Cavarape Alessandro, Bauer Johannes, Bartoli Ettore, Endlich Karlhans, Parekh Niranjan
Department of Experimental and Clinical Pathology and Medicine, Chair of Internal Medicine, University of Udine, Udine, Italy.
Nephrol Dial Transplant. 2003 Sep;18(9):1764-9. doi: 10.1093/ndt/gfg291.
Angiotensin II (Ang II), arginine vasopressin (AVP) and tromboxane A(2) (TxA(2)) are dissimilar vasoconstrictors involved in regulating renal circulation. Whereas Ang II is primarily a physiological modulator, AVP and TxA(2) play important roles under pathological conditions. Previously, we have shown variable importance of intracellular Ca(2+) and protein kinase C for their mode of action (Ang II > AVP >U-46619), but the cell signalling via rho-associated kinase (ROK) is a common pathway. The aim of this study was to determine their sites of action in the renal vascular bed and the corresponding role of ROK at the microvascular level.
Glomerular blood flow (GBF) and luminal diameter of different vessels (10-70 micro m) were measured in the split hydronephrotic kidney of anaesthetized rats. The tissue bath concentration of Ang II, AVP or the TxA(2) agonist U-46619 was adjusted to reduce GBF by approximately 50%. The measurements were repeated after adding a sub-maximal dose of the ROK inhibitor Y-27632 into the bath.
Ang II constricted all vessels significantly, the constriction being least in the proximal segment of the arcuate artery ( approximately 70 micro m). Significant constrictions due to AVP were found only in interlobular and arcuate arteries (20-70 micro m), but not in the afferent and efferent arterioles. U-46619 constricted only the arcuate artery (> or = 50 micro m). Y-27632 (10(-4) M) dilated all vessels significantly and increased GBF by 65%. Thereafter, effects of all agonists were severely attenuated. Control reductions in GBF could be obtained at higher concentrations of AVP (10-fold) and U-46619 (5-fold) and a lesser GBF reduction with Ang II (100-fold) without changes in the respective patterns of vascular constriction.
Our data indicate that the agonists, in the order Ang II, AVP and TxA(2), constrict larger vessels within the renal vascular tree via activation of ROK. Therefore, ROK inhibitors may provide a therapeutic tool to antagonize pathological vasospasm of conduit vessels, which are resistant to other vasodilators.
血管紧张素II（Ang II）、精氨酸加压素（AVP）和血栓素A2（TxA2）是参与调节肾循环的不同血管收缩剂。Ang II主要是一种生理调节剂，而AVP和TxA2在病理条件下起重要作用。此前，我们已表明细胞内Ca2+和蛋白激酶C对它们作用方式的重要性各异（Ang II > AVP > U-46619），但通过rho相关激酶（ROK）的细胞信号传导是一条共同途径。本研究的目的是确定它们在肾血管床中的作用位点以及ROK在微血管水平的相应作用。
在麻醉大鼠的分离肾积水肾脏中测量肾小球血流量（GBF）和不同血管（10 - 70μm）的管腔直径。调整Ang II、AVP或TxA2激动剂U-46619的组织浴浓度，使GBF降低约50%。在浴中加入次最大剂量的ROK抑制剂Y-27632后重复测量。
Ang II使所有血管显著收缩，在弓形动脉近端段（约70μm）收缩最小。AVP引起的显著收缩仅见于小叶间动脉和弓形动脉（20 - 70μm），而在入球小动脉和出球小动脉中未观察到。U-46619仅使弓形动脉（≥50μm）收缩。Y-27632（10-4 M）使所有血管显著扩张，GBF增加65%。此后，所有激动剂的作用均明显减弱。在更高浓度的AVP（10倍）和U-46619（5倍）以及较低浓度的Ang II（100倍）下可获得对照GBF降低，且各自的血管收缩模式无变化。
我们的数据表明，激动剂按Ang II、AVP和TxA2的顺序，通过激活ROK使肾血管树内的较大血管收缩。因此，ROK抑制剂可能提供一种治疗工具，以拮抗对其他血管扩张剂有抗性的传导血管的病理性血管痉挛。
