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

Wang, Qiong; Pelligrino, Dale A.; Baughman, Verna L.; Koenig, Heidi M.; Albrecht, Ronald F.

doi:10.1038/jcbfm.1995.97

Cited by 157 publications

(74 citation statements)

References 18 publications

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“…Furthermore, with only one exception (28), local blockade of neuronal transmission (with TTX) has not been found to alter hypercapniainduced pial arteriolar dilation (23) or hypercapnic cerebral vasodilation in general (3,42). Despite this, hypercapnia elicits a global dilation of pial arterioles, a response that is substantially diminished by selective nNOS blockade (29,37).Because of their unique association with neurons and pial vessels, we hypothesized, therefore, that astrocytes, via the GL, may act to transmit and amplify signals arising in comparatively few cells to the entirety of the pial arteriolar system. To that end, we determined whether injury of the GL [via topical exposure to the purported gliotoxin L-␣-aminoadipic acid (L-␣AAA)] alters hypercapnia-induced pial arteriolar dilation.…”

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“…Hypercapnia would appear to be one such stimulus. With few exceptions (28), evidence from multiple laboratories (9,10,29,30,37) points to neuronal nitric oxide (NO) synthase (nNOS)-generated NO playing major role in adult rodent CO 2 -induced cerebral vasodilation in vivo (including pial arterioles). However, nNOS-containing neurons are sparsely distributed in the rat cerebral cortex and are virtually absent from the outermost cortical layer (layer I) (34).…”

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Influence of the glia limitans on pial arteriolar relaxation in the rat

Xu¹,

Koenig²,

Ye³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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We examined whether damage to the glia limitans (GL), via exposure to the gliotoxin L-␣-aminoadipic acid (L-␣AAA), alters hypercapniainduced pial arteriolar dilation in vivo. Anesthetized female rats were prepared with closed cranial windows. Pial arteriolar diameters were measured using intravital microscopy. L-␣AAA (2 mM) was injected into the space under the cranial windows 24 h before the study, and injury to the GL was confirmed by light microscopy. L-␣AAA was associated with a reduction in pial arteriolar CO 2 reactivity to 40 -50% of the level seen in vehicle-treated controls, with no further reduction in the CO 2 response after nitric oxide (NO) synthase (NOS) inhibition via N -nitro-L-arginine (L-NNA). Subsequent blockade of prostanoid synthesis, via indomethacin (Indo), reduced CO2 reactivity to 10 -15% of normal. In vehicle-treated controls, L-NNA, followed by Indo, reduced the response to ϳ50% and then to 15-20% of the normocapnic value, respectively. On the other hand, L-␣AAA had no effect on vascular responses to the endothelium-dependent vasodilator acetylcholine or the NO donor SNAP and did not alter cortical somatosensory evoked responses. This indicates an absence of any direct L-␣AAA actions on pial arterioles or influence on neuronal transmission. Furthermore, L-␣AAA did not alter the vasodilation elicited by topical application of an acidic artificial cerebrospinal fluid solution, suggesting that the GL influences the pial arteriolar relaxation elicited by hypercapnic, but not local extracellular (EC), acidosis. That differences exist in the mechanisms mediating hypercapniaversus EC acidosis-induced pial arteriolar dilations was further exemplified by the finding that topical application of a neuronal NOS (nNOS)-selective blocker (ARR-17477) reduced the response to hypercapnia (by ϳ65%) but not the response to EC acidosis. Disruption of GL gap junctional communication, using an antisense oligodeoxynucleotide (ODN) connexin43 knockdown approach, was accompanied by a 33% lower CO 2 reactivity versus missense ODN-treated controls. These results suggest that the GL contribution to the hypercapnic vascular response appears to involve the NO-dependent component rather than the prostanoid-dependent component and may involve gap junctional communication. We speculate that the GL may act to facilitate the spread, to pial vessels, of hypercapnia-induced vasodilating signals arising in the comparatively few scattered nNOS neurons that lie well beneath the GL. connexin; gap junction; hypercapnia; L-␣-aminoadipic acid; nitric oxide; prostanoids BECAUSE OF THE INTIMATE ANATOMIC RELATIONSHIP between cerebral resistance vessels and astrocytes (19), it has been postulated that astrocytes play a vital role in the regulation of local perfusion in the brain (7). In fact, experimental evidence to that effect has been published (43). Small pial arterioles (Ͻ50 m), although exhibiting a relative paucity of direct neural connections (8, 33), nevertheless appear to be regulated by extravascular influences (23,38). F...

