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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies utilizing crude brain homogenates have shown that forebrain ischemia results in inhibition of calcium/calmodulin-dependent protein kinase II (CaM kinase II) activity without large-scale proteolysis of the enzyme. In this report, a monoclonal antibody (1C3-3D6) directed against the beta- (60-kDa) subunit of CaM kinase II that does not recognize ischemically altered enzyme was utilized to further investigate the ischemia-induced inhibition of CaM kinase II. Immunohistochemical investigations showed that the ischemia-induced decreased immunoreactivity of CaM kinase II occurred immediately following ischemic insult in ischemia-sensitive cells such as pyramidal cells of the hippocampus. No decrease in CaM kinase II immunoreactivity was observed in ischemia-resistant cells such as granule cells of the dentate gyrus. The decreased immunoreactivity was observed for CaM kinase II balanced for protein staining and calmodulin binding in vitro. In addition, autophosphorylation of CaM kinase II in the presence of low (7 microM) or high (500 microM) ATP did not alter immunoreactivity of the enzyme with 1C3-3D6. The data demonstrate the production of a monoclonal antibody that recognizes the beta-subunit of CaM kinase II in a highly specific manner, but does not recognize ischemic enzyme. Together with previous studies, the data support the hypothesis that rapid, ischemia-induced inhibition of CaM kinase II activity may be involved in the cascade of events that lead to selective neuronal cell loss in stroke.
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PMID:Global forebrain ischemia results in decreased immunoreactivity of calcium/calmodulin-dependent protein kinase II. 132 53

We previously suggested that activation of the protein kinase C-mediated contractile system may participate in the occurrence of chronic cerebral vasospasm. In the present study, we compared segments of normal beagle basilar arteries in vitro with segments of arteries undergoing chronic vasospasm to determine the responsiveness to various agonists such as serotonin, prostaglandin F2 alpha, and phorbol 12,13-diacetate as well as to external Ca2+. We also compared the effects of W-7 (a calmodulin inhibitor), nicardipine (a calcium channel blocker), and H-7 (a protein kinase C inhibitor) on the spontaneous tonus of arterial segments stabilized at a resting tension of 3 g. Compared with normal segments, the responsiveness to each agonist in segments undergoing vasospasm was essentially unchanged whereas the the responsiveness to external Ca2+ was significantly decreased (p less than 0.001). In segments undergoing vasospasm the decrease in resting tension induced by W-7 was markedly diminished (p less than 0.01), that induced by nicardipine was unchanged, and that induced by H-7 was significantly increased (p less than 0.01). Our results indicate that spontaneous tonus due to activation of the protein kinase C system is significantly augmented in segments undergoing vasospasm. Thus this system, rather than the Ca2+/calmodulin system, appears to play a major role in the occurrence of chronic vasospasm.
Stroke 1991 Sep
PMID:Activation of the protein kinase C-mediated contractile system in canine basilar artery undergoing chronic vasospasm. 192 62

Many investigations have shown that calcium and adenosine triphosphate are crucial to central nervous system functions. It is probable that alterations of these substances during central nervous system ischemia are involved in the processes that cause irreversible neural damage. Calcium regulates several protein kinases that are responsible for phosphorylation of proteins vital for many central nervous system functions. Using a rabbit spinal cord ischemia model, we found protein kinase C and calcium/calmodulin-dependent kinase were severely affected during the first hour of ischemia. Protein kinase A was not significantly affected. The time course of lost protein kinase C enzyme activity closely corresponded to irreversible loss of neurologic function, and there is evidence that protein kinase C inhibitor activity is generated. Also, drugs that inhibit protein kinase C increased neurologic damage when administered during the early phases of ischemia. These results suggest that protein phosphorylation, particularly by protein kinase C, is critical to maintenance of neurologic function.
Stroke 1990 Nov
PMID:Protein phosphorylation during ischemia. 223 67

We correlated the efficacy of several clinically relevant pharmacotherapies with their ability to prevent calcium influx into neurons and subsequent binding to calmodulin. We studied the administration of CGS 19755, nimodipine, nicardipine, and combinations of these drugs before or immediately after ischemia in globally ischemic rats. Calcium-calmodulin binding was graded by an immunohistochemical assay after 2 and 24 hours of reperfusion (n = 5-6 at each time period), and histologic damage was graded by light microscopy after 72 hours of reperfusion (n = 6). Calcium-calmodulin binding correlated with the severity of delayed histologic damage in various brain regions. In untreated ischemic control rats, marked calcium-calmodulin binding was seen in CA1 and CA3 after 24 hours of reperfusion (p less than or equal to 0.01). Administered before ischemia, CGS 19755 prevented calcium-calmodulin binding across all brain regions after 2 and 24 hours of reperfusion compared with controls (p less than or equal to 0.05). This effect was most prominent in CA3 and CA1, where the drug also reduced delayed neuronal damage (p less than or equal to 0.05). Lower doses or postischemic administration of CGS 19755, nimodipine, nicardipine, and a combination of postischemic CGS 19755 and nicardipine had a more limited effect on calcium-calmodulin binding and did not protect against delayed neuronal damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Stroke 1990 Nov
PMID:Neuronal protection correlates with prevention of calcium-calmodulin binding in rats. 223 82

