Nitric Oxide Synthase Inhibition in Humans Reduces Cerebral Blood Flow but Not the Hyperemic Response to Hypercapnia

White, Richard P.; Deane, Colin; Vallance, Patrick; Markus, Hugh S.

doi:10.1161/01.str.29.2.467

Cited by 150 publications

(135 citation statements)

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“…A major reason for choosing this technique is that it bypassed the use of NOS inhibitors, which may cause constriction in the MCA (66), potentially invaliding their use with transcranial Doppler ultrasonography. The specificity and sensitivity of plasma nitrite as an index of eNOS have been well demonstrated (33,35).…”

Section: Methodological Considerations and Limitationsmentioning

confidence: 99%

“…In a number of studies, the cerebral vasodilatory response to hypercapnia and hypoxia has been inhibited by L-arginine analogs (30,63), suggesting the involvement of NO; however, results have not been consistent, potentially because of differences in the sensitivity to NOS inhibitors within and between species, including humans (56,66). This problem is compounded in human-based studies, where the extent to which NO inhibitors are able to cross the blood-brain barrier is unclear (23,56,66). Consequently, it is possible that the importance of NO reported in previous human studies using NO inhibitors is underestimated, and no studies have examined the potential exchange of NO over the human brain.…”

mentioning

confidence: 99%

“…Consequently, it is possible that the importance of NO reported in previous human studies using NO inhibitors is underestimated, and no studies have examined the potential exchange of NO over the human brain. It should be acknowledged, however, that NO is unlikely to play an exclusive role in the CBF response to hypercapnia, inasmuch as a residual increase in CBF is seen after NOS inhibition (66). Furthermore, it seems unlikely that reduction in NO plays a major role in the CBF response to hypocapnia in humans, since NO inhibition does not influence the cerebral vasoconstrictor response to hypocapnia in animals (63).…”

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confidence: 99%

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Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases

Peebles

Richards²,

Celi

et al. 2008

Journal of Applied Physiology

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Evidence from animal studies indicates that various vasoactive factors, including release of norepinephrine, endothelin, adrenomedullin, C-natriuretic peptide (CNP), and nitric oxide (NO), may play a role in arterial blood gas-induced alterations in CBF. For the first time, we directly quantified exchange of these vasoactive factors across the human brain. Using the Fick principle and transcranial Doppler ultrasonography, we measured CBF in 12 healthy humans at rest and during hypercapnia (4 and 8% CO 2), hypocapnia (voluntary hyperventilation), and hypoxia (12 and 10% O 2). At each level, blood was sampled simultaneously from the internal jugular vein and radial artery. With the exception of CNP and NO, the simultaneous quantification of norepinephrine, endothelin, or adrenomedullin showed no cerebral uptake or release during changes in arterial blood gases. Hypercapnia, but not hypocapnia, increased CBF and caused a net cerebral release of nitrite (a marker of NO), which was reflected by an increase in the venous-arterial difference for nitrite: 57 Ϯ 18 and 150 Ϯ 36 mol/l at 4% and 8% CO 2, respectively (both P Ͻ 0.05). Release of cerebral CNP was also observed during changes in CO 2 (hypercapnia vs. hypocapnia, P Ͻ 0.05). During hypoxia, there was a net cerebral uptake of nitrite, which was reflected by a decreased venous-arterial difference for nitrite: Ϫ96 Ϯ 14 mol/l at 10% O 2 (P Ͻ 0.05). These data indicate that there is a differential exchange of NO across the brain during hypercapnia and hypoxia and that CNP may play a complementary role in CO 2-induced CBF changes. cerebral circulation; nitric oxide; endothelium RESPIRATORY-INDUCED CHANGES in arterial PCO 2 (Pa CO 2 ) and, to a lesser extent, PO 2 (Pa O 2 ) play a major role in cerebral blood flow (CBF) regulation (9). Elevations in Pa CO 2 (hypercapnia) lead to vasodilation of cerebral arterioles in the downstream bed and a subsequent increase in CBF, whereas a reduction in Pa CO 2 (hypocapnia) leads to vasoconstriction and a subsequent decrease in CBF (28, 65). A fall in Pa O 2 (hypoxia) below a certain threshold (Ͻ40 Torr) also produces cerebral vasodilation (19). These arterial blood gas-induced changes in CBF are mediated through changes in cerebrovascular resistance via alterations in vascular smooth muscle diameter in response to changes in the level of intracellular calcium and/or calcium sensitivity (for review see Ref. 22). Cerebrovascular tone is influenced by several chemical substances, including nitric oxide (NO). NO, synthesized from the terminal guanidino nitrogen atom(s) of L-arginine in a two-step reaction that is catalyzed by the enzyme NO synthase (NOS) (48), is an important vasoactive factor that dilates the cerebral vasculature. Under normal conditions, two isoforms of NOS are expressed in the brain, endothelium-derived NOS (eNOS) and neuronal-derived NOS (nNOS) (61), although evidence for the role of eNOS vs. nNOS in the control of CBF is controversial (3). Vasodilation evoked by NO is initiated by an increase in cGMP (7).Pharmac...

