scholarly journals Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans

2021 ◽  
Author(s):  
Kevin O’Gallagher ◽  
Francesca Puledda ◽  
Owen O’Daly ◽  
Matthew Ryan ◽  
Luke Dancy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Functional Connectivity ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Healthy Human ◽  
Brain Functional Connectivity ◽  
Oxide Synthase

Abstract Aims Neuronal nitric oxide synthase (nNOS) is highly expressed within the cardiovascular and nervous systems. Studies in genetically modified mice suggest roles in brain blood flow regulation while dysfunctional nNOS signaling is implicated in cerebrovascular ischemia and migraine. Previous human studies have investigated the effects of non-selective NOS inhibition but there has been no direct investigation of the role of nNOS in human cerebrovascular regulation. We hypothesised that inhibition of the tonic effects of nNOS would result in global or localized changes in cerebral blood flow, as well as changes in functional brain connectivity. Methods and Results We investigated the acute effects of a selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), on cerebral blood flow and brain functional connectivity in healthy human volunteers (n=19). We performed a randomised, placebo-controlled, crossover study with either intravenous SMTC or placebo, using magnetic resonance imaging protocols with arterial spin labelling and functional resting state neuroimaging. Conclusions These data suggest a fundamental physiological role of nNOS in regulating regional cerebral blood flow and functional connectivity in the human hippocampus. Our findings have relevance to the role of nNOS in the regulation of cerebral perfusion in health and disease. Translational Perspective Animal models have implicated dysfunctional nNOS-mediated signaling in neurovascular and neurodegenerative conditions. This first study of the effects of a selective nNOS inhibitor, S-methyl-thiocitrulliune (SMTC), on the physiological regulation of human cerebral blood flow and brain functional connectivity opens the way to investigation of the effects of nNOS in cerebrovascular disease states. We also demonstrate that an acute infusion of SMTC is safe yet biologically active within the healthy human brain. The therapeutic potential of modulating the nNOS pathway in the brain could now be investigated; e.g. whether inhibition of nNOS activity is valuable in settings of post-ischemia excitotoxicity.

scholarly journals The Role of Neuronal Nitric Oxide Synthase in Regulation of Cerebral Blood Flow in Normocapnia and Hypercapnia in Rats

1995 ◽  
Vol 15 (5) ◽  
pp. 774-778 ◽  
Author(s):  
Qiong Wang ◽  
Dale A. Pelligrino ◽  
Verna L. Baughman ◽  
Heidi M. Koenig ◽  
Ronald F. Albrecht
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Inhibitory Action ◽  
Neuronal Nitric Oxide Synthase ◽  
Muscarinic Agonist ◽  
Doppler Flowmetry ◽  
Nos Inhibitors ◽  
Oxide Synthase

The nitric oxide synthase (NOS) inhibitors, nitro-L-arginine, its methyl ester, and N-monomethyl-L-arginine, have been shown to attenuate resting CBF and hypercapnia-induced cerebrovasodilation. Those agents nonspecifically inhibit the endothelial and neuronal NOS (eNOS and nNOS). In the present study, we used a novel nNOS inhibitor, 7-nitroindazole (7-NI) to examine the role of nNOS in CBF during normocapnia and hypercapnia in fentanyl/N2O-anesthetized rats. CBF was monitored using laser-Doppler flowmetry. Administration of 7-NI (80 mg kg−1 i.p.) reduced cortical brain NOS activity by 57%, the resting CBF by 19–27%, and the CBF response to hypercapnia by 60%. The 60% reduction was similar in magnitude to the CBF reductions observed in previous studies in which nonspecific NOS inhibitors were used. In the present study, 7-NI did not increase the MABP. Furthermore, the CBF response to oxotremorine, a blood–brain barrier permeant muscarinic agonist that induces cerebrovasodilation via endothelium-derived NO, was unaffected by 7-NI. These results confirmed that 7-NI does not influence eNOS; they also indicated that the effects of 7-NI on the resting CBF and on the CBF response to hypercapnia in this study were solely related to its inhibitory action on nNOS. The results further suggest that the NO synthesized by the action of nNOS participates in regulation of basal CBF and is the major, if not the only, category of NO contributing to the hypercapnic CBF response.

