UMLS:C0022116 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Capsaicin (10 microM), KCl (80 mM) or superfusion with a low pH medium (pH 5 or 6) produced a significant increase of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) outflow from the superfused rat isolated soleus muscle. CGRP-LI outflow produced by capsaicin or pH 5 medium was totally abolished in a calcium free medium containing EDTA (1 mM) and the effect of pH 5 medium was prevented by a previous application of capsaicin. Ruthenium red (10 microM) produced a marked inhibition of CGRP-LI release produced by capsaicin or pH 5 medium (69 and 84%, resp.), without affecting that evoked by KCl. These findings demonstrate that protons activate capsaicin-sensitive primary afferents in rat skeletal muscle through a Ruthenium red-sensitive mechanism. Proton-induced CGRP-LI release in skeletal muscle could be of relevance during exercise and/or skeletal muscle ischemia.
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PMID:Release of calcitonin gene-related peptide-like (CGRP-LI) immunoreactivity from rat isolated soleus muscle by low pH, capsaicin and potassium. 127 75

Intrinsic mechanisms of vasodilatation may prevent injury-related ischemia in peripheral nerve endoneurium. We examined local perfusion up to 10 days following local crush, partial injury or simple exposure of the rat sciatic nerve. By employing epineurial hCGRP(8-37), a receptor antagonist of CGRP, and serial hydrogen clearance measurements, we estimated the component of post-injury blood flow related to local CGRP action. Injury-related ischemia was not observed at any of the time points studied at or proximal to injury. Instead, endoneurial blood flow (EBF) increased at 24 h proximal to crush or partial injury, and at 48 h within the crush zone when compared to sham operated controls or to a pooled reference range of EBF. Composite blood flow (F) was also elevated at 48 h and 5 days within the crush zone suggesting hyperemia involving the epineurial plexus, perineurial vessels and AV shunts. hCGRP(8-37) constricted vasa nervorum at most time points but its effect on EBF was maximum and exceeded controls within the crush zone at 48 h. The findings indicate that certain types of nerve injury, including focal crush, are associated with hyperemia, not ischemia. CGRP vasodilatation may account for part of this response, implying a local peptidergic afferent fiber response to nerve trunk injury.
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PMID:Hyperemia of injured peripheral nerve: sensitivity to CGRP antagonism. 133 7

In clinical flap transplantation, ischaemia may alter reinnervation patterns either directly or by affecting angiogenesis. This study presents the effects of ischaemia on innervation in totally denervated, transiently (30 minutes) or prolongedly ischaemic skin flaps studied immunohistochemically with antisera to PGP 9.5, CGRP and VWF. Following transient ischaemia, an increase in PGP-immunoreactive (PGP-IR) and CGRP-IR nerve fibres in distant skin by day 12 was followed by increased innervation in immediately adjacent skin. The latter increase was maintained up to 24 days which allowed near normal innervation at the suture margin and in adjacent flap tissue, 0.5 cm from the margin. There was concomitant reinnervation from the pedicle by day 24. In prolongedly ischaemic flaps, an earlier and more prolonged increase in innervation was seen in the entire surrounding skin, with innervation around the suture line at 24 days resembling that in the transiently ischaemic flaps despite initial complete nerve fibre depletion in this area. Hypertrophic nerve fibre clusters were seen in fibrotic areas overlying the pedicle. Vascular changes were similar in both groups with vascularization preceding reinnervation. There were no significant differences in reinnervation between the transiently and prolongedly ischaemic flaps at 24 days, despite considerable initial variations. Ischaemia, CGRP, mediators of chronic inflammation and epidermal factors appeared to stimulate angiogenesis and reinnervation.
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PMID:Angiogenesis and reinnervation in skin flaps: the effects of ischaemia examined in an animal model. 752 11