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Section: Methodological Considerations and Limitationsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases

Peebles

Richards²,

Celi

et al. 2008

Journal of Applied Physiology

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“…Reduced vasodilatory responses to drug challenge (e.g., nitroglycerin, verapamil) or mechanically induced ischemia provides evidence of endothelial dysfunction that occurs in association with both advanced age and vascular disease (Adams et al, 1998;Bank & Kaiser, 1998;Bank et al, 1995). Dyslipidemia and associated atherosclerosis also play an important role (Claus et al, 1996), as cardiovascular disease is known to contribute to structural changes in cerebral blood vessels, including thickening of the intima media and a breakdown in smooth muscle function (Akopov, Sercombe, & Seylaz, 1996;Tentolouris et al, 2004Tentolouris et al, , 2006Vita, 2005;White, Deane, Vallance, & Markus, 1998). Chronic blood pressure abnormalities also have detrimental mechanical effects on cerebral hemodynamics (Birns, Markus, & Kalra, 2005;Lorberboym, Lampl, Kesler, Sadeh, & Gadot, 2001;Schmidt et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Vascular and cognitive functions associated with cardiovascular disease in the elderly

Cohen

Poppas

Forman

et al. 2008

Journal of Clinical and Experimental Neuropsychology

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This study examines the relationship between systemic vascular function, neurocognitive performance, and structural brain abnormalities on magnetic resonance imaging (MRI) among geriatric outpatients with treated, stable cardiovascular disease and no history of neurological illness (n = 88, ages 56-85 years). Vascular function was assessed by cardiac ejection fraction and output, sequential systolic and diastolic blood pressures, flow mediated brachial artery reactivity (BAR), and carotid intima media thickness (IMT). White matter hyperintensities (WMH) on MRI were quantified and examined relative to cognitive and vascular function. Principal component analysis revealed two primary vascular components: one associated with cardiac function, the other with atherosclerotic burden/endothelial dysfunction. Both factors were significantly associated with cognitive function and WMH volume. Reduced systolic variability and increased IMT were most strongly related to reduced attention, executive function, and information-processing speed. These findings suggest the possibility that systemic vascular indices may provide proxy measures of cerebrovascular dysfunction and reinforce the importance of achieving greater understanding of interaction between systemic vascular disease and brain dysfunction among elderly people with cardiovascular disease.Address correspondence to Ronald A. Cohen, Centers for Behavioral and Preventive Medicine, The CORO Building, 5th Floor, One Hoppin Street, Providence, RI 02903, USA (RCohen@lifespan.org). Vascular cognitive impairments (VCI) occur on a continuum ranging from mild deficits among patients with vascular risk factors such as cardiovascular disease (CVD) to the severe cognitive dysfunction characteristic of vascular dementia (Bowler, Steenhuis, & Hachinski, 1999;Rockwood, 2002;Roman, Erkinjuntti, Wallin, Pantoni, & Chui, 2002). Cardiovascular disease was once thought to convey little risk to the brain given its capacity for vascular autoregulation and sustained cerebral perfusion even under adverse hemodynamic conditions (Lassen, 1964). Brain dysfunction secondary to cardiovascular disease was usually attributed to acute stroke during cardiac surgery (Newman et al., 2001), or in response to cardiac events (e.g., arrhythmia). Yet, patients with severe cardiovascular disease frequently exhibit cognitive problems in the absence of clinically identified stroke (Moser et al., 1999;Paul et al., 2005), particularly in cases of heart failure (Bennett & Sauve, 2003;Bornstein, Starling, Myerowitz, & Haas, 1995), presumably reflecting the impact of reduced cardiac function on the aging brain (Roman, 2004). We have previously shown that both cognitive dysfunction and structural brain abnormalities on magnetic resonance imaging (MRI) are associated with reduced cardiac output among patients with severe cardiovascular disease (Jefferson, Poppas, Paul, & Cohen, 2007a;Jefferson et al., 2007b) and abnormalities of systemic vascular function (Gunstad et al., 2006a;Gunstad et al., 2005;Gunstad e...

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“…The free radical NO is an important mediator in a variety of biological processes in the brain such as vascular integrity, 2 cerebral blood £ow, 3 cerebral vasodilation and autoregulation. 4 However, the molecule appears to be a two-edged sword.…”

Section: Introductionmentioning

confidence: 99%

Oxidative and nitrosative stress in acute ischaemic stroke

Şeneş¹,

Kazan²,

Coşkun³

et al. 2007

Ann Clin Biochem

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AddressesBackground Increased nitric oxide (NO) production may result in further brain damage via nitric oxide synthase uncoupling in patients with acute ischaemic stroke by increasing free radical formation and oxidative stress. In this connection, we measured nitrite and nitrate (NO metabolites), ischaemia-modified albumin (IMA) and thiobarbituric acid-reactive substances (TBARS) in patients with ischaemic stroke.

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Nitric Oxide Synthase Inhibition in Humans Reduces Cerebral Blood Flow but Not the Hyperemic Response to Hypercapnia

Abstract: Background and Purpose-Animal studies suggest that nitric oxide (NO) is important in basal cerebral blood flow (CBF) regulation and that it may mediate the vasodilatory response to carbon dioxide. We investigated its role in the human circulation using the NO synthase inhibitor N

Cited by 150 publications

References 32 publications

Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases

Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases

Vascular and cognitive functions associated with cardiovascular disease in the elderly

Oxidative and nitrosative stress in acute ischaemic stroke

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