Calcium channel blockers such as nicardipine improve outcome after global cerebral ischemia and may attenuate ischemic neuronal injury by preventing calcium influx and binding to calmodulin. We followed the temporal and regional sequence of neuronal calcium-calmodulin binding in normal rats (n = 6), untreated ischemic rats (n = 15), and ischemic rats treated with 0.05 mg/kg/hr s.c. nicardipine (n = 13). After 30 minutes of four-vessel occlusion, 40-microns brain sections were incubated in an anti-calmodulin antibody specific for calmodulin not bound to calcium and brain protein. Light-microscopic sections were examined immediately after ischemia and after 2 and 24 hours of reperfusion. Extensive staining of unbound calmodulin was seen in all hippocampal regions and in the cortex in normal rats. In untreated ischemic control rats, staining was lost, indicating calcium-calmodulin binding immediately after ischemia in all regions. However, after 24 hours, staining returned to normal in the cortex and dentate, and minimal staining returned in CA1 and CA3. Nicardipine-treated animals had significantly less calcium-calmodulin binding in CA1 and in the dentate after 2 hours of reperfusion. This study demonstrates that in clinically relevant doses nicardipine has a limited effect on calcium-calmodulin binding in selectively vulnerable regions after severe ischemia.
Stroke 1990 Jun
PMID:Calcium-calmodulin binding in ischemic rat neurons after calcium channel blocker therapy. 234 99

In Quin-2-loaded erythrocytes of two genetically hypertensive rat strains (spontaneously hypertensive rats, SHR, and the Milan hypertensive strain, MHS) intracellular Ca2+ (Ca2+i) concentration and 45Ca influx rate were increased by 25-30 and 15-20% respectively, in comparison with normotensive controls (Wistar-Kyoto rats, WKY, and rats of the Milan normotensive strain, MNS). After 4 h incubation in the presence of 5 mmol/l sodium vanadate (Na3VO4) as an inhibitor of Ca-ATPase, 45Ca content of intact erythrocytes of SHR was twofold higher while erythrocyte count of stroke-prone SHR (SHRSP) was threefold higher than in WKY. This increase was observed in SHR during the pre-hypertensive stage. Under the same conditions, no difference was noted between MHS and MNS rats. The rate of 32P influx, as well as the concentration of exchangeable chloride, was studied. We failed to detect any significant differences in either parameter between hypertensive and normotensive rats, suggesting that altered cell membrane potential was not responsible for allied Ca fluxes. Erythrocyte shrinking, however, resulted in a two to threefold increase in the rate of 45Ca influx. Neither the rate of 45Ca influx nor Ca2+i were modified by the inhibitor of calmodulin-dependent reactions, R24571 (10 mumol/l). It is suggested that the higher rate of Ca2+ influx in Quin-2-loaded erythrocytes of SHR, as well as the increment in 45Ca content in intact erythrocytes treated with orthovanadate, is due to a change in membrane skeleton organization and cell shrinkage.
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PMID:Calcium transport in erythrocytes of rats with spontaneous hypertension. 284 88

Ciliary movement is generated in the axoneme by the unidirectional sliding of the outer doublets of microtubules produced by the adenosine triphosphate (ATP)-energized dynein arms. It is composed of an effective stroke phase and a passive recovery stroke phase. Two parameters are modulated to determine swimming characteristics of the cell (speed and direction): beat frequency; direction of the effective stroke. They are linked to the internal Ca++ level and to the membrane potential. The membrane governs the internal Ca++ level by regulating Ca++ influx and efflux. It contains voltage-sensitive Ca++ channels through which a passive Ca++ influx, driven by the electrochemical gradient, occurs during step depolarization. The rise of the Ca++ level, up to 6.10-7M triggers ciliary reversal and enhances beat frequency. Ca+ is extruded from cilia by active transport. Ca++ also activates a multistep enzymatic process, the first component of which is a membrane calmodulin-dependent guanylate cyclase. cGMP interacts with Ca++ to modulate the parameters of the ciliary beat. The phosphorylation-dephosphorylation cycle of axoneme and membrane proteins seems to play a major role in controlling ciliary movement. Hyperpolarization of the membrane enhances beat frequency by an unknown mechanism. It could be a modification of the ratio of axonemal bound Ca++ and Mg++, or activation by cyclic adenosine monophosphate (cAMP) produced by a membrane adenylate cyclase. The ciliary membrane behaves as a receptor able to detect modifications of external parameters, and as a transductor transmitting the detected signal by a second or third messengers toward the interior of the cilia. These messengers. acting at different levels, modulate the parameters of the mechanism that generates ciliary movement.
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PMID:Membrane control of ciliary movement in ciliates. 284 95

Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with food admixed, 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)-1- piperazinyl]methyl)isoquinoline (Ro 22-4839), a novel cerebral circulation improver, for a period of 15 weeks starting from 5 weeks of age at an average daily dose of 30.6 or 66.0 mg/kg. As compared with normotensive Wistar Kyoto rats, SHRSP in the control group rapidly developed severe hypertension (244 mmHg at the end of the experiments) accompanied with deterioration of cardiovascular parameters including left ventricular hypertrophy, reduction in pumping ability and increase in peripheral vascular tone. At 20 weeks of age (i.e. at the end of experiments), 75% of SHRSP developed stroke signs and concomitant cerebral edema evidenced by the increases in water and sodium contents in the brain. These stroke symptoms were accompanied with a profound externalized shape change of erythrocytes after in vitro treatment with Ca2+ and ionophore A23187, an increased plasma level of thiobarbituric acid reacting substance (TBARS), a measure of lipid peroxides, and a decreased sensitivity of platelets to ADP. The long-term treatment with Ro 22-4839 prevented the progress of stroke and cerebral edema, although the deteriorated cardiovascular parameters were not prevented by the treatment. This compound was also found to prevent the hypersusceptibility of erythrocyte membrane to Ca2+-ionophore and Ca2+, the hypoaggregability of platelets and the elevated plasma TBARS in SHRSP. These results indicate that the beneficial effects of Ro 22-4839 in SHRSP may be attributable to its calmodulin antagonistic and anti-lipid peroxidative actions but not to its hypotensive action.
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PMID:Preventive effects of the cerebral circulation improver 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)- 1-piperazinyl]methyl)isoquinoline on stroke symptoms in stroke-prone spontaneously hypertensive rats. 367 71

Sustained contraction of isolated canine basilar artery was induced by addition of prostaglandin F2 alpha, prostaglandin E2, hemoglobin-containing solution, or serum. Human platelet aggregation was induced by 1.0 microM adenosine diphosphate. The sustained contraction of basilar artery and the aggregation of platelet, particularly its secondary aggregation, were inhibited in a dose-dependent manner by addition of chlorpromazine or amitriptyline; calmodulin antagonist. The molar concentrations at 50% inhibition by chlorpromazine or amitriptyline were 5.9 to 7.7 microM or 28 to 39 microM for the contraction of basilar artery and 57 microM or 111 microM for the secondary aggregation of platelet. The results were discussed mainly on the basis of interaction of psychotropic drugs and Ca2+, calmodulin-dependent enzymes, particularly myosin light chain phosphorylation.
Stroke
PMID:Responses of isolated canine basilar artery and human platelet to chlorpromazine and amitriptyline. 658 79

Adenylate cyclase activity was investigated in either homogenate or particulate fractions from the frontal cerebral cortex of the gerbil following five experimental conditions of bilateral ischemia. After periods of 15 min ischemia, 15 min ischemia plus 15 min of recirculation or 60 min ischemia the enzyme generally displayed enhanced responses to GTP, norepinephrine (NE), dopamine (DA), NE + GTP and DA + GTP. Pretreatment of the gerbils with methylprednisolone, allopurinol or indomethacin did not significantly influence the outcome of these findings. When the animals were subjected to 60 min ischemia plus 15 min of reflow, enzyme responses to the stimulatory agents including forskolin and NaF were all reduced. Pretreatment with methylprednisolone, allopurinol or indomethacin prevented the damage to adenylate cyclase in the 60 min ischemia plus 15 min reflow animals. When animals were made ischemic for 15 min followed by one week of recovery, enzyme sensitivity to GTP, calmodulin-Ca++, NE, combinations thereof and forskolin were reduced in only the particulate fractions. Enzyme damage was reversed following methylprednisolone. Enzyme damage may result from generation of free radicals during reflow and drugs that either inhibit synthesis pathways generating free radicals, stabilize cell membranes or act as free radical scavengers may be therapeutically beneficial under specific conditions of stroke.
Stroke
PMID:Protective action by methylprednisolone, allopurinol and indomethacin against stroke-induced damage to adenylate cyclase in gerbil cerebral cortex. 670 40


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