Effects of ischemia on brain blood flow and oxygen consumption of newborn pigs

Leffler, Charles W.; Busija, David W.; Mirro, R.; Armstead, William M.; Beasley, Donathan G.

doi:10.1152/ajpheart.1989.257.6.h1917

Cited by 39 publications

(49 citation statements)

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“…Ischemia was verified by cessation of blood flow in the vessels observed through the cranial window. By using microspheres, we have shown repeatedly that the CBF in all examined brain areas is virtually zero during the ischemic period (5,8,25). Venous blood was withdrawn as necessary to maintain mean arterial blood pressure (MABP) near normal values.…”

Section: Methodsmentioning

confidence: 99%

Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets

Domoki

Kis

Nagy

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets. Am J Physiol Heart Circ Physiol 289: H368-H373, 2005. First published February 25, 2005 doi:10.1152/ajpheart.00887.2004, an activator of mitochondrial ATP-sensitive K ϩ (mitoKATP) channels, is neuroprotective, but the mechanism of action is unclear. We tested whether Diaz preserves endothelium-dependent (hypercapnia) or -independent [iloprost (Ilo)] cerebrovascular dilator responses after ischemia-reperfusion (I/R) in newborn pigs and whether the effect of Diaz is sensitive to 5-hydroxydecanoate (5-HD), an inhibitor of mitoK ATP channels. Anesthetized, ventilated piglets (n ϭ 48) were equipped with closed cranial windows. Changes in diameter of pial arterioles were determined with intravital microscopy in response to graded hypercapnia (5-10% CO 2-21% O2-balance N2, n ϭ 25) or Ilo (0.1-1 g/ml, n ϭ 18) before and 1 h after 10 min of global I/R. Experimental groups were pretreated with vehicle, NS-398 (a selective cyclooxygenase-2 inhibitor, 1 mg/kg), Diaz (3 mg/kg), or 5-HD (20 mg/kg) ϩ Diaz. Potential direct effects of Diaz and 5-HD on hypercapnic vasodilation were also tested in the absence of I/R (n ϭ 5). To confirm the direct effect of Diaz on mitochondria, mitochondrial membrane potential in cultured piglet cerebrovascular endothelial cells was monitored using Mito Tracker Red. Hypercapnia resulted in dose-dependent pial arteriolar vasodilation, which was attenuated by ϳ70% after I/R in vehicle-and NS-398-treated animals. Diaz and 5-HD did not affect the CO 2 response. Diaz significantly preserved the postischemic vasodilation response to hypercapnia, but not to Ilo. Diaz depolarized mitochondria in cultured piglet cerebrovascular endothelial cells, and 5-HD completely abolished the protective effect of Diaz, both findings indicate a role for mitoK ATP channels. In summary, preservation of arteriolar dilator responsiveness by Diaz may contribute to neuroprotection. pial arteriole; iloprost; NS-398; 5-hydroxydecanoate; intravital microscopy; endothelium INADEQUATE RESPIRATION and/or cerebral hypoperfusion may lead to asphyxia or cerebral ischemia-reperfusion (I/R) in neonates and are significant causes of perinatal morbidity/ mortality (6). Compared with stroke management in adults, perinatal stroke management has a major advantage, because in developed countries nearly all babies can receive instant medical care. Effective and low-risk neuroprotective treatment (even pretreatment in some cases) can, in theory, reduce irreversible neurological damage.Mitochondria have recently been shown to play an important role in the mechanism of brain injury after I/R. In addition to being the major site of ATP synthesis and numerous metabolic processes, mitochondria are involved in intracellular Ca 2ϩ homeostasis, produce large amounts of reactive oxygen species (ROS), and are the source of apoptogenic proteins (7). Because these mechanisms have been identified as important factors leading to cell death after I/R...

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Section: Methodsmentioning

confidence: 99%

Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets

Domoki

Kis

Nagy

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…In groups 5 and 6, the left common carotid artery (CCA) was ligated and catheterized distally to provide access for intra-arterial phorbol 12,13-dibutyrate (PDB) injection. In piglets, ligation of one carotid artery has no detectable effect on CBF (19,21). The piglets were intubated via tracheotomy and artificially ventilated with room air.…”

