Role of nitric oxide, adenosine,N-methyl-d-aspartate receptors, and neuronal activation in hypoxia-induced pial arteriolar dilation in rats

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

doi:10.1016/0006-8993(95)01105-6

Cited by 77 publications

(43 citation statements)

References 24 publications

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“…First, present and previous (40) findings have indicated that, with the exception of ovariectomized females, in vivo responses to vasodilators that act directly on pial arteriolar smooth muscle or through the endothelium, in rats, are not affected by Cx43 knockdown or blockers of gap junctional communication. Second, previous findings from our laboratory showed that the hypercapnic response in pial arterioles is not dependent on the endothelium and appears to be primarily controlled by extravascular influences (23,38). On the other hand, the signal transduction mechanisms involved in hypercapnia-induced pial arteriolar responses at the cortical surface may be unique (e.g., in contrast to exogenous SNAP or ACh) in their dependence on intravascular gap junctions.…”

Section: Discussionmentioning

confidence: 82%

“…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). For many years, investigators have utilized pial arterioles as surrogates in studies on the regulation of cerebral arteriolar function in vivo.…”

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confidence: 99%

“…Moreover, it is unlikely that other neuronal factors influence the hypercapnic response of pial arterioles, because nitroxidergic innervation of these arterioles does not extend to vessels smaller than ϳ100 m in diameter (33). 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).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 82%

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confidence: 99%

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confidence: 99%

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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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“…In piglets, neurally mediated dilation (39) also appears to involve NO. In adult rats, the origin of the NO involved in glutamatergic and hypoxic cerebral dilation appears to be nNOS rather than endothelial NOS (eNOS) (46).…”

Section: Discussionmentioning

confidence: 99%

Contributions of astrocytes and CO to pial arteriolar dilation to glutamate in newborn pigs

Leffler

Parfenova²,

Fedinec

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

106

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Astrocytes can act as intermediaries between neurons and cerebral arterioles to regulate vascular tone in response to neuronal activity. Release of glutamate from presynaptic neurons increases blood flow to match metabolic demands. CO is a gasotransmitter that can be related to neural function and blood flow regulation in the brain. The present study addresses the hypothesis that glutamatergic stimulation promotes perivascular astrocyte CO production and pial arteriolar dilation in the newborn brain. Experiments used anesthetized newborn pigs with closed cranial windows, piglet astrocytes, and cerebrovascular endothelial cells in primary culture and immunocytochemical visualization of astrocytic markers. Pial arterioles and arteries of newborn pigs are ensheathed by astrocytes visualized by glial fibrillary acidic protein staining. Treatment (2 h) of astrocytes in culture with L-2-␣-aminoadipic acid (L-AAA), followed by 14 h in toxin free medium, dose-dependently increased cell detachment, suggesting injury. Conversely, 16 h of continuous exposure to L-AAA caused no decrease in endothelial cell attachment. In vivo, topical L-AAA (2 mM, 5 h) disrupted the cortical glia limitans histologically. Such treatment also eliminated pial arteriolar dilation to the astrocytedependent dilator ADP and to glutamate but not to isoproterenol or CO. Glutamate stimulated CO production by the brain surface that also was abolished following L-AAA. In contrast, tetrodotoxin blocked dilation to N-methyl-D-aspartate but not to glutamate, isoproterenol, or CO or the glutamate-induced increase in CO. The concurrent loss of CO production and pial arteriolar dilation to glutamate following astrocyte injury suggests astrocytes may employ CO as a gasotransmitter for glutamatergic cerebrovascular dilation. glia limitans; cerebrovascular circulation; gasotransmitter; glia toxin IN THE CEREBROVASCULAR circulation, signals to vascular smooth muscle can come from endothelium, nerves, astrocytes, or pericytes, which interact to form a neurovascular unit (15). L-Glutamic acid (glutamate) is the principal excitatory neurotransmitter in the central nervous system (38). It is a dilator of cerebral arterioles in vivo (8, 12), although direct effects of glutamate on the vascular smooth muscle are uncertain. Release of glutamate from presynaptic neurons dilates cerebral arterioles, causing blood flow to increase to match metabolic demands (37).Astrocytes are the most abundant cell type in the higher mammalian brain. They function as intermediaries between neurons and cerebral arterioles in regulation of cerebral vascular tone in response to neuronal activity, thereby adjusting cerebral blood flow to metabolism (15,25). Whether astrocytes are involved in dilation in response to glutamate released at excitatory synapses and the nature of astrocyte-derived vasodilator(s) employed remain uncertain.The gas CO is produced physiologically by catabolism of heme to CO, iron, and biliverdin (36). This reaction is catalyzed by heme oxygenase (HO) with oxidation of...

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“…LCBF is sensitive to numerous biochemical substances (K , adenosine, nitric oxide), whose activity changes during neuronal activation and under hypercapnia [2,[27][28][29][30]. It has been observed that acidification caused by CO 2 inhalation enhances nitric oxide synthase activity and K ϩ release and produces long-lasting changes in intracellular Ca 2ϩ and the calmodulin activity, as well as in the adenosine release [27,[30][31][32][33]. In the present study, we demonstrated that hypercapnia caused a decline in the pH level because of a change in H ϩ concentration (Table 1).…”

Section: Discussionmentioning

confidence: 99%