Takase H, Moreau P, Küng C F, Nava E, Lüscher T F
University Hospital, Bern, Switzerland.
Hypertension. 1996 Jan;27(1):25-31. doi: 10.1161/01.hyp.27.1.25.
The objective of this study was to examine the effects of long-term antihypertensive therapy on blood pressure and vascular responses of resistance arteries during prolonged inhibition of nitric oxide synthesis. Four groups of 6-week-old Wistar-Kyoto rats were treated with either placebo as controls or N omega-nitro-L-arginine methyl ester (L-NAME) alone or in combination with verapamil or with trandolapril. Drugs were given orally for 6 weeks or short-term in vitro to vessels obtained from untreated rats. Endothelium-dependent and -independent relaxations as well as contractions were studied in isolated perfused mesenteric and renal arteries with an arteriograph. Kidney nitric oxide synthase activity was also evaluated. Verapamil and trandolapril prevented the increase in systolic blood pressure and the blunted acetylcholine-induced relaxations that occurred with L-NAME treatment without improving the nitric oxide synthase activity. Both antihypertensive regimens also normalized sensitivity to sodium nitroprusside, which was enhanced by L-NAME. In contrast, short-term in vitro preincubation with verapamil or trandolaprilat in the presence of L-NAME did not improve the impaired relaxations to acetylcholine. Long-term but not short-term therapy with a calcium antagonist or angiotensin-converting enzyme inhibitor improved the blunted endothelium-dependent relaxations in nitric oxide-deficient hypertension. These findings strongly suggest that the role of other vasodilator systems, which normally do not regulate vascular tone, is enhanced with long-term but not short-term treatment with these drugs. These observations emphasize the potential importance of these treatments in the management of hypertension in which nitric oxide production is diminished.
本研究的目的是在一氧化氮合成长期受抑制的情况下，考察长期抗高血压治疗对血压及阻力动脉血管反应的影响。将四组6周龄的Wistar-Kyoto大鼠分别作为对照用安慰剂处理，或单独用Nω-硝基-L-精氨酸甲酯（L-NAME）处理，或与维拉帕米联合处理，或与trandolapril联合处理。药物经口服给药6周，或对未处理大鼠的血管进行短期体外给药。使用血管造影仪在离体灌注的肠系膜动脉和肾动脉中研究内皮依赖性和非依赖性舒张以及收缩情况。还评估了肾脏一氧化氮合酶活性。维拉帕米和trandolapril可防止L-NAME治疗引起的收缩压升高以及乙酰胆碱诱导的舒张反应减弱，且未改善一氧化氮合酶活性。两种抗高血压方案还使对硝普钠的敏感性恢复正常，而L-NAME可增强这种敏感性。相比之下，在L-NAME存在的情况下，用维拉帕米或trandolaprilat进行短期体外预孵育并不能改善对乙酰胆碱的舒张功能受损情况。钙拮抗剂或血管紧张素转换酶抑制剂的长期而非短期治疗可改善一氧化氮缺乏型高血压中内皮依赖性舒张反应减弱的情况。这些发现有力地表明，其他通常不调节血管张力的血管舒张系统的作用在这些药物的长期而非短期治疗后增强。这些观察结果强调了这些治疗在一氧化氮生成减少的高血压管理中的潜在重要性。
