(Stroke. 1995;26:864-869.)
© 1995 American Heart Association, Inc.
Articles |
Nitro-L-Arginine Analogues
Dose- and Time-Related Nitric Oxide Synthase Inhibition in Brain
From the Departments of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Md.
Background and Purpose The purpose of the present study
was to measure cortical nitric oxide synthase (NOS) activity and
determine the appropriate doses of
N
-nitro-L-arginine methyl ester
(L-NAME) or N-nitro-L-arginine
(L-NNA) for near-complete enzyme inhibition in dogs, cats, and pigs. We
anticipated that NOS inhibition was dose- and time-dependent and
questioned if the dose-response relationship was related to the
specific drug or animal species.
Methods Saline or L-NAME or L-NNA in escalating doses was administered to pentobarbital-anesthetized pigs, dogs, and cats. Brain temperature and arterial blood gas, hemoglobin, and blood pressure levels were maintained within the physiological range. Cortical tissue was biopsied at baseline and 30, 120, and 360 minutes after agent administration for measurement of NOS activity by isotopic assay of the conversion of [14C]arginine to [14C]citrulline.
Results L-NAME produced >70% enzyme inhibition at a dose of 20 mg/kg across the species tested. Arterial blood pressure was elevated at 30 minutes after L-NAME treatment. However, consistent decreases in brain NOS activity required a longer period of time. Near-complete inhibition was apparent in most animals by 120 minutes and persisted for 6 hours after administration. A smaller dose of L-NNA was required for >70% enzyme inhibition in the cats and dogs (10 mg/kg). Near-complete NOS inhibition was evident in most animals at 30 minutes after L-NNA administration, which also persisted for 6 hours. In pigs, this same level of inhibition required 20 mg/kg.
Conclusions These results suggest that administration of L-NAME and L-NNA diminishes brain NOS activity in a dose- and time-dependent manner and that the duration of effect is at least 6 hours.
Key Words: cerebral circulation • nitric oxide • nitric oxide synthase • nitro-L-arginine analogues
This article has been cited by other articles:
 |
|
 |
|
  C. N. Young, J. P. Fisher, K. M. Gallagher, A. Whaley-Connell, K. Chaudhary, R. G. Victor, G. D. Thomas, and P. J. Fadel Inhibition of nitric oxide synthase evokes central sympatho-excitation in healthy humans J. Physiol., October 15, 2009; 587(20): 4977 - 4986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Mendrinos, I. K. Petropoulos, G. Mangioris, D. N. Papadopoulou, A. N. Stangos, and C. J. Pournaras Lactate-Induced Retinal Arteriolar Vasodilation Implicates Neuronal Nitric Oxide Synthesis in Minipigs Invest. Ophthalmol. Vis. Sci., November 1, 2008; 49(11): 5060 - 5066. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Takaki, K. Morikawa, M. Tsutsui, Y. Murayama, E. Tekes, H. Yamagishi, J. Ohashi, T. Yada, N. Yanagihara, and H. Shimokawa Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice J. Exp. Med., September 1, 2008; 205(9): 2053 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ding, Y.-L. Li, and H. D. Schultz Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits J Appl Physiol, July 1, 2008; 105(1): 14 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Daubert, D. Liu, I. H. Zucker, and V. L. Brooks Roles of nitric oxide and angiotensin II in the impaired baroreflex gain of pregnancy Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2007; 292(6): R2179 - R2187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ramchandra, C. J. Barrett, S.-J. Guild, F. McBryde, and S. C. Malpas Role of renal sympathetic nerve activity in hypertension induced by chronic nitric oxide inhibition Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1479 - R1485. