Izuta M, Clavier N, Kirsch J R, Traystman R J
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Md. 21287-4963, USA.
Stroke. 1995 Jun;26(6):1079-85. doi: 10.1161/01.str.26.6.1079.
Because tonic production of nitric oxide (NO) is important in regulating cerebrovascular tone and NO may be important in the mechanism of brain injury from focal ischemia, we speculated that stroke predisposition in spontaneously hypertensive stroke-prone rats (SHR-SP) may be related to impaired tonic production of NO. This study was designed to test the hypothesis that the cerebral blood flow (CBF) response to inhibition of NO synthase in SHR-SP would be different than that observed in normal Wistar-Kyoto (WKY) rats and non-stroke-prone spontaneously hypertensive rats (SHR).
Pentobarbital-anesthetized, mechanically ventilated rats were tested for CBF response to saline, 5 or 20 mg/kg IV of NG-monomethyl-L-arginine (L-NMMA), or 20 mg/kg IV of N omega-nitro-L-arginine (L-NA). In addition, specificity for an NO-dependent mechanism was assessed by determining the ability to reverse any alteration in CBF with L-arginine. Hemorrhage was used to minimize any increase in mean arterial blood pressure (MABP) from NO synthase inhibition. In a separate cohort of rats, differential sensitivity of NO synthase for inhibition by nitro-arginine analogues was determined.
Baseline MABP was greater in SHR-SP (185 +/- 3, n = 38) and SHR (169 +/- 3, n = 38) compared with WKY rats (101 +/- 2 mm Hg, n = 38, P < .05). Baseline CBF was similar between strains; however, cerebrovascular resistance was higher in SHR-SP (2.16 +/- 0.09, n = 27) and SHR (1.94 +/- 0.07, n = 27) compared with WKY rats (1.23 +/- 0.06 mm Hg/mL per minute per 100 g, n = 27, P < .05). CBF was unchanged with 5 mg/kg L-NMMA or with L-arginine in the absence of L-NMMA in each strain. CBF decreased similarly in SHR and SHR-SP (n = 9 each) in response to 20 mg/kg L-NMMA (SHR, 85 +/- 6 to 67 +/- 6; SHR-SP, 87 +/- 7 to 69 +/- 5 mL/min per 100 g) and was completely reversed by L-arginine. CBF did not decrease with 20 mg/kg L-NMMA in WKY rats. Administration of L-NA (n = 5 each) produced similar reduction of CBF (WKY rats, 67 +/- 6%; SHR, 49 +/- 9%; SHR-SP, 61 +/- 6% of baseline) and inhibition of NO synthase in each strain (approximately 80% inhibition).
There was no difference in the cerebrovascular response to NO synthase inhibition in SHR-SP and non-stroke-prone SHR. Therefore, it is unlikely that an altered sensitivity of NO synthase to inhibition can explain predisposition to stroke in SHR-SP.
由于一氧化氮（NO）的持续性生成在调节脑血管张力中起重要作用，且NO可能在局灶性缺血性脑损伤机制中具有重要意义，我们推测自发性高血压易中风大鼠（SHR-SP）的中风易感性可能与NO的持续性生成受损有关。本研究旨在验证以下假设：SHR-SP中脑血流量（CBF）对一氧化氮合酶抑制的反应与正常Wistar-Kyoto（WKY）大鼠和非中风易发性自发性高血压大鼠（SHR）中观察到的反应不同。
对戊巴比妥麻醉、机械通气的大鼠进行测试，观察其对生理盐水、静脉注射5或20 mg/kg NG-单甲基-L-精氨酸（L-NMMA）或静脉注射20 mg/kg Nω-硝基-L-精氨酸（L-NA）的CBF反应。此外，通过测定L-精氨酸逆转CBF任何改变的能力来评估对NO依赖性机制的特异性。采用出血措施使一氧化氮合酶抑制引起的平均动脉血压（MABP）升高最小化。在另一组大鼠中，测定硝基精氨酸类似物对一氧化氮合酶抑制的差异敏感性。
与WKY大鼠（101±2 mmHg，n = 38，P <.05）相比，SHR-SP（185±3，n = 38）和SHR（169±3，n = 38）的基线MABP更高。各品系间基线CBF相似；然而，与WKY大鼠（1.23±0.06 mmHg/mL每分钟每100 g，n = 27，P <.05）相比，SHR-SP（2.16±0.09，n = 27）和SHR（1.94±0.07，n = 27）的脑血管阻力更高。在每个品系中，5 mg/kg L-NMMA或无L-NMMA时L-精氨酸对CBF无影响。SHR和SHR-SP（各n = 9）对20 mg/kg L-NMMA的反应中CBF类似地降低（SHR，85±6至67±6；SHR-SP，87±7至69±5 mL/min每100 g），且被L-精氨酸完全逆转。WKY大鼠中20 mg/kg L-NMMA未使CBF降低。给予L-NA（各n = 5）使每个品系的CBF产生类似程度的降低（WKY大鼠，67±6%；SHR，49±9%；SHR-SP，61±6%的基线）并抑制一氧化氮合酶（约80%抑制）。
SHR-SP和非中风易发性SHR对一氧化氮合酶抑制的脑血管反应无差异。因此，一氧化氮合酶对抑制的敏感性改变不太可能解释SHR-SP的中风易感性。
