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Investigation of the inhibitory effect of N(G)-nitro-L-arginine methyl ester on the antihypertensive effect of the angiotensin AT1 receptor antagonist, GR138950.
Br J Pharmacol. 1997 Dec; 122(7):1385-94.BJ

Abstract

1. 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.

Authors+Show Affiliations

Disease Sciences, Glaxo Wellcome Medicines Research Centre, Stevenage, Hertfordshire.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9421286

Citation

Anderson, I K., and G M. Drew. "Investigation of the Inhibitory Effect of N(G)-nitro-L-arginine Methyl Ester On the Antihypertensive Effect of the Angiotensin AT1 Receptor Antagonist, GR138950." British Journal of Pharmacology, vol. 122, no. 7, 1997, pp. 1385-94.
Anderson IK, Drew GM. Investigation of the inhibitory effect of N(G)-nitro-L-arginine methyl ester on the antihypertensive effect of the angiotensin AT1 receptor antagonist, GR138950. Br J Pharmacol. 1997;122(7):1385-94.
Anderson, I. K., & Drew, G. M. (1997). Investigation of the inhibitory effect of N(G)-nitro-L-arginine methyl ester on the antihypertensive effect of the angiotensin AT1 receptor antagonist, GR138950. British Journal of Pharmacology, 122(7), 1385-94.
Anderson IK, Drew GM. Investigation of the Inhibitory Effect of N(G)-nitro-L-arginine Methyl Ester On the Antihypertensive Effect of the Angiotensin AT1 Receptor Antagonist, GR138950. Br J Pharmacol. 1997;122(7):1385-94. PubMed PMID: 9421286.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Investigation of the inhibitory effect of N(G)-nitro-L-arginine methyl ester on the antihypertensive effect of the angiotensin AT1 receptor antagonist, GR138950. AU - Anderson,I K, AU - Drew,G M, PY - 1998/1/8/pubmed PY - 1998/1/8/medline PY - 1998/1/8/entrez SP - 1385 EP - 94 JF - British journal of pharmacology JO - Br J Pharmacol VL - 122 IS - 7 N2 - 1. 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. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/9421286/Investigation_of_the_inhibitory_effect_of_N_G__nitro_L_arginine_methyl_ester_on_the_antihypertensive_effect_of_the_angiotensin_AT1_receptor_antagonist_GR138950_ L2 - https://doi.org/10.1038/sj.bjp.0701531 DB - PRIME DP - Unbound Medicine ER -