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Influence of the glia limitans on pial arteriolar relaxation in the rat

Xu¹,

Koenig²,

Ye³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…3,4 In the cerebral circulation, neuronal and/or endothelial nitric oxide (NO) is known as the regulator of acidosisinduced dilation. [7][8][9][10] Recently, Lindauer et al 11 found that in isolated rat middle cerebral artery, denudation did not alter the vessel response to acidosis, favoring neuronal but not endothelial NO as a modulator of pH-dependent vasoreactivity in this preparation. In addition, ATP-sensitive potassium (K ATP ) channels in vascular smooth muscle have received attention as major contributors to acidosis-induced dilation in pial vessels and basilar artery.…”

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Role of Endothelial Nitric Oxide and Smooth Muscle Potassium Channels in Cerebral Arteriolar Dilation in Response to Acidosis

Horiuchi

Dietrich

Hongo

et al. 2002

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Background and Purpose-Potassium channels or nitric oxide or both are major mediators of acidosis-induced dilation in the cerebral circulation. However, these contributions depend on a variety of factors such as species and vessel location. The present study was designed to clarify whether potassium channels and endothelial nitric oxide are involved in acidosis-induced dilation of isolated rat cerebral arterioles. Methods-Cerebral arterioles were cannulated and monitored with an inverted microscope. Acidosis (pH 6.8 to 7.4) produced by adding hydrogen ions mediated dilation of the cerebral arterioles in a concentration-dependent manner. The role of nitric oxide and potassium channels in response to acidosis was examined with several specific inhibitors and endothelial damage. Results-The dilation was significantly inhibited by potassium chloride (30 mmol/L) and glibenclamide (3 mol/L; ATP-sensitive potassium channel inhibitor). We found that 30 mol/L BaCl 2 (concentration-dependent potassium channel inhibitor) also affected the dilation; however, an additional treatment of 3 mol/L glibenclamide did not produce further inhibition. Tetraethylammonium ion (1 mmol/L; calcium-activated potassium channel inhibitor) and 4-aminopyridine (100 mol/L; voltage-dependent potassium channel inhibitor) as well as ouabain (10 mol/L; Na-K ATPase inhibitor) and N-methylsulphonyl-6-(2-proparglyloxyphenyl) hexanamide (1 mol/L; cytochrome P450 epoxygenase inhibitor) did not alter acidotic dilation. N -Monomethyl-L-arginine (10 mol/L) and N -nitro-L-arginine (10 mol/L) as nitric oxide synthase inhibitor blunted the dilation. Furthermore, the dilation was significantly attenuated after the endothelial impairment. Additional treatment with glibenclamide (3 mol/L) further reduced the dilation in response to acidosis. Conclusions-Endothelial nitric oxide and smooth muscle ATP-sensitive potassium channels contribute to acidosisinduced dilation of rat cerebral arterioles. Endothelial damage caused by pathological conditions such as subarachnoid hemorrhage or traumatic brain injury may contribute to reduced blood flow despite injury-induced cerebral acidosis.

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“…In contrast to the local vasomotor response to levodopa, which is likely driven by the engagement of endothelial D 1 receptors, CO 2 -mediated vasodilation is regulated downstream by the effects of nitric oxide on vascular tone (20,21). We note that, while the HC CBF response appears to be sensitive to local capillary density (see above), the vasomotor levodopa response likely is also influenced to some degree by this factor.…”

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confidence: 86%