1. Although the physical nature of sigma (sigma) receptors have not yet been fully defined, several classes of selective ligands have been characterised, demonstrating a plethora of physiological actions. In the present review, the authors have set out to highlight two important aspects of the biological activities of sigma ligands, their neuroprotective and anti-amnesic effects. 2. The sigma ligands present a therapeutic potential as neuroprotective agents in brain ischemia. The neuroprotective activity of many non-selective sigma ligands is primarily a result of their affinity for the NMDA receptor complex. However, selective sigma ligands are also neuroprotective, possibly by inhibition of the ischemic-induced presynaptic release of excitotoxic amino acids. 3. The sigma 1 ligands prevent the experimental amnesia induced by muscarinic cholinergic antagonists at either the learning, consolidation or retention phase of the mnesic process. This effect involves a potentation of acetylcholine release induced by sigma 1 ligands selectively in the hippocampal formation and cortex. 4. The sigma 1 receptor ligands also attenuate the learning impairment induced by dizocilpine, a non-competitive antagonist of the NMDA receptor, and may relate to the potentiating effect of sigma 1 ligands on several NMDA receptor-mediated responses previously described in vitro and in vivo in the hippocampus. This effect is shared by NPY- and CGRP-related peptides and by neuroactive steroids, confirming the in vitro evidences of functional interactions between the sigma 1 receptors and these different systems. 5. Additional amnesia models also seem to be alleviated by sigma 1 ligands, such as phencyclidine-induced cognitive dysfunctions, and amnesia induced by the calcium channel blocker nimodipine, or by exposure to carbon monoxide. Furthermore, a preliminary study in an animal model of age-related memory deficits, the senescence-accelerated mouse, strengthened the therapeutic potentials of selective sigma 1 receptor ligands in aging-related pathologies.
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PMID:Neuroprotective and anti-amnesic potentials of sigma (sigma) receptor ligands. 907 59

Calcitonin gene-related peptide [CGRP]--a powerful vasodilator, is a 37 amino acid peptide that is find primarily in the central and peripheral nervous system. It affects the regulation of local blood flow, smooth muscle tone and glandular secretion. It is an endocrine regulator and in the lungs it also exerts a bronchoconstricting effect. CGRP has a proliferative effect on human endothelial cells. Therefore, it is important for the formation of new vessels, example, in ischemia, inflammations, and in the healing of wounds. Plasma levels of CGRP are increase in patients with chronic cardiac failure and sepsis, indicating that CGRP may be another important peptide in chronic illness. We have therefore measured the release of this peptide and another sensory peptide [Substance P (SP)]; a vasoconstrictor peptide [Endothelin (ET)]; and a perivascular peptide [Neuropeptide Y (NPY)], within 24 hours of injury, in the plasma of patients with soft tissue injury. Neuropeptides were measure by enzyme immunoassay technique. Median: (lower quartile-upper quartile) in pmol/L CGRP level was elevated in patients [50.37: (12.4-110.9)] compared to controls [13.9: (10.9-36.96)] p<0.05; Endothelin and NPY did not vary much between groups p=NS; ET: patients [8.7: (1.7-87.1), controls 8.8: (1.7-32.9)]; NPY: Patients [11.7: (10.5-14.99), controls 11: (10.3-12.8)]. SP was increase in patients [302.3: (79.9-707.3)], than controls [5.6: (3.2-36.6)] p<0.05. Furthermore, Elastase (a decisive marker for inflammation and infectious complications), was measure (ng/L), and found to be slightly higher in patients (102: 25.5-223), than controls (91.8: 45.9-127). In summary, plasma levels of sensory peptides increased significantly, in patients with soft tissue injury, in contrast to vasocostrictor peptides that remained unchanged. These sensory peptides may yet be another group of neuromodulators playing a significant role in immune, pain, inflammatory and wound healing in soft tissue injury patients.
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PMID:Calcitonin gene-related peptide and other neuropeptides in the plasma of patients with soft tissue injury. 1050 54

