Effects of ischemia on cerebrovascular responses to N-methyl-D-aspartate in piglets

Busija, David W.; Meng, Wei; Bari, Ferenc; McGough, P. S.; Errico, Robert A.; Tobin, Joseph R.; Louis, Thomas M.

doi:10.1152/ajpheart.1996.270.4.h1225

Cited by 36 publications

(51 citation statements)

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“…In piglets, hypoxia, global ischemia, and asphyxia attenuate NMDA-induced dilation in a dose and timedependent manner (7,12,13) via ROS produced by COX activity (5,35). Endothelial cells are damaged by ischemia (20), but their role in the attenuation of NMDA-induced vasodilation is not supported by the present study.…”

Section: Discussioncontrasting

confidence: 62%

N-methyl-d-aspartate-induced vasodilation is mediated by endothelium-independent nitric oxide release in piglets

Domoki

Perciaccante

Shimizu

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. N-methyl-D-aspartate-induced vasodilation is mediated by endothelium-independent nitric oxide release in piglets. Am J Physiol Heart Circ Physiol 282: H1404-H1409, 2002. First published November 23, 2001 10.1152/ajpheart. 00523.2001.-N-methyl-D-aspartate (NMDA) elicits pial arteriolar dilation that has been associated with neuronal nitric oxide (NO) production. However, endothelial factors or glial P-450 epoxygenase products may play a role. We tested whether NMDA-induced pial vasodilation 1) primarily involves NO diffusion from the parenchyma to the surface arterioles, 2) involves intact endothelial function, and 3) involves a miconazole-sensitive component. Arteriolar diameters were determined using closed cranial window-intravital microscopy in anesthetized piglets. NMDA (10-100 M) elicited virtually identical dose-dependent dilations in paired arterioles (r ϭ 0.94, n ϭ 15). However, NMDA-but not bradykinin (BK)-induced dilations of arteriolar sections over large veins were reduced by 31 Ϯ 1% (means Ϯ SE, P Ͻ 0.05, n ϭ 4) compared with adjacent sections on the cortical surface. Also, 100 M NMDA increased cerebrospinal fluid levels of NO metabolites from 3.7 Ϯ 1.0 to 5.3 Ϯ 1.2 M (P Ͻ 0.05, n ϭ 6). Endothelial stunning by intracarotid injection of phorbol 12,13-dibutyrate did not affect NMDA-induced vasodilation but attenuated vascular responses to hypercapnia and BK by ϳ70% (n ϭ 7). Finally, miconazole (n ϭ 6, 20 M) pretreatment and coapplication with NMDA did not alter vascular responses to NMDA. In conclusion, NMDA appears to dilate pial arterioles exclusively through release and diffusion of NO from neurons to the pial surface in piglets. cerebral circulation; miconazole; pial arterioles; bradykinin PREVIOUS STUDIES suggest that stimulation of N-methyl-D-aspartate (NMDA) receptors on cortical neurons results in dose-dependent pial arteriolar dilation via a mechanism involving neuronal nitric oxide (NO) synthase (nNOS) activation and subsequent NO release in newborn pigs (11,29). Because cerebral resistance vessels and cortical astroglia lack NMDA receptors, cerebral vasodilation to NMDA must be initiated by substances released from activated neurons (30,38). Similar involvement of NO in NMDA-induced pial arteriolar vasodilation or increased cerebral blood flow (CBF) have been observed in many other species (14,32,40). Glutamate receptor activation either by nervous or pharmacological stimulation results in increased blood flow in a variety of regions, such as the cerebral cortex (25, 33, 41), striatum (10), hippocampus (18), cerebellum (3), and medulla (16) in rats. In all these regions, NO seems to be involved in the mechanism of CBF increase, and the major glutamate receptor subtype appears to be the NMDA receptor, except in the cerebellum (3, 40). However, many of the details of this relationship between activation of NMDA receptors and cerebrovascular dilation are unclear. Whereas there is agreement that NO is essential for NMDAinduced arteriolar dilation, it is unclear whether parenchymal-derived N...

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Section: Discussioncontrasting

confidence: 62%

N-methyl-d-aspartate-induced vasodilation is mediated by endothelium-independent nitric oxide release in piglets

Domoki

Perciaccante

Shimizu

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…Depressed postischemic cerebrovascular dilation is present after global cerebral ischemia (Clavier et al, 1994;Rosenblum and Wormley, 1995;Busija et al, 1996), but less is known about the effects of transient ischemia on microcirculatory response to vasoconstrictors. Our previous studies and those of others show that global ischemic brain injury can attenuate contractile responses to 5-HT (Watanabe et al, 2001;Fadyukova et al, 2004) and to arterial hypercapnia (Nelson et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Restores Postischemic Sensitivity to the Thromboxane Mimetic U46619 in Rat Pial Artery

