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)

We performed quantitative autoradiography to determine sequential alterations in the binding of muscarinic cholinergic and adenosine A1 receptors and of an L-type calcium channel blocker in the gerbil hippocampus following repeated brief ischemic insults. [3H]Quinuclidinyl benzilate (QNB). [3H]cyclohexyladenosine (CHA) and [3H]PN200-110 were used to label muscarinic and adenosine A1 receptors and L-type calcium channels, respectively. Changes at 1 h, 6 h, 1 day, 4 days and 1 month after three 2-min ischemic insults were compared with changes after single 2- or 6-min ischemia. Two-minute ischemia, which causes no histopathological neuronal damage, produced no persistent alterations in binding sites. We observed a transient and mild increase in binding activities, especially in [3H]CHA binding, at 1 h of recirculation. Following 6-min ischemia and three 2-min ischemic insults. [3H]QNB and [3H]PN200-110 binding decreased by more than 50% in the CA1 subfield by 1 month, but [3H]CHA binding decreased transiently by 20-30% at 4 days when delayed neuronal death of hippocampal CA1 pyramidal cells took place. Reductions in binding, especially in [3H]QNB binding, following three 2-min ischemic insults were greater and appeared earlier than those after 6-min ischemia. Furthermore, alterations extended to the CA3 subfield and the dentate gyrus following repeated insults. Thus, alterations in receptor binding after repeated ischemic insults were greater than those after equivalent single period of ischemia.
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PMID:Sequential changes in muscarinic acetylcholine, adenosine A1 and calcium antagonist binding sites in the gerbil hippocampus following repeated brief ischemia. 165 79

We performed receptor autoradiography to determine sequential alterations in the binding of muscarinic cholinergic and adenosine A1 receptors and of a voltage dependent L-type calcium channel blocker 1 h-1 month after transient cerebral ischemia in the gerbil brain. [3H]Quinuclidinyl benzilate (QNB), [3H]cyclohexyladenosine (CHA) and [3H]PN200-110 were used to label muscarinic and adenosine A1 receptors and L-type calcium channels, respectively. Transient ischemia was induced for 10 min. [3H]QNB and [3H]CHA binding showed no significant alteration in selectively vulnerable areas at an early stage (1-24 h) of recirculation. However, the dentate molecular layer which was resistant to ischemia revealed a significant decrease in the [3H]CHA binding sites 24 h after ischemia. Thereafter, the [3H]QNB and [3H]CHA binding showed significant reduction in most of selectively vulnerable areas. Marked reduction was especially found in the dorsolateral part of striatum and the hippocampal CA1 sector which was the most vulnerable to ischemia. In contrast, [3H]PN200-110 binding showed a transient elevation in the hippocampal CA1 sector, the dentate molecular layer and the thalamus 1 h of recirculation. However, the striatum and neocortex revealed no alteration in the [3H]PN200-110 binding. Thereafter, the reduction in the [3H]PN200-110 binding was seen only in the dorsolateral part of the striatum and the hippocampal CA1 sector. The results suggest that transient cerebral ischemia can cause the alterations in the binding of muscarinic cholinergic and adenosine A1 receptors and of L-type calcium channel blocker in most of selectively vulnerable areas.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Postischemic alteration of muscarinic acetylcholine, adenosine A1 and calcium antagonist binding sites in selectively vulnerable areas: an autoradiographic study of gerbil brain. 166 8

