Lefèvre-Borg F, Lorrain J, Lechaire J, Thiry C, Hicks P E, Cavero I
Laboratoiries d'Etudes et de Recherches Synthélabo, Paris, France.
J Cardiovasc Pharmacol. 1988 Apr;11(4):444-55. doi: 10.1097/00005344-198804000-00010.
In pentobarbital-anesthetized rats prepared for hemodynamic measurements with Doppler flow probes, intravenous (i.v.) infusions of fenoldopam (2.5 - 160.0 micrograms/kg/min during 15 min) decreased mean carotid artery blood pressure, total peripheral, hindquarter, renal, and mesenteric vascular resistances and increased renal blood flow strongly. The hypotensive effects attained a maximum within the first 3 min of infusion but waned by greater than 30% at the end of fenoldopam administration. This tolerance was observed for calculated total peripheral and hindquarter vascular resistances and to a lesser extent for mesenteric resistance. However, it was absent on the renal vascular bed. Pretreatment with either enalapril, pepstatine, or bilateral nephrectomy significantly increased the hypotensive response to fenoldopam and attenuated the development of tolerance. In conscious spontaneously hypertensive rats (SHR), enalapril potentiated strongly the small blood pressure-lowering activity of fenoldopam. The fall in blood pressure produced by fenoldopam was specifically blocked by SCH 23390, an antagonist of DA-1 dopamine receptors. In normotensive vasopressin-supported pithed rats given phenoxybenzamine plus propranolol, fenoldopam, like SCH 23390, blocked the vasodepressor effects of i.v. bolus injection of dopamine and fenoldopam. In pithed rats, fenoldopam evoked a pressor response that was significantly reduced by enalapril, SCH 23390, or bilateral nephrectomy. In conclusion, fenoldopam exerts DA-1 agonist and antagonist effects. The latter property, together with the activation of the renin-angiotensin system, appears to be responsible for the development of tolerance to the fenoldopam evoked-hypotension. The lack of a tolerance at the level of the renal vascular bed is possibly due to the existence of a large population of DA-1 receptors in this region.
在用多普勒血流探头准备进行血流动力学测量的戊巴比妥麻醉大鼠中，静脉输注非诺多泮（15分钟内2.5 - 160.0微克/千克/分钟）可降低平均颈动脉血压、总外周、后肢、肾和肠系膜血管阻力，并显著增加肾血流量。降压作用在输注的前3分钟内达到最大值，但在非诺多泮给药结束时减弱超过30%。这种耐受性在计算的总外周和后肢血管阻力中观察到，肠系膜阻力的耐受性较小。然而，肾血管床不存在这种情况。用依那普利、胃酶抑素或双侧肾切除进行预处理可显著增加对非诺多泮的降压反应并减弱耐受性的发展。在清醒的自发性高血压大鼠（SHR）中，依那普利强烈增强了非诺多泮的小幅度降压活性。非诺多泮引起的血压下降被DA - 1多巴胺受体拮抗剂SCH 23390特异性阻断。在给予苯氧苄胺加普萘洛尔的正常血压血管加压素支持的去大脑大鼠中，非诺多泮与SCH 23390一样，阻断了静脉推注多巴胺和非诺多泮的血管减压作用。在去大脑大鼠中，非诺多泮引起的升压反应被依那普利、SCH 23390或双侧肾切除显著降低。总之，非诺多泮发挥DA - 1激动剂和拮抗剂作用。后一种特性，连同肾素 - 血管紧张素系统的激活，似乎是对非诺多泮诱发低血压产生耐受性的原因。肾血管床水平缺乏耐受性可能是由于该区域存在大量DA - 1受体。
