Gao H, Peng B, Welch W J, Wilcox C S
Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, District of Columbia 20007, USA.
Am J Physiol. 1997 May;272(5 Pt 2):R1493-500. doi: 10.1152/ajpregu.1997.272.5.R1493.
These studies tested whether activation of central thromboxane (Tx)A2/prostaglandin (PG) H2 receptors raises blood pressure (BP). Messenger RNA for TxA2/PGH2 receptors was detected in normal Sprague-Dawley rat brain and in rat neuronal and astroglial brain cells in culture. The mean arterial blood pressure (MAP) was recorded in conscious rats during graded administration of the TxA2/PGH2 receptor agonist U-46,619 given intracerebroventricularly or intravenously. Because the pressor responses to intracerebroventricular (but not intravenous) U-46,619 were significantly greater in-high-salt compared with low-salt rats, high-salt rats were used for subsequent studies. The rise in MAP with intracerebroventricular administration of U-46,619 was greater than with intravenous administration and was more sustained. A comparison of plasma radioactivity after intracerebroventricular or intravenous injection of [3H]U-46,619 demonstrated that approximately 35% of the drug reached the systemic circulation by 5-15 min after intracerebroventricular administration. Coadministration of a TxA2/PGH2 antagonist, ifetroban, by intravenous or intracerebroventricular routes blocked the pressor responses induced by U-46,619. The half-maximal inhibition for blockade of responses was substantially lower for intracerebroventricular than for intravenous responses (intracerebroventricular: 0.03 +/- 0.01 vs. intravenous: 3.1 +/- 0.6 micrograms/kg; P < 0.001). The intravenous administration of ifetroban (10 micrograms/kg) caused a greater (P < 0.02) inhibition of pressor responses to U-46,619 (1 microgram/kg) given intravenously (81 +/- 3%) compared with U-46,619 given intracerebroventricularly (40 +/- 13%). In conclusion, TxA2/PGH2 receptor mRNA is expressed in neurons, glial, and brain stem of normal rats. The central administration of a TxA2/PGH2 mimetic raises blood pressure by interaction with specific central and peripheral receptors. This response is augmented in rats fed a high-salt compared with a low-salt diet.
这些研究测试了中枢血栓素（Tx）A2/前列腺素（PG）H2受体的激活是否会升高血压（BP）。在正常的斯普拉格-道利大鼠脑以及培养的大鼠神经元和星形胶质脑细胞中检测到了TxA2/PGH2受体的信使核糖核酸。在清醒大鼠经脑室内或静脉内分级给予TxA2/PGH2受体激动剂U-46,619期间记录平均动脉血压（MAP）。由于与低盐大鼠相比，高盐大鼠对脑室内（而非静脉内）U-46,619的升压反应明显更大，因此后续研究使用高盐大鼠。脑室内给予U-46,619时MAP的升高幅度大于静脉给药，且持续时间更长。对脑室内或静脉内注射[3H]U-46,619后的血浆放射性进行比较表明，脑室内给药后5至15分钟，约35%的药物进入体循环。通过静脉或脑室内途径共同给予TxA2/PGH2拮抗剂艾非曲班可阻断U-46,619诱导的升压反应。脑室内反应阻断的半数最大抑制浓度显著低于静脉内反应（脑室内：0.03±0.01对静脉内：3.1±0.6微克/千克；P<0.001）。静脉给予艾非曲班（10微克/千克）对静脉内给予U-46,619（1微克/千克）的升压反应的抑制作用（81±3%）大于对脑室内给予U-46,619的抑制作用（40±13%）（P<0.02）。总之，TxA2/PGH2受体信使核糖核酸在正常大鼠的神经元、胶质细胞和脑干中表达。中枢给予TxA2/PGH2模拟物通过与特定的中枢和外周受体相互作用来升高血压。与低盐饮食的大鼠相比，高盐饮食的大鼠的这种反应增强。
