DePasquale M J, Fossa A A, Holt W F, Mangiapane M L
Department of General Pharmacology, Pfizer Inc., Groton, Conn. 06340.
Hypertension. 1992 Jun;19(6 Pt 2):668-71. doi: 10.1161/01.hyp.19.6.668.
Oral administration of the angiotensin II receptor subtype 1 (AT1) antagonist DuP 753 causes long-lasting lowering of mean arterial pressure in spontaneously hypertensive rats. We examined whether the antihypertensive action of DuP 753 is a result of inhibition of brain angiotensin II. In normal spontaneously hypertensive rats, we found that intracerebroventricular DuP 753 (10 micrograms) blocked the pressor action of intracerebroventricular angiotensin II (100 ng); however, intracerebroventricular DuP 753 (10 micrograms) had no effect on the pressor response to 300 ng/kg angiotensin II administered intravenously (48 +/- 3 mm Hg in the presence of intracerebroventricular DuP 753 versus 49 +/- 4 mm Hg in its absence). In both normal and furosemide-treated spontaneously hypertensive rats (low Na+ diet plus furosemide), intracerebroventricular DuP 753 alone at 10 or 100 micrograms caused transient but significant pressor responses; however, no significant reduction in pressure (versus controls) was observed over the next 48 hours. In contrast to its central effects, we found that oral DuP 753 (10 or 30 mg/kg) in normal spontaneously hypertensive rats resulted in sustained mean arterial pressure decreases of up to -74 mm Hg. These data suggest that, although the pressor effect of brain angiotensin II is mediated by the AT1 receptor, blockade of these receptors does not lower blood pressure in spontaneously hypertensive rats. In the spontaneously hypertensive rat, DuP 753 depresses blood pressure by blockade of peripheral, not central, AT1 receptors.
口服血管紧张素II 1型（AT1）拮抗剂DuP 753可使自发性高血压大鼠的平均动脉压持续降低。我们研究了DuP 753的降压作用是否是抑制脑内血管紧张素II的结果。在正常自发性高血压大鼠中，我们发现脑室内注射DuP 753（10微克）可阻断脑室内注射血管紧张素II（100纳克）的升压作用；然而，脑室内注射DuP 753（10微克）对静脉注射300纳克/千克血管紧张素II的升压反应无影响（脑室内注射DuP 753时为48±3毫米汞柱，未注射时为49±4毫米汞柱）。在正常和用速尿治疗的自发性高血压大鼠（低钠饮食加用速尿）中，单独脑室内注射10或100微克DuP 753可引起短暂但显著的升压反应；然而，在接下来的48小时内未观察到压力有显著降低（与对照组相比）。与其中枢作用相反，我们发现正常自发性高血压大鼠口服DuP 753（10或30毫克/千克）可使平均动脉压持续降低高达-74毫米汞柱。这些数据表明，虽然脑内血管紧张素II的升压作用是由AT1受体介导的，但阻断这些受体并不会降低自发性高血压大鼠的血压。在自发性高血压大鼠中，DuP 753通过阻断外周而非中枢的AT1受体来降低血压。