Propionyl-L-carnitine (PC) protects perfused rat hearts against damage by ischemia-reperfusion. Activation of L-type calcium channel play a role on ischemia-reperfusion damage. Therefore, we studied the effect of PC on some properties of L-type calcium channels in an in vitro preparation from human myocardium sarcolemma (from patients with idiopathic dilated cardiomyopathy). Binding of the L-type calcium channel blockers isradipine [3H]-PN 200-110 (PN) to plasma membrane preparations revealed a single population of binding sites (total number: Bmax = 213 +/- 34 fM/mg protein and affinity: Kd = 152 +/- 19 nM; n = 6). The characteristics of these binding sites were evaluated in the presence and in the absence of Ca2+ and of calcium blockers (D-888, a verapamillike drug, and diltiazem). Incubation in a Ca2(+)-containing buffer increased the affinity of PN binding sites. Binding sites for PN were modulated by organic calcium channel blockers; in competition isotherms at 37 degrees C, D-888 (desmethoxyverapamil) decreased the PN binding, whereas diltiazem increased it. These results strongly suggest that the site labelled by PN is the voltage-operated calcium channel of the human myocardium. The addition of PC (1 mM) to plasma membranes labelled with PN at 37 degrees C decreased the affinity of the binding; this effect was counteracted by the addition of Ca2+ to the medium. This result was consistent with a competition between Ca2+ and PC. The effect of PC incubation at 4 degrees C was the opposite; at this temperature PC increased the affinity of the binding sites and the effect was obscured by Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of propionyl-L-carnitine on L-type calcium channels in human heart sarcolemma. 185 33

To provide evidence to support the calcium hypothesis of cerebral ischemia, we examined the effects of extracellular calcium and calcium antagonists (verapamil, flunarizine, nicardipine) on in vitro 'ischemia' using guinea pig hippocampal slices. As a model of in vivo ischemia we used a state of both glucose and oxygen deprivation. Recovery of dentate antidromic field response and histological changes were used as indices of cell damage. After 10 min of deprivation in standard Krebs-Ringer solution, the field potentials exhibited minimum recovery and dentate neurons were severely damaged. Damaged neurons had pyknotic nuclei and swollen cytoplasms. Drugs were added and the calcium concentration was changed during 30 min of pre-deprivation and during deprivation. In the first experiment we demonstrated that pre-treated calcium antagonists protect the dentate granule cells against glucose and oxygen deprivation. The order of the protective potency was flunarizine greater than verapamil much greater than nicardipine. In the second experiment we also showed that neuronal damage caused by deprivation is dependent on the extracellular concentration of calcium. Our data show that extracellular calcium is partially responsible for 'ischemic' neuronal injury in the hippocampal slice. Both low calcium and voltage-gated calcium channel blockers can preserve an antidromic population spike. Conversely, high calcium in the bath can worsen the damage caused by in vitro 'ischemia' to hippocampal slices.
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PMID:Effects of calcium and calcium antagonists against deprivation of glucose and oxygen in guinea pig hippocampal slices. 207 10

We and others have proposed that cytokine-stimulated nitric oxide (NO) production is responsible for reversible myocardial depression in sepsis, trauma and ischemia. An effect of NO on cardiac sarcolemmal L-type calcium channels has also recently been proposed. The spontaneous beating rate of neonatal cardiac myocytes is regulated by the sarcolemmal L-type calcium channel. Accordingly, we sought to determine if cytokine-stimulated NO production could also regulate beating rates of neonatal cardiac myocytes. Treatment of neonatal rat cardiac myocytes with TNF, IL-1, IL-6, 10(-5)M NMA, or 10(-3)M NMA significantly enhanced spontaneous beating rates compared to untreated myocytes in serum-free media for 48 hours (p < or = .01; n = 12 for each). Only IL-1 treatment resulted in significant nitrite levels vs. control over 48 hours (4.2 +/- 0.7 vs. 0.3 +/- 0.2 nmoles/1.25 x 10(-5) cells, respectively) (n = 12). Nitrite production by IL-1 was inhibited by 10(-3)M NMA but not 10(-5)M NMA (0.3 +/- 0.2 vs. 4.1 +/- 0.6 nmoles; p < .01; n = 12). The addition of 10(-5)M NMA to TNF, IL-1, and IL-6 did not alter the effect of the cytokines on the spontaneous beating rates of the cardiac cells (p < or = .01; n = 12 for each). These results strongly suggest that cytokines and NMA affect cardiac myocyte spontaneous beating rates through mechanisms independent of NO.
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PMID:Chronotropic effects of cytokines and the nitric oxide synthase inhibitor, L-NMMA, on cardiac myocytes. 752 6