Various organs, including heart, kidneys, liver or brain, respond to brief exposures to ischemia with an increased resistance to severe ischemia/reperfusion and this phenomenon is called "preconditioning". No study so far has been undertaken to check whether such short, repeated gastric ischemic episodes protect gastric mucosa against severe damage caused by subsequent prolonged ischemia/reperfusion and, if so, what could be the mechanism of this phenomenon. The ischemic preconditioning was induced by short episodes of gastric ischemia (occlusion of celiac artery from one to five times, for 5 min each) applied 30 min before prolonged (30 min) ischemia followed by 3 h of reperfusion or 30 min before topical application of strong mucosal irritants, such as 100% ethanol, 25% NaCl or 80 mM taurocholate. Exposure to regular 30-min ischemia, followed by 3-h reperfusion, produced numerous severe gastric lesions and significant fall in the gastric blood flow and prostaglandin E(2) generation. Short (5-min) ischemic episodes (1-5 times) by itself failed to cause any gastric lesions, but significantly attenuated those produced by ischemia/reperfusion. This protection was accompanied by a reversal of the fall in the gastric blood flow and prostaglandin E(2) generation and resembled that induced by classic gastric mild irritants. These protective and hyperemic effects of standard preconditioning were significantly attenuated by pretreatment with cyclooxygenase-2 and cyclooxygenase-1 inhibitors, such as indomethacin, Vioxx, resveratrol and nitric oxide (NO)-synthase inhibitor, N(G)-nitro-L-arginine (L-NNA). The protective and hyperemic effects of standard preconditioning were restored by addition of 16,16 dm prostaglandin E(2) or L-arginine, a substrate for NO synthase, respectively. Gastroprotective and hyperemic actions of standard ischemic preconditioning were abolished by pretreatment with capsaicin-inactivating sensory nerves, but restored by the administration of exogenous CGRP to capsaicin-treated animals. Gene and protein expression of cyclooxygenase-1, but not cyclooxygenase-2, were detected in intact gastric mucosa and in that exposed to ischemia/reperfusion with or without ischemic preconditioning, whereas cyclooxygenase-2 was overexpressed only in preconditioned mucosa. We conclude that: (1) gastric ischemic preconditioning represents one of the most powerful protective interventions against the mucosal damage induced by severe ischemia/reperfusion as well as by topical mucosal irritants in the stomach; (2) gastric ischemic preconditioning resembles the protective effect of "mild irritants" against the damage by necrotizing substances in the stomach acting via "adaptive cytoprotection" and involves several mediators, such as prostaglandin derived from cyclooxygenase-1 and cyclooxygenase-2, NO originating from NO synthase and sensory nerves that appear to play a key mechanism of gastric ischemic preconditioning.
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PMID:Ischemic preconditioning, the most effective gastroprotective intervention: involvement of prostaglandins, nitric oxide, adenosine and sensory nerves. 1156 57

