PHOSPHOINOSITOL PATHWAY DEFECT IN ESSENTIAL HYPERTENSION

高血压病患者内皮功能受损 一氧化氮(NO)活性。虽然它的机制尚不清楚，但我们已经 先前的研究表明，这种异常并不局限于受体 或G蛋白水平。为了调查血管内皮细胞 HTS功能障碍与细胞内更远端的缺陷有关 信号转导，我们研究了前臂血流对 动脉内输注异丙肾上腺素(ISO；50-200 ng/min)，β2 通过Gs蛋白/cAMP途径刺激NO释放的激动剂， 和乙酰胆碱(Ach；7.5-30微克/分钟)，一种内皮激动剂， 在12名正常血压(NTS)患者中，通过Gi/o/磷酸肌醇途径发挥作用 和12个HTS。同时重复输注ISO 静脉滴注NO合成阻滞剂L-NMMA(4微克/分)。这个 与对照组相比，HTS患者对ACh的血管扩张反应显著降低 至NTS(最大流量：10.4+/-4.6vs.14.4+/-3.7mL/min/dL；P=0.008)。 然而，在NTS和HTS中，ISO的血管扩张作用相似 (最大流量：14.4+/-5.4vs13.5+/-5mL/min/dL；P=0.56)， 在两组中，L-NMMA显著且同等程度地削弱了(22%+/-15%) NTS组+/-16%，HTS组23+/-16%，P=0.83。血管扩张剂对钠的反应 外源性NO供体硝普钠(0.8-3.2微克/分钟)也是类似的 两组均未经L-NMMA修饰。因此，在HTS受损的情况下 ACh的内皮依赖性血管扩张反应中的NO释放 β2-肾上腺素能刺激被保存下来。这些发现表明 高血压患者的内皮功能异常至少部分是 与磷酸肌醇途径的缺陷有关。

Patients with essential hypertension (HTs) have impaired endothelial nitric oxide (NO) activity. Although its mechanism is unknown, we have previously shown that the abnormality is not localized at the receptor or the G protein level. To investigate whether the endothelial dysfunction of HTs is related to a more distal defect in intracellular signal transduction, we studied the forearm blood flow response to intraarterial infusion of isoproterenol (ISO; 50-200 ng/min), a beta2 agonist that stimulates NO release through the Gs protein/cAMP pathway, and acetylcholine (Ach; 7.5-30 microg/min), an endothelial agonist that acts through the Gi/o/phosphoinositol pathway, in 12 normotensives (NTs) and 12 HTs. The infusion of ISO was repeated during the concurrent infusion of L-NMMA (4 micromol/min), a blocker of NO synthesis. The vasodilator response to ACh was significantly reduced in HTs compared to NTs (maximum flow: 10.4+/-4.6 vs. 14.4+/-3.7 mL/min/dL; P=0.008). However, the vasodilator effect of ISO was similar in NTs and HTs (maximum flow: 14.4+/-5.4 vs 13.5+/-5 mL/min/dL; P=0.56), and was significantly and equally blunted by L-NMMA in both groups (22+/-15% in NTs vs 23+/-16% in HTs; P=0.83). The vasodilator response to sodium nitroprusside (0.8-3.2 microg/min), an exogenous NO donor, was similar in both groups and not modified by L-NMMA. Thus, in HTs with impaired endothelium-dependent vasodilation to ACh, the NO release in response to beta2- adrenergic stimulation is preserved. These findings suggest that the endothelial abnormality in hypertension is at least partly related to a defect in the phosphoinositol pathway.