In the present study, we investigated the possibility that MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, owes its potent neuroprotective properties to calcium channel blocking ability rather than to its NMDA receptor antagonism. Rat hippocampal slices were exposed to a long hypoxic period (20 min) from which only 13.8% recovered their neuronal function after 30 min of reoxygenation. The recovery rate of neuronal function from 20-min hypoxia was increased to 100% when slices were pretreated with 5 microM MK-801. DL-2-amino-5-phosphonovalerate (APV), a competitive NMDA receptor antagonist, even at relatively high concentration (100 microM), provided only marginal protection against such severe hypoxic insult. The L-type calcium channel blocker diltiazem (DILT) was more effective than APV in protecting hypoxic slices against neuronal damage. Combining suboptimal concentrations of DILT and MK-801 produced a neuroprotective effect with significantly exceeded the calculated additive effect of the two drugs. Such synergism could not be demonstrated between DILT and APV, a combination that produced only the expected additive neuroprotective effect. The observed synergy between the calcium channel blocker (DILT) and MK-801, along with other studies that demonstrated interaction between these two drugs, led us to postulate that MK-801 possesses calcium channel blocking properties through which its neuroprotective effect is exerted. These calcium channels could either be of the L-type or otherwise, channels which are being activated only under stressful conditions, such as hypoxia or ischemia.
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PMID:Synergism between diltiazem and MK-801 but not APV in protecting hippocampal slices against hypoxic damage. 758 30

Calcium-induced calcium release (CICR) from sarcoplasmic reticulum (SR) may contribute to calcium depletion of SR during the infusion of cardioplegic solution, which may protect the intracellular calcium overload observed during myocardial reperfusion. We have, therefore, investigated (1) the ability of ryanodine-containing cardioplegic solution to enhance myocardial protection and (2) the influence of diltiazem, L-type calcium channel blocker, on the ryanodine-enhanced cardioprotective effect in the isolated working rat heart. Hearts (n = 6-8/group) from male Wistar rats were aerobically (37 degrees C) perfused (20 min) with bicarbonate buffer (Ca2+ = 2.4 mM). This was followed by a 3 min infusion of St. Thomas' Hospital cardioplegic solution containing (1) 0 nmol/L of ryanodine or (2) 1.75 nmol/L of ryanodine combined with various concentrations of diltiazem (0, 0.13, 0.25 and 0.50 mumol/L). Hearts were then subjected to 40 min of normothermic (37 degrees C) global ischemia and 35 min of reperfusion (15 min Langendorff, 20 min working). (1) The recovery of aortic flow (%AF) was 52.2 +/- 3.5% in the ryanodine-free group. (2) %AF was 72.0 +/- 1.4%, 50.0 +/- 2.6*, 61.7 +/- 3.2* and 58.3 +/- 2.8*% in the 0, 0.13, 0.25 and 0.50 mumol/L diltiazem groups, respectively (*p < 0.05 vs the 0 mumol/L diltiazem group). Creatine kinase (CK) leakage during Langendorff reperfusion was less in the 0 mumol/L diltizaem (plus 1.75 nmol/L ryanodine) group than the ryanodine-free group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Diltiazem abolishes the effect of ryanodine in St. Thomas' Hospital cardioplegic solution on the post-ischemic functional recovery]. 788 56

We have examined the significance of the serotonergic system in the pathophysiology of ischemic brain damage. Permanent occlusion of the middle cerebral artery (MCA) was performed in male NMRI mice. After 48 h, the animals received a transcardiac injection of carbon black. The area of ischemia was restricted to the neocortex and its size was determined planimetrically by means of an image analyzing system. In control experiments, the NMDA antagonist dizocilpine (MK-801), the AMPA/kainate antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline) and the L-type calcium channel blocker nimodipine all produced a significant reduction in ischemic injury of the mouse neocortex. Interestingly, all of the 5-HT1A agonists tested (ipsapirone, CM 57493 [4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-tetrahydropyridine ] and urapidil) were equally efficacious in reducing ischemic injury. On the other hand, the 5-HT2 antagonist naftidrofuryl failed to protect the brain tissue significantly against ischemic brain damage. Roxindole, a 5-HT1A agonist and 5-HT uptake inhibitor, was the most potent serotonergic compound tested. In order to examine the effects of 5-HT1A receptor activation in a different context, 10 min of forebrain ischemia was induced in male Wistar rats by a bilateral occlusion of the common carotid arteries combined with systemic hypotension. Administration of the 5-HT1A agonist CM 57493 reduced the neuronal damage within the ventral hippocampus and the entorhinal cortex as assessed histologically 7 days after ischemia. Finally, we found that 5-HT1A agonists are capable of reducing neuronal damage of cultured neocortical and hippocampal neurons subjected to a chemical hypoxia or glutamate in a dose dependent manner. These data suggest that 5-HT, released during ischemia, may have protective effects in the pathophysiology of ischemic brain damage through a direct action on neurons mediated via the inhibitory 5-HT1A receptor subtype. The results obtained from different in vivo and in vitro models indicate that 5-HT1A agonists are promising agents for the treatment of ischemic brain disorders.
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PMID:Effects of serotonergic drugs in experimental brain ischemia: evidence for a protective role of serotonin in cerebral ischemia. 811 77

