Kim Soo Mi, Chen Limeng, Mizel Diane, Huang Yuning G, Briggs Josie P, Schnermann Jurgen
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 10, Rm. 4D51, 10 Center Drive-MSC 1370, Bethesda, MD 20892, USA.
Am J Physiol Renal Physiol. 2007 Jan;292(1):F415-22. doi: 10.1152/ajprenal.00317.2006. Epub 2006 Sep 5.
In the current experiments, we determined the response of plasma renin concentration (PRC) to acute intraperitoneal administration of furosemide (40 mg/kg), hydralazine (2 mg/kg), isoproterenol (10 mg/kg), candesartan (50 microg), or quinaprilate (50 microg) in conscious wild-type (WT) and cyclooxygenase (COX)-2-/- mice on three different genetic backgrounds (mixed, C57BL/6, 129J). PRC was measured in plasma obtained by tail vein puncture. Basal PRC was significantly lower in COX-2-/- than WT mice independent of genetic background (51, 10, and 17% of WT in mixed, 129J, and C57BL/6). All five acute interventions caused significant increases of PRC in both COX-2+/+ and -/- mice, but the response was consistently less in COX-2-deficient mice (e.g., DeltaPRC in ng ANG I x ml(-1) x h(-1) caused by furosemide, isoproterenol, hydralazine, quinaprilate, or candesartan 4,699 +/- 544, 3,534 +/- 957, 2,522 +/- 369, 9,453 +/- 1,705, 66,455 +/- 21,938 in 129J WT, and 201 +/- 78, 869 +/- 275, 140 +/- 71, 902 +/- 304, 2,660 +/- 954 in 129J COX-2-/-). A low-NaCl diet and enalapril for 1 wk caused a 14-fold elevation of PRC in COX-2-/- mice and was associated with a greatly increased PRC response to acute furosemide (DeltaPRC 201 +/- 78 before and 15,984 +/- 2,397 after low Na/enalapril). As measured by radiotelemetry, blood pressure and heart rate responses to furosemide, hydralazine, isoproterenol, candesartan, or quinaprilate were not different between COX-2 genotypes. In conclusion, chronic absence of COX-2 reduces renin expression, release, and PRC and is associated with a reduced ability to alter PRC during acute stimulation regardless of the nature of the stimulus. COX-2 activity does not appear to be a mandatory and specific requirement for furosemide-stimulated renin secretion.
在当前实验中，我们测定了清醒的野生型（WT）和环氧合酶（COX）-2基因敲除小鼠在三种不同遗传背景（混合、C57BL/6、129J）下，血浆肾素浓度（PRC）对腹腔内急性注射呋塞米（40 mg/kg）、肼屈嗪（2 mg/kg）、异丙肾上腺素（10 mg/kg）、坎地沙坦（50 μg）或喹那普利拉（50 μg）的反应。通过尾静脉穿刺获取血浆来测量PRC。无论遗传背景如何，COX-2基因敲除小鼠的基础PRC均显著低于WT小鼠（在混合、129J和C57BL/6背景中分别为WT的51%、10%和17%）。所有这五种急性干预均使COX-2+/+和-/-小鼠的PRC显著升高，但COX-2基因缺陷小鼠的反应始终较小（例如，在129J WT小鼠中，呋塞米、异丙肾上腺素、肼屈嗪、喹那普利拉或坎地沙坦引起的PRC变化量[以ng ANG I×ml⁻¹×h⁻¹为单位]分别为4,699±544、3,534±957、2,522±369、9,453±1,705、66,455±21,938，而在129J COX-2基因敲除小鼠中分别为201±78、869±275、140±71、902±304、2,660±954）。低钠饮食和依那普利干预1周使COX-2基因敲除小鼠的PRC升高了14倍，并且与对急性呋塞米的PRC反应大幅增加相关（低钠/依那普利处理前PRC变化量为201±78，处理后为15,984±2,397）。通过无线电遥测测量发现，COX-2不同基因型小鼠对呋塞米、肼屈嗪、异丙肾上腺素、坎地沙坦或喹那普利拉的血压和心率反应并无差异。总之，长期缺乏COX-2会降低肾素表达、释放及PRC，并且与急性刺激期间改变PRC的能力降低相关，无论刺激的性质如何。COX-2活性似乎并非呋塞米刺激肾素分泌的必需且特定条件。
