Petersen J S, Shalmi M, Abildgaard U, Christensen N J, Christensen S
Department of Pharmacology, University of Copenhagen, Denmark.
Pharmacol Toxicol. 1992 Jan;70(1):3-12. doi: 10.1111/j.1600-0773.1992.tb00417.x.
Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non-selective alpha-adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide-induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n = 6) was compared with time control animals (n = 9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n = 9), 0.3 (n = 6), 1.0 (n = 7) and 3.0 mg/kg/hr (n = 6). Phentolamine infusion reduced norepinephrine-induced increase in blood pressure at all three dose levels (n = 5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose-dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose-dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FELi) increased to 65 +/- 3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52 +/- 3% during furosemide alone. At steady-state conditions (120-180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume-depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FELi = 48 +/- 2% versus 39 +/- 1% in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular alpha-adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide-induced volume contraction.
为了研究静脉输注非选择性α-肾上腺素能受体拮抗剂酚妥拉明是否能阻断速尿诱导的容量收缩期间的代偿性钠重吸收，在清醒大鼠中进行了清除实验。通过测量菊粉清除率、钠和水的尿排泄率以及锂清除率，分离了对近端和远端肾单位节段的影响。将静脉输注0.3mg/kg/hr酚妥拉明（n = 6）的肾脏效应与时间对照动物（n = 9）进行比较。速尿以恒定静脉输注（7.5mg/kg/hr）给药，同时在四个剂量水平输注酚妥拉明：0（n = 9）、0.3（n = 6）、1.0（n = 7）和3.0mg/kg/hr（n = 6）。在所有三个剂量水平（n = 5）下，酚妥拉明输注均降低了去甲肾上腺素引起的血压升高。酚妥拉明输注诱导了短暂的抗利尿和延长的利钠反应。与仅给予速尿的大鼠相比，酚妥拉明剂量依赖性地减弱了对速尿的利尿和利钠峰值反应。这种效应与平均动脉压的剂量依赖性降低有关。利钠反应降低是由于远端肾单位节段的钠排泄分数降低（在所有酚妥拉明剂量下）和肾小球滤过率降低（1.0和3.0mg/kg/hr酚妥拉明）。在速尿利钠峰值反应期间，酚妥拉明剂量为0.3mg/kg/hr时，锂排泄分数（FELi）增加到65±3%，而仅给予速尿时仅增加到52±3%。在输注速尿加0.3mg/kg/hr酚妥拉明后的稳态条件下（速尿输注开始后120 - 180分钟），动物仍处于容量耗竭状态，但近端小管中的代偿性肾小管钠重吸收受到抑制（FELi = 48±2%，而仅给予速尿的大鼠为39±1%）。在速尿输注期间，血浆肾上腺素增加了700%，血浆去甲肾上腺素增加了50%。这些结果与全身交感神经活动增加以及近端小管α-肾上腺素能受体在急性速尿诱导的容量收缩期间介导代偿性钠重吸收中的作用一致。