The L-type calcium channel antagonist, isradipine, reduces brain ischemia in animal models of ischemic stroke. These effects of isradipine appear more pronounced in dopamine (DA) rich brain regions. These same DA-rich brain regions have also been shown to be the areas most affected by cocaine-induced ischemic changes. Using a novel quantified approach to single photon emission computerized tomography, we demonstrated that isradipine pre-treatment prevented cocaine-induced ischemic changes, especially in these DA-rich brain regions. This is the first demonstration that any medication, including isradipine, can prevent the ischemic effects of cocaine on brain blood flow. Isradipine may, therefore, be a useful therapeutic agent for the prevention of brain ischemia in cocaine addicts.
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PMID:Isradipine prevents global and regional cocaine-induced changes in brain blood flow: a preliminary study. 960 May 78

Mibefradil is a novel calcium channel blocker with activity at both L-type and T-type calcium channels. There are data suggesting that this compound can protect the ischemic/reperfused myocardium in spite of the fact that there is a very low abundance of T-type calcium channels within ventricular tissue. The aims of this study were two-fold. First, we wished to study the protective effect of mibefradil on ischemia/reperfusion injury in the isolated rat heart using infarct size as the endpoint of injury. In this respect, we compared mibefradil with amlodipine, a well-known and potent L-type calcium channel blocker, and with ischemic preconditioning, an intervention known to reduce infarct size consistently. Secondly, we investigated the possible mechanisms through which protection was achieved. For this second purpose, we examined the effects on protection of glibenclamide (an ATP-dependent K+ channel blocker) and chelerythrine (a protein kinase C inhibitor). Isolated rat hearts were perfused in the Langendorff mode at constant pressure. Control, mibefradil-treated (0.3 microM), mibefradil plus glibenclamide (50 microM), and mibefradil plus chelerythrine (10 microM) treated hearts underwent 35 minutes regional ischemia followed by 120 minutes reperfusion. At the end of the experiments, infarct size was determined with triphenyltetrazolium chloride and was expressed as a percentage of the ischemic risk zone (I/R%). A significant reduction in infarct size with mibefradil treatment was observed (I/R 11.1 +/- 2.1% vs. 35.5 +/- 3.1% in controls). This was comparable with the infarct reduction seen with two 5-minute cycles of ischemic preconditioning (17.7 +/- 2.5%). Amlodipine 0.1 microM, a concentration that caused equivalent coronary vasodilatation as that produced by mibefradil treatment, had no significant effect on infarct size (I/R 29.7 +/- 3.5%). The protective effect of mibefradil was not significantly modified by the presence of the PKC inhibitor chelerythrine 10 microM (I/R 19.1 +/- 4.9%) but was abolished when glibenclamide 50 microM was coadministered with mibefradil prior to ischemia (I/R 28.1 +/- 4.7%). Neither chlelerythrine nor glibenclamide alone had any influence on infarct size. We conclude from these data that mibefradil, unlike amlodipine, markedly reduces infarct size in the rat isolated heart. This protection is sensitive to inhibition by glibenclamide, suggesting that KATP channel opening may be an important additional and novel mechanism of mibefradil's action.
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PMID:Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism. 1037 26


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