Kurihara N, Alfie M E, Sigmon D H, Rhaleb N E, Shesely E G, Carretero O A
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI, USA.
Hypertension. 1998 Nov;32(5):856-61. doi: 10.1161/01.hyp.32.5.856.
The role of neural nitric oxide synthase (nNOS) in regulating blood pressure (BP) remains uncertain. Recently it was reported that in mice lacking functional endothelial NOS (eNOS) genes (-/-), acute administration of a nonselective NOS inhibitor, Nw-nitro-L-arginine, decreased mean BP, suggesting that NO released by non-eNOS isoforms increases BP. Because the inducible NOS isoform is not constitutively expressed and when induced causes hypotension, we hypothesize that it is NO produced by nNOS that increases BP in the absence of eNOS activity. To test this hypothesis, we studied the acute effect of selective and nonselective nNOS inhibitors on BP and cerebellar NOS activity in eNOS (-/-), wild-type (+/+), and heterozygous (+/-) mice as well as in +/+ mice with renovascular hypertension. Because it is not known whether the decrease in BP caused by acute NOS inhibition in -/- mice can occur chronically, we also studied the effect of chronic NOS inhibition on both BP and cerebellar NOS activity. eNOS (-/-) mice had higher BP than +/+ or +/-mice, and acute administration of the selective nNOS inhibitor 7-nitroindazole (7-NI) decreased their mean BP from 137+/-13 to 124+/-12 mm Hg (P<0.01). In +/+, +/-, or renovascular hypertensive +/+ mice, 7-NI caused a small but insignificant rise from 105+/-5 to 110+/-6 mm Hg, from 115+/-9 to 119+/-13 mm Hg, and from 146+/-6 to 150+/-6 mm Hg, respectively. Fifteen minutes after administration of 7-NI, cerebellar NOS activity decreased by 70%; however, this inhibitory effect was brief, since 2 hours after 7-NI administration NOS returned toward control values. Chronic oral or intraperitoneal administration of 7-NI did not inhibit cerebellar NOS activity, whereas the nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) decreased this activity by 50%. Therefore, we studied the effect of chronic L-NAME administration (4 weeks) on BP. In -/- mice, chronic L-NAME administration decreased BP from 135+/-4 to 120+/-3 mm Hg (P<0.05), whereas in +/+ and +/-mice, as expected, it increased BP from 109+/-2 to 125+/-3 mm Hg (P<0.001) and from 107+/-6 to 119+/-5 mm Hg (P<0.02), respectively. After L-NAME administration was stopped, BP returned to baseline. These results suggest that in eNOS -/- mice, NO derived from nNOS increases BP both acutely and chronically.
神经型一氧化氮合酶（nNOS）在调节血压（BP）中的作用仍不明确。最近有报道称，在缺乏功能性内皮型一氧化氮合酶（eNOS）基因的小鼠（-/-）中，急性给予非选择性一氧化氮合酶抑制剂Nω-硝基-L-精氨酸可降低平均血压，这表明非eNOS同工型释放的一氧化氮会升高血压。由于诱导型一氧化氮合酶同工型不是组成性表达，且诱导时会导致低血压，我们推测在缺乏eNOS活性的情况下，是nNOS产生的一氧化氮升高了血压。为了验证这一假设，我们研究了选择性和非选择性nNOS抑制剂对eNOS（-/-）、野生型（+/+）和杂合子（+/-）小鼠以及肾血管性高血压的+/+小鼠的血压和小脑一氧化氮合酶活性的急性影响。由于尚不清楚-/-小鼠中急性一氧化氮合酶抑制引起的血压降低是否会长期发生，我们还研究了慢性一氧化氮合酶抑制对血压和小脑一氧化氮合酶活性的影响。eNOS（-/-）小鼠的血压高于+/+或+/-小鼠，急性给予选择性nNOS抑制剂7-硝基吲唑（7-NI）可使其平均血压从137±13降至124±12 mmHg（P<0.01）。在+/+、+/-或肾血管性高血压的+/+小鼠中，7-NI分别使其血压从105±5小幅升高至110±6 mmHg、从115±9升高至119±13 mmHg、从146±6升高至150±6 mmHg，但差异无统计学意义。给予7-NI 15分钟后，小脑一氧化氮合酶活性降低了70%；然而，这种抑制作用是短暂的，因为给予7-NI 2小时后，一氧化氮合酶活性恢复至对照值。慢性口服或腹腔注射7-NI并未抑制小脑一氧化氮合酶活性，而非选择性一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME）可使该活性降低50%。因此，我们研究了慢性给予L-NAME（4周）对血压的影响。在-/-小鼠中，慢性给予L-NAME可使血压从135±4降至120±3 mmHg（P<0.05），而在+/+和+/-小鼠中，则如预期那样使血压分别从109±2升高至125±3 mmHg（P<0.001）和从107±6升高至119±5 mmHg（P<0.02）。停止给予L-NAME后，血压恢复至基线水平。这些结果表明，在eNOS -/-小鼠中，源自nNOS的一氧化氮可急性和慢性升高血压。