Leptin, a product of ob gene controlling food intake, has recently been detected in the stomach and shown to be released by CCK and implicated in gastroprotection against various noxious agents but it is unknown whether centrally applied leptin influences ischemia-reperfusion (I/R)-induced gastric erosions that progress into deeper gastric ulcerations. In this study we compared the effects of leptin and CCK-8 applied intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) on gastric mucosal lesions induced by I/R and topical application of 75% ethanol. Several major series of Wistar rats were used to examine the effects of leptin and CCK applied centrally on gastroprotection against I/R and ethanol in rats with A) vagotomy by cutting of vagal nerves, B) suppression of NO-synthase with L-NNA (20 mg/kg i.p.), C) inactivation of sensory nerves by capsaicin (125 mg/kg s.c.) and D) inhibition of CGRP receptors with CGR(8-37) (100 microg/kg i.p.) applied with or without the i.c.v. pretreatment with leptin or CCK-8. Rats were anesthetized 1 h after ethanol administration or at 3 h and 3 days upon the end of ischemia to measure the gastric blood flow (GBF) and then to determine the area of gastric lesions by planimetry. Blood was withdrawn for the measurement of plasma leptin and gastrin levels by radioimmunoassay (RIA). Leptin (0.1-20 microg/kg i.p.) dose-dependently attenuated gastric lesions induced by 75% ethanol and I/R; the dose reducing these lesions by 50% (ED50) was 8 microg/kg and 6 microg/kg, respectively and this protective effect was similar to that obtained with CCK-8 applied in a standard dose of 10 microg/kg i.p. This protective effect of leptin was accompanied by a significant increase in GBF and plasma gastrin levels whereas CCK-8 increased plasma leptin levels but failed to affect plasma gastrin levels. Leptin and CCK-8 applied i.c.v. in a dose of 625 ng/rat reduced significantly the area of I/R induced gastric lesions and raised the GBF and plasma leptin levels with the extent similar to those achieved with peripheral administration of leptin or CCK-8 (10 microg/kg i.p.). The protective and hyperemic effects of centrally administered leptin or CCK-8 (625 ng/rat i.c.v.) were completely abolished by vagotomy and significantly attenuated by sensory denervation with capsaicin or by CGRP antagonist, CGRP(8-37). The pretreatment with L-NNA to inhibit NO-synthase activity attenuated significantly the protective and hyperemic effects of CCK but not those of leptin while capsaicin denervation counteracted leptin-induced protection and rise in the GBF but attenuated significantly those of CCK. We conclude that: 1) central leptin exerts a potent gastroprotective activity against I/R-induced gastric erosions that progress into deeper gastric lesions and this protection depends upon vagal activity and sensory nerves and involves hyperemia probably mediated by NO and 2) leptin mimics the gastroprotective effect of CCK and may be implicated in the protective and hyperemic actions of this peptide against mucosal damage evoked by I/R.
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PMID:Brain-gut axis in gastroprotection by leptin and cholecystokinin against ischemia-reperfusion induced gastric lesions. 1178 60

Adrenomedullin (AM) is a potent depressor peptide whose vascular action is suggested to involve nitric oxide (NO) release. To explore the role of endogenous AM in vascular and renal function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists AM(22-52) and CGRP(8-37) on the renal perfusion pressure (RPP) of kidneys isolated from AM transgenic (TG)/heterozygote knockout (KO) mice and wild-type littermates (WT). Furthermore, we evaluated the renal function and histology 24 hours after bilateral renal artery clamp for 45 minutes in TG, KO, and WT mice. Baseline RPP was significantly lower in TG than in KO and WT mice (KO 93.4+/-4.6, WT 85.8+/-4.2, TG 72.4+/-2.4 mm Hg [mean+/-SE], P<0.01). ACh and AM caused a dose-related reduction in RPP, but the degree of vasodilatation was smaller in TG than that in KO and WT (%DeltaRPP 10(-7) mol/L ACh: KO -48.1+/-3.9%, WT -57.5+/-5.6%, TG -22.8+/-4.8%, P<0.01), whereas N(G)-nitro-L-arginine methyl ester (L-NAME) caused greater vasoconstriction in TG (%DeltaRPP 10(-4) mol/L: KO 33.1+/-3.3%, WT 55.5+/-7.2%, TG 152.6+/-21.2%, P<0.01). Both AM antagonists increased RPP in TG to a greater extent compared with KO and WT mice (%DeltaRPP 10(-6) mol/L CGRP(8-37): KO 12.8+/-2.6%, WT 19.4+/-3.6%, TG 41.8+/-8.7%, P<0.01). In mice with ischemic kidneys, serum levels of urea nitrogen and renal damage scores showed smaller values in TG and greater values in KO mice (urea nitrogen: KO 104+/-5>WT 98+/-15>TG 38+/-7 mg/dL, P<0.05 each). Renal NO synthase activity was also greater in TG mice. However, the differences in serum urea nitrogen and renal damage scores among the 3 groups of mice were not observed in mice pretreated with L-NAME. In conclusion, AM antagonists increased renal vascular tone in WT as well as in TG, suggesting that endogenous AM plays a role in the physiological regulation of the vascular tone. AM is likely to protect renal tissues from ischemia/reperfusion injury through its NO releasing activity.
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PMID:Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury: studies on transgenic/knockout mice of adrenomedullin gene. 1193 26

