Global Ischemia Impairs ATP-Sensitive K
            <sup>+</sup>
            Channel Function in Cerebral Arterioles in Piglets

Bari, Ferenc; Louis, Thomas M.; Meng, Wei; Busija, David W.

doi:10.1161/01.str.27.10.1874

Cited by 78 publications

(64 citation statements)

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“…Indomethacin has been suggested to inhibit prostacyclin receptors (33), and a 'double-blockade' effect both at the enzyme and receptor level may explain the conspicuous efficacy of indomethacin. Unfortunately, others found iloprost-induced vasodilation intact after indomethacin (8). Conceivably, indomethacin may interfere quite specifically with the yet unknown, enigmatic mechanism of hypercapnia-induced vasodilation.…”

Section: Cox-dependent Vascular Responses In Pigsmentioning

confidence: 99%

“…However, COX inhibitors may also indirectly produce neuroprotection by preserving the ischemia-sensitive elements of cerebrovascular reactivity. Indeed, indomethacin prevented the postischemic attenuation of cerebrovascular reactivity to numerous stimuli that dilated pial arterioles through COX-independent pathways (7,8). However, a number of ischemia-sensitive vasodilatory mechanisms are themselves COX-dependent, thus COXinhibitors given for neuroprotection should simultaneously impair cerebrovascular control to some extent.…”

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confidence: 99%

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Selective Inhibitors Differentially Affect Cyclooxygenase-Dependent Pial Arteriolar Responses in Newborn Pigs

et al. 2005

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Cyclooxygenase (COX)-derived prostanoids play an important role in the cerebrovascular control of newborns. In humans and in the widely accepted model of piglets, both the COX-1 and the COX-2 isoforms are expressed in cerebral arteries. However, the involvement of these isoforms in cerebrovascular control is unknown. Therefore we tested if specific inhibitors of COX-1 and/or COX-2 would differentially affect pial arteriolar responses to COX-dependent stimuli in piglets. Anesthetized, ventilated piglets (n ϭ 35) were equipped with a closed cranial window, and changes in pial arteriolar diameters (baseline ‫001ف‬ m) to hypercapnia (ventilation with 5-10% CO 2 , 21% O 2 , balance N 2 ), arterial hypotension (40 mm Hg MABP achieved by blood withdrawal), and Ach (Ach, 10 -100 M) were determined via intravital microscopy. Arteriolar responses were repeatedly tested 15 min after IV administration of selective COX-1 and COX-2 inhibitors SC-560 and NS-398 (1-1 mg/kg), and nonselective inhibitors indomethacin (0.3-1 mg/kg), acetaminophen (30 mg/kg), and ibuprofen (30 mg/kg). Hypercapnia resulted in concentration-dependent, reversible, ‫02ف(‬ -40%) increases in pial arteriolar diameters that were unaffected by NS-398, SC-560, acetaminophen and ibuprofen. In contrast, 0.3 mg/kg indomethacin significantly reduced, 1 mg/kg virtually abolished the vasodilation. Arterial hypotension elicited ‫)%02-51ف(‬ vasodilation that was similarly reduced by NS-398 and indomethacin but was unaltered by SC-560. Ach dose-dependently constricted pial arterioles. This response was similarly attenuated by NS-398, indomethacin, and ibuprofen, but left intact by SC-560. We conclude that the assessed COX-dependent vascular reactions appear to depend largely on COX-2 activity. However, hypercapnia-induced vasodilation was found indomethacin-sensitive instead of a COX-dependent response in the piglet. Cyclooxygenase (COX) is the rate-limiting enzyme of prostanoid biosynthesis and ubiquitously found in most cells including microvascular endothelium and vascular smooth muscle (VSM). COX has two major isoforms coded by different genes (COX-1 and COX-2) that can now be targeted with selective inhibitors. More molecular variants exist as suggested by the recent description of a splice-variant of COX-1, putatively named COX-3 (1). In the piglet cerebral arteries, both COX-1 and COX-2 mRNA-s are expressed with COX-2 being the dominant constitutive isoform (2).COX-activity plays opposing roles in the cerebral circulation under physiologic and pathologic conditions. In normoxia, COX-derived metabolites play an important role in the control of VSM in many cerebrovascular regulatory pathways (3). In contrast, uncontrolled COX-activity under hypoxic/ischemic stress may be an ample source of superoxide anions and proinflammatory prostanoids involved in cellular injury and cell death (4,5). In fact, COX-inhibitors have pronounced neuroprotective effects in many neonatal and adult experimental models of hypoxia and stroke. In the piglet, the direct protective effec...

