N（G）-硝基-L-精氨酸甲酯对血管紧张素AT1受体拮抗剂GR138950降压作用的抑制效果研究。

Investigation of the inhibitory effect of N(G)-nitro-L-arginine methyl ester on the antihypertensive effect of the angiotensin AT1 receptor antagonist, GR138950.

作者信息

Anderson I K, Drew G M

机构信息

Disease Sciences, Glaxo Wellcome Medicines Research Centre, Stevenage, Hertfordshire.

出版信息

Br J Pharmacol. 1997 Dec;122(7):1385-94. doi: 10.1038/sj.bjp.0701531.

DOI:10.1038/sj.bjp.0701531

PMID:9421286

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565088/

Abstract

The effect of systemic administration of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) on the antihypertensive effects of the angiotensin AT1 receptor antagonist, GR138950, the angiotensin-converting enzyme (ACE) inhibitor, enalapril, or hydralazine has been evaluated in unrestrained, conscious renal artery ligated hypertensive (RALH) rats. The effect of the phosphodiesterase type V inhibitor, zaprinast on the antihypertensive effect of GR138950 in RALH rats was also examined. The effect of GR138950 on blood pressure, and plasma and urine cyclic GMP levels was compared to that of zaprinast in conscious RALH rats. 2. GR138950, enalapril or hydralazine caused marked reductions in blood pressure associated with immediate tachycardia in conscious RALH rats. L-NAME pretreatment attenuated the antihypertensive effects of GR138950 or enalapril but not that of hydralazine in conscious RALH rats. The initial tachycardia caused by GR138950 or enalapril but not hydralazine was attenuated by L-NAME pretreatment. L-NAME alone caused a transient (20 min) pressor response and a prolonged (6 h) bradycardia in conscious RALH rats. 3. Pretreatment with indomethacin did not affect the cardiovascular effect of GR138950 in conscious RALH rats. Indomethacin alone did not significantly change basal blood pressure or heart rate in RALH rats. 4. Zaprinast pretreatment did not affect the antihypertensive effect of GR138950 in conscious RALH rats but potentiated the depressor response to sodium nitroprusside. Zaprinast alone caused a small reduction in basal blood pressure but did not change basal heart rate in RALH rats. 5. The antihypertensive effect of GR138950 was not associated with an increase in plasma or urine cyclic GMP levels in conscious RALH rats, whereas zaprinast caused a small fall in blood pressure associated with increases in plasma and urine cyclic GMP. 6. The ability of L-NAME to inhibit the antihypertensive action of GR138950 or enalapril suggests that these agents release nitric oxide (NO) and/or enhance the cardiovascular effects of NO as part of their mechanism of action. However, the inability of zaprinast to potentiate the antihypertensive effects of GR138950 and the finding that GR138950 did not increase urine and plasma cyclic GMP levels are not consistent with this view. Attenuation of the response to GR138950 or enalapril, but not hydralazine, suggests a selective interaction between L-NAME and inhibitors of the renin-angiotensin system, although the nature of this interaction is unknown.

摘要

已在未束缚的清醒肾动脉结扎高血压（RALH）大鼠中评估了一氧化氮合酶抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME）全身给药对血管紧张素AT1受体拮抗剂GR138950、血管紧张素转换酶（ACE）抑制剂依那普利或肼屈嗪降压作用的影响。还研究了磷酸二酯酶V型抑制剂扎普司特对RALH大鼠中GR138950降压作用的影响。在清醒的RALH大鼠中，将GR138950对血压、血浆和尿液中环鸟苷酸（cGMP）水平的影响与扎普司特的影响进行了比较。2. GR138950、依那普利或肼屈嗪可使清醒RALH大鼠的血压显著降低，并伴有即刻心动过速。L-NAME预处理减弱了GR138950或依那普利的降压作用，但未减弱肼屈嗪在清醒RALH大鼠中的降压作用。L-NAME预处理减弱了GR138950或依那普利引起的初始心动过速，但未减弱肼屈嗪引起的心动过速。单独使用L-NAME可使清醒RALH大鼠产生短暂（20分钟）的升压反应和持久（6小时）的心动过缓。3. 吲哚美辛预处理不影响GR138950在清醒RALH大鼠中的心血管作用。单独使用吲哚美辛不会显著改变RALH大鼠的基础血压或心率。4. 扎普司特预处理不影响GR138950在清醒RALH大鼠中的降压作用，但增强了对硝普钠的降压反应。单独使用扎普司特可使基础血压略有降低，但不改变RALH大鼠的基础心率。5. GR138950的降压作用与清醒RALH大鼠血浆或尿液中环GMP水平的升高无关，而扎普司特可使血压略有下降，并伴有血浆和尿液中环GMP的升高。6. L-NAME抑制GR138950或依那普利降压作用的能力表明，这些药物释放一氧化氮（NO）和/或增强NO的心血管作用是其作用机制的一部分。然而，扎普司特不能增强GR138950的降压作用，以及GR138950不会增加尿液和血浆中环GMP水平的发现与这一观点不一致。对GR138950或依那普利反应的减弱，而非对肼屈嗪反应的减弱，提示L-NAME与肾素-血管紧张素系统抑制剂之间存在选择性相互作用，尽管这种相互作用的性质尚不清楚。