Qadri Fatimunnisa, Arens Thomas, Schwarz Eike-Christian, Häuser Walter, Dendorfer Andreas, Dominiak Peter
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
J Hypertens. 2003 Sep;21(9):1687-94. doi: 10.1097/00004872-200309000-00018.
Blockade of neuronal nitric oxide synthase (nNOS) in the brain induced an increase in mean arterial pressure of spontaneously hypertensive rats (SHR). We hypothesize that increased nitric oxide (NO) synthesis in the brain compensates for hypertension. Therefore, we measured NOS activity in different brain regions in SHR at prehypertensive, onset and established hypertension, and compared with age-matched Wistar-Kyoto (WKY) rats.
NOS activity was measured by the ability of tissue homogenate to convert [3H]l-arginine to [3H]l-citrulline in a Ca2+- and NADPH-dependent manner.
NOS activity was impaired in the cerebral cortex and brainstem of prehypertensive SHR. At established hypertension, SHR showed an augmentation in NOS activity in hypothalamus and brainstem. Chronic treatment of SHR with the angiotensin-1 converting enzyme (ACE)-inhibitor, enalapril, and the AT(1) receptor antagonist, losartan, normalized NOS activity in the hypothalamus but not in the brainstem. Treatment with a peripheral vasodilator, hydralazine, did not affect NOS activity.
Attenuated NOS activity in the cortex and brainstem of prehypertensive SHR may play a role in the pathogenesis of hypertension. The upregulated NOS activity in the hypothalamus and brainstem of SHR possibly serves to compensate for hypertension. Hypothalamic, but not brainstem, NO is involved in antihypertensive effects of ACE inhibition and AT(1) receptor blockade. Since a blood pressure decrease per se had no effect on NOS activity, it appears that central sympathetic activity influenced by endogenous angiotensin II, rather than blood pressure, represents the stimulus for the increased NOS activity in the hypothalamus of SHR.
阻断大脑中的神经元型一氧化氮合酶（nNOS）可使自发性高血压大鼠（SHR）的平均动脉压升高。我们推测大脑中一氧化氮（NO）合成增加可代偿高血压。因此，我们测定了SHR在高血压前期、发病期和高血压确立期不同脑区的一氧化氮合酶（NOS）活性，并与年龄匹配的Wistar-Kyoto（WKY）大鼠进行比较。
通过组织匀浆在Ca2+和NADPH依赖的方式下将[3H]L-精氨酸转化为[3H]L-瓜氨酸的能力来测定NOS活性。
高血压前期SHR的大脑皮质和脑干中NOS活性受损。在高血压确立期，SHR下丘脑和脑干中的NOS活性增强。用血管紧张素转换酶（ACE）抑制剂依那普利和AT（1）受体拮抗剂氯沙坦长期治疗SHR，可使下丘脑的NOS活性恢复正常，但脑干中的NOS活性未恢复正常。用外周血管扩张剂肼屈嗪治疗不影响NOS活性。
高血压前期SHR皮质和脑干中NOS活性减弱可能在高血压发病机制中起作用。SHR下丘脑和脑干中上调的NOS活性可能是为了代偿高血压。下丘脑而非脑干中的NO参与了ACE抑制和AT（1）受体阻断的降压作用。由于血压下降本身对NOS活性没有影响，因此似乎内源性血管紧张素II影响的中枢交感神经活动而非血压，是SHR下丘脑NOS活性增加的刺激因素。