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Section: Cox-dependent Vascular Responses In Pigsmentioning

confidence: 99%

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confidence: 99%

Selective Inhibitors Differentially Affect Cyclooxygenase-Dependent Pial Arteriolar Responses in Newborn Pigs

et al. 2005

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“…Thus, indomethacin pretreatment preserves arteriolar dilator responses to CGRP, apri kalim, and iloprost after ischemia . 43,44 There are at least three striking parallels between behavior of glutaminergic receptors and K channels with respect to cerebrovascular control mechanisms following ischemic stress . First, effects of ischemia are usually transient.…”

Section: Cerebrovascular Receptors and Ion Channelsmentioning

confidence: 99%

Regulation of Cerebral Microcirculation. Update.

et al. 2000

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Abstract. The present symposium during Brain 99 was convened to explore the current aspects of the neural (extrinsic and intrinsic) and chemical control of the microvasculature in the brain with specific relevance to stimuli and rapid flow responses. N. Suzuki demonstrated the presence of neurokinin-1 receptors along the axons of vasoactive intestinal polypeptide-containing cerebrovascular para sympathetic nerves. Since the receptors were activated by substance P, calcitonin gene-related peptide and neurokinin released from coexisting sensory nerve fibers, the parasympathetic (vasodilating) fibers could effect rapid local flow increases. N. Suzuki, however, considered this as part of an elaborate de fensive network protecting the brain from invasions by noxious substances. E. Hamel discussed the responses of the microvessels to neurotransmitters and suggested that nitric oxide (NO) released from intrinsic neurons may serve as a relay in the flow activation responses by intracerebral cholinergic fi bers originating in the basal forebrain nuclei. D. Busija summarized a vasodilating system of activated N-methyl-D-asparate receptors located on neurons involving Ca influx-NO production, and activated ATP-sensitive potassium channels located in the vascular system. According to Busija, such inter actions were disrupted during hypoxia and ischemia due to cyclooxygenase-derived superoxide anion. M. Lauritzen observed a 10 times larger increase in blood flow on stimulation of the climbing nerve as compared with that following the parallel nerve stimulation. The former transmitters are considered by him to be NO and K, and the latter NO and adenosine. Each speaker singled out NO as a common mediator for the microvasculature in the rapid local flow increases. (Keio J Med 49 (1): 26-34, March 2000)

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“…In our laboratory, the newborn piglet model has long been used to study the morphology and functional responses of cerebrovascular system in physiologic and pathologic conditions [61][62][63][64][65][66][67]. We and others have repeatedly shown that hypoxic-ischemic stress in newborn piglets severely attenuated CR to various so called "hypoxia-ischemia sensitive" stimuli determined in pial arterioles 1 hour after the insult [61,64,[68][69][70].…”

Section: Animal Models In Hie Researchmentioning

confidence: 99%

“…Blood pressure, tissue oxygenation and body temperature were not monitored and potential derangements in these parameters over the course of the 24h survival period could occur and contribute to the observed attenuation of CR. Furthermore, confounding data emanated from a more recent set of studies, in which the attenuated CR to numerous stimuli (hypercapnia, NMDA, the ATP-sensitive potassium channel agonist aprikalim, and the prostacyclin analogue iloprost) spontaneously recovered 2-4 hours after hypoxic/ischemic stress [62,63,68]. In these studies, global cerebral ischemia was also performed with the same technique, however, in anesthetized animals and the duration of the anoxic stress was only 10 min.…”

Section: Map-2 Densitymentioning

confidence: 99%

Hydrogen is neuroprotective and preserves neurovascular reactivity following asphyxia in newborn pigs

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Global Ischemia Impairs ATP-Sensitive K ⁺ Channel Function in Cerebral Arterioles in Piglets

Abstract: Ischemia transiently eliminates cerebral arteriolar dilation to activation of ATP-sensitive K+ channels; arteriolar responses are suppressed at 1 hour and return toward normal over 2 to 4 hours. In addition, reduced responsiveness can be prevented by prior treatment with indomethacin.

Cited by 78 publications

References 24 publications

Selective Inhibitors Differentially Affect Cyclooxygenase-Dependent Pial Arteriolar Responses in Newborn Pigs

Selective Inhibitors Differentially Affect Cyclooxygenase-Dependent Pial Arteriolar Responses in Newborn Pigs

Regulation of Cerebral Microcirculation. Update.

Hydrogen is neuroprotective and preserves neurovascular reactivity following asphyxia in newborn pigs

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Global Ischemia Impairs ATP-Sensitive K + Channel Function in Cerebral Arterioles in Piglets

Abstract: Ischemia transiently eliminates cerebral arteriolar dilation to activation of ATP-sensitive K+ channels; arteriolar responses are suppressed at 1 hour and return toward normal over 2 to 4 hours. In addition, reduced responsiveness can be prevented by prior treatment with indomethacin.

Cited by 78 publications

References 24 publications

Selective Inhibitors Differentially Affect Cyclooxygenase-Dependent Pial Arteriolar Responses in Newborn Pigs

Selective Inhibitors Differentially Affect Cyclooxygenase-Dependent Pial Arteriolar Responses in Newborn Pigs

Regulation of Cerebral Microcirculation. Update.

Hydrogen is neuroprotective and preserves neurovascular reactivity following asphyxia in newborn pigs

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Global Ischemia Impairs ATP-Sensitive K ⁺ Channel Function in Cerebral Arterioles in Piglets