Jameson M, Dai F X, Lüscher T, Skopec J, Diederich A, Diederich D
Department of Medicine, University of Kansas Medical Center, Kansas City 66103.
Hypertension. 1993 Mar;21(3):280-8. doi: 10.1161/01.hyp.21.3.280.
Vascular relaxations are impaired in adult spontaneously hypertensive rats (SHRs) because of increased production of an endothelium-derived, cyclooxygenase-dependent contractile factor or factors. To test the hypothesis that alterations in endothelial function precede and contribute to the development of overt hypertension in SHRs, we compared in myographs endothelium-mediated relaxations of mesenteric resistance arteries from 4-week-old SHRs and Wistar-Kyoto (WKY) rats. Acetylcholine (10(-9) to 10(-4) M) induced comparable relaxations in SHR and WKY arteries precontracted (ED50) with norepinephrine. In arteries obtained from SHRs but not from WKY rats, relaxations were replaced by contractile responses with higher concentrations of acetylcholine (10(-6) to 10(-5) M). The contractile responses were endothelium dependent, were augmented by nitro L-arginine (10(-4) M), and were prevented by pretreatment with indomethacin (10(-5) M) or 3-amino-1,2,4-triazole (10(-3) M), an inhibitor of superoxide anion production via the cyclooxygenase pathway. Inhibition of thromboxane synthetase (CGS-13080, 5 x 10(-5) M) and antagonism of prostaglandin H2/thromboxane A2 receptors (SQ-29,548, 5 x 10(-5) M) failed to block the contractile response to acetylcholine in SHR arteries. Acetylcholine-mediated relaxations were significantly impaired in mesenteric arteries from 16-week-old SHRs but not from WKY rats. Endothelium-independent relaxations produced by sodium nitroprusside and contractile responses to norepinephrine and endothelin were comparable in arteries from SHRs and WKY rats of all ages. In summary, endothelium-dependent relaxations of mesenteric arteries from "prehypertensive" SHR rats were impaired by the production of a contractile factor (or factors) that appears to be superoxide anions.
成年自发性高血压大鼠（SHR）的血管舒张功能受损，原因是一种内皮源性、环氧化酶依赖性收缩因子或多种收缩因子的产生增加。为了验证内皮功能改变先于并促成SHR明显高血压发展这一假说，我们在肌动描记器中比较了4周龄SHR和Wistar-Kyoto（WKY）大鼠肠系膜阻力动脉的内皮介导舒张。乙酰胆碱（10⁻⁹至10⁻⁴ M）在去甲肾上腺素预收缩的SHR和WKY动脉中诱导出相当的舒张（半数有效剂量）。在从SHR而非WKY大鼠获取的动脉中，较高浓度的乙酰胆碱（10⁻⁶至 10⁻⁵ M）会使舒张被收缩反应取代。这些收缩反应依赖于内皮，可被硝基L-精氨酸（10⁻⁴ M）增强，并可通过用吲哚美辛（10⁻⁵ M）或3-氨基-1,2,4-三唑（10⁻³ M，一种通过环氧化酶途径抑制超氧阴离子产生的抑制剂）预处理来预防。抑制血栓素合成酶（CGS-13080，5×10⁻⁵ M）以及拮抗前列腺素H2/血栓素A2受体（SQ-29548，5×10⁻⁵ M）未能阻断SHR动脉中对乙酰胆碱的收缩反应。乙酰胆碱介导的舒张在16周龄SHR的肠系膜动脉中显著受损，但在WKY大鼠中未受损。硝普钠产生的非内皮依赖性舒张以及对去甲肾上腺素和内皮素的收缩反应在各年龄段的SHR和WKY大鼠的动脉中相当。总之，“高血压前期”SHR大鼠肠系膜动脉的内皮依赖性舒张因一种似乎是超氧阴离子的收缩因子（或多种收缩因子）的产生而受损。
