唑（1mg/kg，一种神经元型一氧化氮合酶同工型的相对选择性抑制剂）消除。奈必洛尔的利钠作用被所有三种一氧化氮合酶抑制剂减弱，但不能完全逆转。在2mg/kg的剂量下，奈必洛尔使肾一氧化氮排泄增加70.7%。这种作用可被L-NMMA（1mg/kg）完全消除。奈必洛尔（2mg/kg）使血浆肾素活性从14.6±1.49降至6.5±1.66ng血管紧张素I/ml/h（p<0.01）。结果表明，在麻醉大鼠中，奈必洛尔具有显著的肾血管舒张作用，并增加液体和溶质的尿排泄。奈必洛尔对肾血流动力学的作用被认为是通过刺激一氧化氮合酶介导的，可能是诱导型同工型。由于没有一种一氧化氮合酶抑制剂能完全消除奈必洛尔的利钠作用，该药物在肾小管的作用可能涉及一种与一氧化氮无关的额外机制。