Qin

Hurn

Littleton-Kearney

2005

J Cereb Blood Flow Metab

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The objectives of the study were to (1) characterize the dose-response relationship to the TXA 2 analog, U46619 (0.01, 0.1, and 1 lmol/L) after global cerebral ischemia, (2) determine whether chronic 17b-estradiol (E2) replacement alters this relationship, and (3) determine if E2's mechanisms are transduced through cognate estrogen receptors. Rats were assigned to five groups (n ¼ 6): placeboimplanted ovariectomized (OVX) females, OVX plus chronic E2 (CE), OVX plus acute E2 (AE), OVX plus chronic E2 plus the estrogen receptor inhibitor ICI 182,780 (CEI), and OVX plus acute E2 plus ICI 182,780 (AEI). Rats were anesthetized, intubated, cannulated (femoral artery and vein), fitted with a closed cranial window, and subjected to 15-min reversible forebrain ischemia (4-vessel occlusion, 4-VO) and 60 mins of reperfusion. Arterial blood gases, intrawindow pressure, and temperature were controlled. Vessel diameter was measured before and 5 mins after superfusion of each concentration of U46619. Compared with preischemic responses, contractile response to U46619 was depressed at all concentrations after ischemia in the OVX group. In the chronic E2 and acute E2 groups, contractile response to 1 lmol/L of U46619 was normalized to near baseline values. However, in the CEI and the AEI groups, postischemic vasoconstriction was similar to that observed in the OVX rats. We conclude that E2 targets the cerebral microvasculature to preserve postischemic pial artery reactivity and that the effect is receptor mediated. Restoration of normal constriction to vascular agonists may be an important mechanism by which E2 protects the vasculature and diminishes tissue damage after ischemia.

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“…In previous studies, we showed that cerebrovascular responses to exogenous NO remain intact after 10 min of ischemia (13) or 15 min of hypoxia (4), thereby further indicating the neuronal basis for this response. In addition, cortical NO synthase (NOS) activity is not affected by ischemia (13). Therefore, impairment of vasodilation after cerebral ischemia is not due to decreased NOS activity or reduced vascular responsiveness to NO but to a modulation of the response to NMDA at the neuronal level.…”

Section: Discussionmentioning

confidence: 99%

“…However, NMDAinduced arteriolar dilation is highly susceptible to hypoxic or ischemic insults. Thus, even short periods of hypoxia or ischemia dramatically reduce arteriolar dilator responses to NMDA in a dose-and time-dependent manner (4,5,12,13). The mechanisms of impairment of NMDA-induced dilation to hypoxia or ischemia are complex.…”

mentioning

confidence: 99%

“…The mechanisms of impairment of NMDA-induced dilation to hypoxia or ischemia are complex. However, vascular responses to NO remain intact, indicating that the attenuation of NMDA vascular responsiveness that follows hypoxia or ischemia is due to effects from the insult that occurs at the level of the neurons (13,16). These local neuronal effects appear to involve events related to the production of superoxide anion and other reactive oxygen species (ROS) via the activated cyclooxygenase (COX) pathway and from damaged mitochondria (2,4,5,16,17,26,29).…”

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confidence: 99%

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Effects of hypothermia on neuronal-vascular function after cerebral ischemia in piglets

Perciaccante

Domoki

Puskar

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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We determined whether cerebral arteriolar dilation to N-methyl-d-aspartate (NMDA), a response dependent on stimulation of cortical neurons and inhibited by anoxic stress, would be preserved by hypothermia during and following ischemia. Pial arteriolar diameters in anesthetized piglets were determined via intravital microscopy. Arteriolar responses to NMDA (10, 50, and 100 μmol/l) were measured before and 1 h after 10 min of global ischemia. Piglets were exposed to either total body or selective brain cooling (33–34°C). Arteriolar dilation to lower doses or to 100 μmol/l NMDA was not affected by hypothermia alone (51 ± 3 vs. 46 ± 7%, normothermia vs. hypothermia; n = 7) in nonischemic animals. However, arteriolar responses to 100 μmol/l NMDA were clearly attenuated after ischemia despite body cooling during ischemia (53 ± 3 vs. 32 ± 6%; n = 8), hypothermia during ischemia and early reperfusion (49 ± 10 vs. 20 ± 3%; n = 8), or selective brain cooling (48 ± 5 vs. 20 ± 5%; n = 10). In contrast, pretreatment with indomethacin resulted in complete preservation of NMDA-induced vasodilation after ischemia. Thus, hypothermia fails to protect against neuronal dysfunction during ischemia.

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Effects of ischemia on cerebrovascular responses to N-methyl-D-aspartate in piglets

Cited by 36 publications

References 0 publications

N-methyl-d-aspartate-induced vasodilation is mediated by endothelium-independent nitric oxide release in piglets

N-methyl-d-aspartate-induced vasodilation is mediated by endothelium-independent nitric oxide release in piglets

Estrogen Restores Postischemic Sensitivity to the Thromboxane Mimetic U46619 in Rat Pial Artery

Effects of hypothermia on neuronal-vascular function after cerebral ischemia in piglets

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