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Daubert and V. L. Brooks Nitric oxide impairs baroreflex gain during acute psychological stress Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R955 - R961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Augustyniak, R. G. Victor, D. A. Morgan, and W. Zhang L-NAME- and ADMA-induced sympathetic neural activation in conscious rats Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R726 - R732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sampei, J. A. Ulatowski, Y. Asano, H. Kwansa, E. Bucci, and R. C. Koehler Role of nitric oxide scavenging in vascular response to cell-free hemoglobin transfusion Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1191 - H1201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Mueller, C. M. Foley, and E. M. Hasser Hindlimb unloading alters nitric oxide and autonomic control of resting arterial pressure in conscious rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2005; 289(1): R140 - R147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhang, T. E. Wilson, S. Witkowski, J. Cui, C. G. Crandall, and B. D. Levine Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H863 - H869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Rawls, R. J. Tallarida, A. M. Gray, E. B. Geller, and M. W. Adler L-NAME (N{omega}-Nitro-L-Arginine Methyl Ester), a Nitric-Oxide Synthase Inhibitor, and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a Cannabinoid Agonist, Interact to Evoke Synergistic Hypothermia J. Pharmacol. Exp. Ther., February 1, 2004; 308(2): 780 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Malik and J. E. Fewell Thermoregulation in rats during early postnatal maturation: importance of nitric oxide Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2003; 285(6): R1366 - R1372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nagaoka, T. Sakamoto, F. Mori, E. Sato, and A. Yoshida The Effect of Nitric Oxide on Retinal Blood Flow during Hypoxia in Cats Invest. Ophthalmol. Vis. Sci., September 1, 2002; 43(9): 3037 - 3044. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Xu, G. D. Fink, and J. J. Galligan Nitric oxide-independent effects of tempol on sympathetic nerve activity and blood pressure in DOCA-salt rats Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H885 - H892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Steiner, J. Antunes-Rodrigues, S. M. McCann, and L. G. S. Branco Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic region of the rat brain Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2002; 282(2): R584 - R593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Soares de Moura, A. A. S. Rios, L. F. de Oliveira, A. C. Resende, M. de Lemos Neto, E. J. A. Santos, M. L. G. Correia, and T. Tano The Effects of Nitric Oxide Synthase Inhibitors on the Sedative Effect of Clonidine Anesth. Analg., November 1, 2001; 93(5): 1217 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. NAKANO, S.-D. LEE, A. D. RAY, J. A. KRASNEY, and G. A. FARKAS Role of Nitric Oxide in Thermoregulation and Hypoxic Ventilatory Response in Obese Zucker Rats Am. J. Respir. Crit. Care Med., August 1, 2001; 164(3): 437 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Xu, G. D. Fink, A. Chen, S. Watts, and J. J. Galligan Nitric oxide-independent effects of tempol on sympathetic nerve activity and blood pressure in normotensive rats Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H975 - H980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sener and F. G. Smith Nitric oxide modulates arterial baroreflex control of heart rate in conscious lambs in an age-dependent manner Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2255 - H2263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Steiner, E. C. Carnio, and L. G. S. Branco Role of neuronal nitric oxide synthase in hypoxia-induced anapyrexia in rats J Appl Physiol, September 1, 2000; 89(3): 1131 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Eshima, Y. Hirooka, H. Shigematsu, I. Matsuo, G. Koike, K. Sakai, and A. Takeshita Angiotensin in the Nucleus Tractus Solitarii Contributes to Neurogenic Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition Hypertension, August 1, 2000; 36(2): 259 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Almeida, E. C. Carnio, and L. G. S. Branco Role of nitric oxide in hypoxia inhibition of fever J Appl Physiol, December 1, 1999; 87(6): 2186 - 2190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. El-Haddad, C. R. Chao, S.-X. Ma, and M. G. Ross Nitric oxide modulates spontaneous swallowing behavior in near-term ovine fetus Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1999; 277(4): R981 - R986. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Matsumoto, Y. Iida, H. Wakamatsu, K. Ohtake, K. Nakakimura, L. Xiong, and T. Sakabe The Effects of NG-Nitro-L-Arginine-Methyl Ester on Neurologic and Histopathologic Outcome After Transient Spinal Cord Ischemia in Rabbits Anesth. Analg., September 1, 1999; 89(3): 696 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Mizuta, T. Takahashi, and C. Owyang Nitrergic regulation of colonic transit in rats Am J Physiol Gastrointest Liver Physiol, August 1, 1999; 277(2): G275 - G279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sander, B. Chavoshan, and R. G. Victor A Large Blood Pressure–Raising Effect of Nitric Oxide Synthase Inhibition in Humans Hypertension, April 1, 1999; 33(4): 937 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Baylis, J. Harvey, B. R. Santmyire, and K. Engels Pressor and Renal Vasoconstrictor Responses to Acute Systemic Nitric Oxide Synthesis Inhibition Are Independent of the Sympathetic Nervous System and Angiotensin II J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 693 - 698. [Abstract] [Full Text]
|
|
|
|
|
|
R. Zatz and C. Baylis Chronic Nitric Oxide Inhibition Model Six Years On Hypertension, December 1, 1998; 32(6): 958 - 964. [Full Text] [PDF]
|
|
|
|
|
|
A. A. Steiner, E. C. Carnio, J. Antunes-Rodrigues, and L. G. S. Branco Role of nitric oxide in systemic vasopressin-induced hypothermia Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1998; 275(4): R937 - R941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. H. Barros and L. G. S. Branco Effect of nitric oxide synthase inhibition on hypercapnia-induced hypothermia and hyperventilation J Appl Physiol, September 1, 1998; 85(3): 967 - 972. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Takano, S. Manchikalapudi, X.-L. Tang, Y. Qiu, A. Rizvi, A. K. Jadoon, Q. Zhang, and R. Bolli Nitric Oxide Synthase Is the Mediator of Late Preconditioning Against Myocardial Infarction in Conscious Rabbits Circulation, August 4, 1998; 98(5): 441 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Stingele, D. A. Wilson, R. J. Traystman, and D. F. Hanley Tyrosine confounds oxidative electrochemical detection of nitric oxide Am J Physiol Heart Circ Physiol, May 1, 1998; 274(5): H1698 - H1704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Schleien, J. W. Kuluz, and B. Gelman Hemodynamic effects of nitric oxide synthase inhibition before and after cardiac arrest in infant piglets Am J Physiol Heart Circ Physiol, April 1, 1998; 274(4): H1378 - H1385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Murakami, J.-L. Liu, H. Yoneyama, Y. Nishida, K. Okada, H. Kosaka, H. Morita, and I. H. Zucker Blockade of neuronal nitric oxide synthase alters the baroreflex control of heart rate in the rabbit Am J Physiol Regulatory Integrative Comp Physiol, January 1, 1998; 274(1): R181 - R186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Bolli, S. Manchikalapudi, X.-L. Tang, H. Takano, Y. Qiu, Y. Guo, Q. Zhang, and A. K. Jadoon The Protective Effect of Late Preconditioning Against Myocardial Stunning in Conscious Rabbits Is Mediated by Nitric Oxide Synthase : Evidence That Nitric Oxide Acts Both as a Trigger and as a Mediator of the Late Phase of Ischemic Preconditioning Circ. Res., December 19, 1997; 81(6): 1094 - 1107. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. R. Kirsch, A. Bhardwaj, L. J. Martin, D. F. Hanley, and R. J. Traystman Neither L-Arginine nor L-NAME Affects Neurological Outcome After Global Ischemia in Cats Stroke, November 1, 1997; 28(11): 2259 - 2265. [Abstract] [Full Text]
|
|
|
|
|
|
B. P. Wagner, R. Stingele, M. A. Williams, D. A. Wilson, R. J. Traystman, and D. F. Hanley NO contributes to neurohypophysial but not other regional cerebral fluorocarbon-induced hyperemia in cats Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1994 - H2000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bolli, Z. A. Bhatti, X.-L. Tang, Y. Qiu, Q. Zhang, Y. Guo, and A. K. Jadoon Evidence That Late Preconditioning Against Myocardial Stunning in Conscious Rabbits Is Triggered by the Generation of Nitric Oxide Circ. Res., July 19, 1997; 81(1): 42 - 52. [Abstract] [Full Text]
|
|
|
|
|
|
M. Sander, J. Hansen, and R. G. Victor The Sympathetic Nervous System Is Involved in the Maintenance but Not Initiation of the Hypertension Induced by N{omega}-Nitro-L-Arginine Methyl Ester Hypertension, July 1, 1997; 30(1): 64 - 70. [Abstract] [Full Text]
|
|
|
|
|
|
C. S. Tietjen, J. R. Kirsch, N. Clavier, and R. J. Traystman Time-Dependent Inhibition of Oxotremorine-Induced Cerebral Hyperemia by N{omega}-Nitro-L-Arginine in Cats Stroke, November 1, 1995; 26(11): 2160 - 2165. [Abstract] [Full Text]
|
|