Trigeminal afferent neurons express ionotropic P2X receptors for extracellular ATP which are known to be sensitive to low interstitial pH. Both conditions - ATP release and tissue acidosis - may occur in the dura following the ischemia phase of migraine attacks. Aim of this study was to investigate whether and how ATP and protons may cooperate in exciting meningeal afferents. After removal of the cerebral hemispheres hemisected scull cavities of adult Wistar rats were used as organ bath of their own lining, the dura mater. The dura was chemically stimulated and the amounts of immunoreactive calcitonin gene-related peptide (iCGRP) and prostaglandin E(2) (PGE(2)) released into incubation fluid were measured using enzyme immunoassays. Stimulation with ATP (10(-4) and 10(-3)M) augmented iPGE(2) release dose-dependently whereas iCGRP secretion was minimally enhanced only if the dura had previously been depleted of extracellular ATP using hexokinase. Acid buffer solutions (pH 5.9 and 5.4) resulted in pH-dependent increase of iCGRP release but reduced iPGE(2) release. Purines (ATP 10(-3)>UTP 10(-4)M>ATP 10(-4)M) and PGE(2) (10(-5)M) were found to facilitate the proton-induced increase in iCGRP release. The proton-reduction of PGE(2) release was overcome by adding ATP (10(-3)M). S(+)-flurbiprofen (10(-6)M) suppressed both the basal and stimulated iPGE(2) release and prevented the ATP(10(-4)M)-induced facilitation of the proton response. The facilitating effect of ATP was also blocked under suramin, a non-selective P2 antagonist, and under reactive blue, an non-selective P2Y-antagonist, but not under pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid, a P2X-antagonist. The present results provide evidence that ATP has poor, if at all, direct excitatory effects on CGRP-containing trigeminal nerve endings in the isolated dura and its facilitatory action seems to depend on G-protein coupled P2Y receptors and secondary PGE(2) release. The UTP effect and the antagonist profile is indicative for the P2Y(2) receptor subtype.
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PMID:ATP can enhance the proton-induced CGRP release through P2Y receptors and secondary PGE(2) release in isolated rat dura mater. 1204 22

Adrenomedullin (AM) is a potent vasoactive peptide and plays an important role in cardiovascular function. In this study, we delivered the AM gene locally into the heart, using a catheter-based technique to investigate the signaling mechanism mediated by AM in protection against cardiomyocyte apoptosis induced by acute ischemia/reperfusion. After adenovirus-mediated gene delivery, highly efficient and specific expression of luciferase, green fluorescent protein, or recombinant human AM was identified in the left ventricle. Delivery of the AM gene 5 days before ischemia/reperfusion attenuated myocardial apoptosis identified by in situ dUTP nick-end labeling and DNA laddering, and the effect was blocked by the AM antagonist human calcitonin gene-related peptide (CGRP 8 to 37). AM gene transfer increased phosphorylation of Akt and glycogen synthase kinase (GSK-3beta) but reduced GSK-3beta and caspase-3 activities in the heart. The effects of AM on GSK-3beta and caspase-3 activities were blocked by CGRP (8-37) and by adenovirus containing dominant-negative Akt (DN-Akt). Furthermore, in cultured cardiomyocytes, AM also attenuated apoptosis induced by hypoxia/reoxygenation, which was accompanied by increased phospho-GSK-3beta but reduced GSK-3 and caspase-3 activities. GSK-3 and caspase-3 activities were both blocked by Ad.DN-Akt and lithium, whereas only caspase-3 was inhibited by its inhibitor Z-VAD. The effects of AM on anti-apoptosis and promoting cell viability were blocked by DN-Akt but not by constitutively active Akt, lithium, or Z-VAD. These results indicate that AM protects against cardiomyocyte apoptosis induced by ischemia/reperfusion injury through the Akt-GSK-caspase signaling pathway.
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PMID:Adrenomedullin protects against myocardial apoptosis after ischemia/reperfusion through activation of Akt-GSK signaling. 1466 48

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