Section: Methodsmentioning

confidence: 99%

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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“…Techniques for induction of total cerebral ischemia in the piglet have been well documented (8,9). Briefly, total cerebral ischemia was accomplished by infusing artificial CSF into a hollow bolt in the cranium to maintain an intracranial pressure 15 mm Hg greater than the numeric mean of systolic and diastolic arterial blood (9).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, total cerebral ischemia was accomplished by infusing artificial CSF into a hollow bolt in the cranium to maintain an intracranial pressure 15 mm Hg greater than the numeric mean of systolic and diastolic arterial blood (9). Intracranial pressure was monitored via a sidearm of the cranial window.…”

Section: Methodsmentioning

confidence: 99%

“…Intracranial pressure was monitored via a sidearm of the cranial window. Blood flow in pial arterioles, viewed with a microscope and video monitor, stopped completely on elevation of intracranial pressure and did not resume until the pressure was lowered (9). To prevent the arterial pressure from rising inordinately (Cushing response), venous blood was withdrawn as necessary to maintain mean arterial pressure no greater than 100 mm Hg.…”

Section: Methodsmentioning

confidence: 99%

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NOC/oFQ and NMDA Contribute to Piglet Hypoxic Ischemic Hypotensive Cerebrovasodilation Impairment

Armstead

2002

Pediatric Research

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Previous studies have observed that hypotensive pial artery dilation was blunted after hypoxia-ischemia. In unrelated studies, the opioid nociceptin/orphanin FQ (NOC/oFQ) was observed to contribute to hypoxic ischemic impairment of N-methyl-Daspartate (NMDA)-induced pial dilation. This study determined the contribution of NOC/oFQ and NMDA to hypoxic ischemic hypotensive cerebrovasodilation impairment in newborn pigs equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased PO 2 to 33 Ϯ 3 mm Hg. Topical NOC/oFQ (10 Ϫ10 M), the cerebrospinal fluid concentration after hypoxia-ischemia, had no effect on pial artery diameter by itself but attenuated hypotension (mean arterial blood pressure decrease of 44 Ϯ 2%) -induced pial artery dilation (35 Ϯ 2% versus 22 Ϯ 3%). Hypotensive pial artery dilation was blunted by hypoxia-ischemia, but such dilation was partially protected by pretreatment with the putative NOC/oFQ receptor antagonist, [F/G] NOC/oFQ (1-13) NH 2 (10 Ϫ6 M; 29 Ϯ 2%, sham control; 7 Ϯ 2%, hypoxia-ischemia; and 13 Ϯ 2%, hypoxia-ischemia and [F/G] NOC/oFQ (1-13) NH 2 ). Coadministration of the NMDA antagonist MK801 (10 Ϫ5 M) with NOC/oFQ(10 Ϫ10 M) partially prevented hypotensive pial dilation impairment. Similarly, pretreatment with MK801 partially protected hypoxic ischemia impairment of hypotensive pial dilation (35 Ϯ 2%, sham control; 7 Ϯ 1%, hypoxiaischemia; 22 Ϯ 2%, hypoxia-ischemia ϩ MK801). These data show that NOC/oFQ and NMDA contribute to hypoxic ischemic hypotensive cerebrovasodilation impairment. These data suggest that NOC/oFQ modulation of NMDA vascular activity also contributes to such hypotensive impairment. Episodes of inadequate oxygen supply to the brain can result in significant neurologic sequelae. Babies are frequently exposed to either combined or sequential hypoxia and ischemia insults during the perinatal period because of problems with delivery or respiratory management after delivery (1). One contributor to neurologic damage is thought to be cerebrovascular dysfunction. For example, the major neurologic manifestations of brain injury in the premature infant are spastic motor deficits (1). The major neuropathologic outcomes for the latter are periventricular leukomalacia and periventricular hemorrhagic infarction (1). One contributor to periventricular leukomalacia is the pressure-passive cerebral circulation, which, in turn, can result from systemic hypotension (1). One potential pathogenic factor in such white matter injury is excess extracellular glutamate, an excitatory amino acid (1). However, little attention has been paid to the functional implications of vascular abnormalities to glutamate after an H/I insult.During the last 5 y, several groups have isolated and cloned a new G protein-coupled receptor that showed high homology with opioid receptors (2). The peptide ligand for this receptor does not bind to classic opioid receptors (, ␦, ) and was named orphanin FQ by Reinscheid et al. (3) because its s...

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Effects of ischemia on brain blood flow and oxygen consumption of newborn pigs

Cited by 39 publications

References 0 publications

Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets

Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets

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

NOC/oFQ and NMDA Contribute to Piglet Hypoxic Ischemic Hypotensive Cerebrovasodilation Impairment

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