Inhibition of Neuronal Nitric Oxide Synthase by 7-Nitroindazole: Effects upon Local Cerebral Blood Flow and Glucose Use in the Rat

• Published in: Journal of cerebral blood flow and metabolism Vol. 15; no. 5; pp. 766 - 773
• Main Authors: Kelly, Paul A. T., Ritchie, Isobel M., Arbuthnott, Gordon W.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.09.1995; Lippincott Williams & Wilkins
• Subjects: Amino Acid Oxidoreductases - metabolism; Animals; Biochemistry and metabolism; Biological and medical sciences; Brain - cytology; Brain - metabolism; Central nervous system; Cerebrovascular Circulation - drug effects; Fundamental and applied biological sciences. Psychology; Glucose - metabolism; Indazoles - pharmacology; Male; Neurons - metabolism; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Vertebrates: nervous system and sense organs; Local cerebral glucose utilization; 7-Nitroindazole; Local cerebral blood flow; Cerebrovascular control; Nitric oxide; Regional blood flow; Rat; Enzyme; Rodentia; Central nervous system; Enzyme inhibitor; Exploration; Glucose; Experimental study; Metabolism; Nitric-oxide synthase; Vertebrata; Mammalia; Animal; Hemodynamics; Oxidoreductases; Brain (vertebrata)
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.1995.96

The novel nitric oxide synthase inhibitor 7-nitroindazole (7-NI) is relatively specific for the neuronal isoform of the enzyme and in this study we have used this compound to investigate the physiological role of perivascular nitric oxide-containing nerves in the cerebrovascular bed. Following injection of 7-NI (25 or 50 mg/kg, i.p.), cerebral blood flow and glucose utilization were measured in the conscious rat using the fully quantitative [14C]iodoantipyrine and 2-[14C]deoxyglucose techniques, respectively. Neither dose of the drug produced any change in arterial blood pressure, confirming a lack of effect upon the endothelial isoform of the enzyme, although there was a pronounced decrease in heart rate (−28% by 10 min postinjection). Throughout the brain 25 mg/kg 7-NI i.p. resulted in decreases in blood flow of between −20% in the hippocampus and −58% in the substantia nigra. Increasing the dose to 50 mg/kg resulted in a further generalized decrease, to almost −60% in parts of the thalamus and hippocampus, but in every animal this higher dose of 7-NI also produced randomly distributed areas of relative hyperaemia, which were most commonly found in those areas where the most intense hypoperfusion was otherwise in evidence. Despite these changes in blood flow, in all but a very few areas of the brain no significant decrease in glucose use was measured at either of the two doses of 7-NI. Thus despite the greater specificity of 7-NI for neuronal nitric oxide synthase, the cerebrovascular effects of the drug in vivo are very similar to that reported for the arginine analogues. However, these data do suggest that nitric oxide-releasing neurones in the brain may have an important role to play in the regulation of cerebral blood flow.