Nguyen P V, Parent A, Deng L Y, Flückiger J P, Thibault G, Schiffrin E L
Experimental Hypertension Laboratory, Clinical Research Institute of Montreal, Canada.
Hypertension. 1992 Feb;19(2 Suppl):II98-104. doi: 10.1161/01.hyp.19.2_suppl.ii98.
The vasoconstrictor effect, the binding, and the response of inositol phosphates to endothelin-1 (ET-1) were investigated in blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats within 2 weeks of development of hypertension and in uninephrectomized control rats. In DOCA-salt and uninephrectomized rats, plasma levels of endothelin were similar (1.2 +/- 0.1 fmol/ml). Thoracic aorta and mesenteric artery rings devoid of endothelium presented significantly decreased responses to increasing concentrations of ET-1. Binding of ET-1 to mesenteric artery membranes was significantly lower in DOCA-salt rats (106 +/- 22 fmol/mg protein) than in uninephrectomized rats (172 +/- 19 fmol/mg protein, p less than 0.05), whereas affinity was similar. Phosphoinositide metabolism was examined in aorta and mesenteric arteries after incubation with [3H]myoinositol. Inositol phosphates were separated by high-performance liquid chromatography. In response to 100 nmol/l ET-1, accumulation of inositol 1,4,5-trisphosphate after 20 seconds and of inositol monophosphate, inositol bisphosphate, and inositol 1,3,4-triphosphate after 30 minutes (in the presence of 25 mmol/l LiCl) were significantly lower in DOCA-salt hypertensive than in uninephrectomized control rats, in both aorta and mesenteric arteries. In conclusion, decreased density of ET-1 receptors in DOCA-salt hypertensive rats results in decreased activation of phospholipase C and, consequently, reduced vasoconstriction induced by ET-1. Because the decrease in vasoconstrictor effects of ET-1 is found in the absence of endothelium, it is likely that receptor downregulation rather than prior receptor occupancy underlies these findings.
在醋酸脱氧皮质酮（DOCA）-盐性高血压大鼠高血压发展的2周内以及单侧肾切除的对照大鼠中，研究了血管收缩效应、内皮素-1（ET-1）的结合以及肌醇磷酸对ET-1的反应。在DOCA-盐性大鼠和单侧肾切除大鼠中，内皮素的血浆水平相似（1.2±0.1 fmol/ml）。无内皮的胸主动脉和肠系膜动脉环对ET-1浓度增加的反应显著降低。DOCA-盐性大鼠中ET-1与肠系膜动脉膜的结合（106±22 fmol/mg蛋白）显著低于单侧肾切除大鼠（172±19 fmol/mg蛋白，p<0.05），而亲和力相似。用[3H]肌醇孵育后，检测主动脉和肠系膜动脉中的磷酸肌醇代谢。肌醇磷酸通过高效液相色谱法分离。在100 nmol/l ET-1刺激下，DOCA-盐性高血压大鼠的主动脉和肠系膜动脉中，20秒后肌醇1,4,5-三磷酸的积累以及30分钟后（在25 mmol/l LiCl存在下）肌醇单磷酸、肌醇二磷酸和肌醇1,3,4-三磷酸的积累均显著低于单侧肾切除对照大鼠。总之，DOCA-盐性高血压大鼠中ET-1受体密度降低导致磷脂酶C激活减少，从而使ET-1诱导的血管收缩减弱。由于在无内皮的情况下发现ET-1的血管收缩效应降低，这些发现可能是由于受体下调而非先前的受体占据所致。
