Barthelmebs M, Mayer P, Thomas A, Grima M, Imbs J L
Institut de Pharmacologie, URA DO589 CNRS, Université Louis Pasteur, Faculté de Médecine, Strasbourg, France.
Hypertens Res. 1995 Jun;18 Suppl 1:S131-6. doi: 10.1291/hypres.18.supplementi_s131.
Both insulin-dependent diabetes mellitus (IDDM) and unilateral nephrectomy (UNX) are associated with an increase in the glomerular filtration rate. Glomerular hyperfiltration has been linked to intraglomerular hypertension in both conditions, although it has only been linked to the development of nephropathy in diabetes. In this study, we examined the possibility of preventing diabetic nephropathy through early dopamine (DA) prodrugs treatment and we also investigated the participation of endogenous DA in the acute functional adaptation of the remaining kidney after UNX. In an animal model of IDDM (steptozotocin-treated Wistar rats), the early increase in the glomerular filtration rate was prevented by treatment with DA prodrugs (L-dopa or gludopa), an effect which was mimicked by fenoldopam (a D1 agonist) and suppressed by carbidopa and SCH 23390 (a D1 antagonist). An increase in endorenal DA synthesis and the subsequent stimulation of vascular D1 receptors appears to prevent early glomerular hyperfiltration in diabetic rats. However, in a long-term study lasting more than one year, streptozotocin-diabetic Wistar rats (unlike to diabetic Munich Wistar rats) failed to develop overt nephropathy characterized by albuminuria and systemic hypertension. During long-term treatment of diabetic rats with L-dopa, the renal availability of DA was diminished. The acute adaptation of the remaining kidney to UNX took the form of an early transient pressor effect with a moderate increase in the glomerular filtration rate and renal blood flow, and a marked decrease in tubular sodium reabsorption. SCH 23390 suppressed the hemodynamic and tubular responses to UNX, suggesting that endogenous DA plays a key role.
胰岛素依赖型糖尿病（IDDM）和单侧肾切除（UNX）均与肾小球滤过率升高有关。在这两种情况下，肾小球高滤过都与肾小球内高压有关，尽管它仅与糖尿病肾病的发生有关。在本研究中，我们研究了通过早期多巴胺（DA）前体药物治疗预防糖尿病肾病的可能性，并且我们还研究了内源性DA在UNX后剩余肾脏的急性功能适应中的作用。在IDDM动物模型（链脲佐菌素处理的Wistar大鼠）中，DA前体药物（左旋多巴或谷多巴）治疗可预防肾小球滤过率的早期升高，非诺多泮（一种D1激动剂）可模拟这种作用，而卡比多巴和SCH 23390（一种D1拮抗剂）可抑制这种作用。肾内DA合成增加以及随后对血管D1受体的刺激似乎可预防糖尿病大鼠早期肾小球高滤过。然而，在一项持续一年以上的长期研究中，链脲佐菌素诱导的糖尿病Wistar大鼠（与糖尿病慕尼黑Wistar大鼠不同）未出现以蛋白尿和全身性高血压为特征的明显肾病。在用左旋多巴长期治疗糖尿病大鼠期间，肾脏中DA的可用性降低。剩余肾脏对UNX的急性适应表现为早期短暂的升压作用，同时肾小球滤过率和肾血流量适度增加，而肾小管钠重吸收明显减少。SCH 23390抑制了对UNX的血流动力学和肾小管反应，表明内源性DA起关键作用。