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

1995 ◽  
Vol 15 (5) ◽  
pp. 766-773 ◽  
Author(s):  
Paul A. T. Kelly ◽  
Isobel M. Ritchie ◽  
Gordon W. Arbuthnott
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Nitric Oxide Synthase ◽  
Physiological Role ◽  
Neuronal Nitric Oxide Synthase ◽  
Conscious Rat ◽  
Arterial Blood ◽  
Oxide Synthase ◽  
The Brain

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.

Role of Neuronal Nitric Oxide Synthase in Regulating Retinal Blood Flow During Flicker-Induced Hyperemia in Cats

2015 ◽  
Vol 56 (5) ◽  
pp. 3113 ◽  
Author(s):  
Takafumi Yoshioka ◽  
Taiji Nagaoka ◽  
Youngseok Song ◽  
Harumasa Yokota ◽  
Tomofumi Tani ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Retinal Blood Flow ◽  
Oxide Synthase

scholarly journals Feedback Control of Glomerular Vascular Tone in Neuronal Nitric Oxide Synthase Knockout Mice

2001 ◽  
Vol 12 (8) ◽  
pp. 1599-1606
Author(s):  
VOLKER VALLON ◽  
TIMOTHY TRAYNOR ◽  
LUCIANO BARAJAS ◽  
YUNING G. HUANG ◽  
JOSIE P. BRIGGS ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Knockout Mice ◽  
Neuronal Nitric Oxide Synthase ◽  
Distal Tubule ◽  
Flow Pressure ◽  
Oxide Synthase ◽  
Stop Flow

Abstract. For further elucidation of the role of neuronal nitric oxide synthase (nNOS) in macula densa (MD) cells, experiments were performed in anesthetized nNOS knockout mice (nNOS -/-). At comparable levels of arterial BP, renal blood flow was not significantly different between nNOS +/+ and nNOS -/- (1.7 ± 0.2 versus 1.4 ± 0.1 ml/min), and autoregulation of renal blood flow was maintained to a pressure level of approximately 85 mmHg in both groups of mice (n = 6 in each group). The fall in proximal tubular stop-flow pressure in response to an increase in loop of Henle perfusion rate from 0 to 30 nl/min was comparable in nNOS +/+ and -/- mice (40.7 ± 1.6 to 32 ± 2 mmHg versus 40.6 ± 1.6 to 31.6 ± 2 mmHg; not significant; n = 13 versus 18 nephrons). Luminal application of the nonselective NOS inhibitor nitro-L-arginine (10-3 and 10-2 M) enhanced the perfusion-dependent fall in stop-flow pressure in nNOS +/+ (7 ± 1 to 13 ± 2 mmHg; P < 0.05) but not in nNOS -/- (7 ± 1 to 8 ± 1 mmHg; not significant) mice. nNOS -/- mice exhibited a lower nephron filtration rate, compared with nNOS +/+, during free-flow collections from early distal tubules (influence of MD intact, 7 ± 0.7 versus 10.9 ± 1 nl/min; P = 0.002) but not from late proximal tubule (influence of MD minimized, 10.1 ± 1 versus 11.7 ± 1 nl/min; not significant; n = 16 nephrons). Distal Cl concentration and fractional absorption of fluid or chloride up to the early distal tubule was not different between nNOS -/- and +/+ mice. The data indicate that nNOS in MD tonically attenuates the GFR-lowering influence of ambient luminal NaCl, which may serve to increase the fluid and electrolyte load to the distal tubule, consistent with a role of MD nNOS in tubuloglomerular feedback resetting.

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