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

Recent studies suggest that phospholipid-sensitive, Ca2+-dependent protein kinase C participates in contractile responses of vascular smooth muscle. This study characterizes vascular reactivity to protein kinase C activators in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Helical strips of mesenteric arteries were mounted in organ chambers for measurement of isometric contractions (responses were normalized as a percentage of maximal force in response to 100 mM KCl; in SHRSP, 350 +/- 16 mg; in WKY, 335 +/- 21 mg). Arteries from SHRSP contracted faster and developed greater force than arteries from WKY (168 +/- 9% vs 143 +/- 3%) in response to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. Arteries from SHRSP (0.6 X 10(-8) M) were more sensitive to the phorbol ester than those from WKY (2.2 X 10(-8) M), as indicated by the dose of the phorbol ester required to produce 50% of the maximal response to KCl. Additionally, SHRSP arteries were more sensitive to the contractile effects of mezerein, a non-phorbol ester activator of protein kinase C. Ca2+-free solution (1.0 mM EGTA) and verapamil (10(-7) M) caused relaxation (approximately -60%) of contractions in response to the phorbol ester (10(-6) M). Addition of 10(-6) M of the phorbol ester to arteries that were preincubated in Ca2+-free solution (1.0 mM EGTA for 30 minutes) elicited submaximal contractions (in SHRSP, 26 +/- 4%; in WKY, 38 +/- 7%). Upon addition of 1.6 mM Ca2+, arteries from SHRSP contracted faster (t1/2 = 2.7 +/- 0.6 minutes) than those from WKY (8.2 +/- 0.5 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced vascular reactivity to protein kinase C activators in genetically hypertensive rats. 359 82

Aggregation and secretion of washed platelets from stroke-prone spontaneously hypertensive rats (SHRSP) were greatly reduced by the development of the hypertension compared with those of platelets from age-matched normotensive Wistar-Kyoto rats (WKY). Concomitantly, thrombin-induced phosphorylation of the 47 kDa protein in SHRSP platelets was significantly decreased. However, TPA-induced aggregation, secretion and 47 kDa protein phosphorylation in SHRSP platelets were similar to those in WKY platelets. These results suggest that protein kinase C activity and its substrate were normally present in SHRSP platelets and that defects in the receptor-mediated activation of protein kinase C. This defective protein phosphorylation may be an underlying mechanism for the dysfunction of SHRSP platelets.
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PMID:Defects of thrombin-induced protein phosphorylation in platelets from stroke-prone spontaneously hypertensive rats. 394 26

The central nervous system myelin basic protein (MBP) stimulates the release of several peptide hormones including insulin and glucagon. This could be associated with the development of hyperglycaemia in neurological disorders such as stroke, in which MBP is known to leak into blood circulation. In the present study the mechanism of insulin and glucagon release was investigated by using short-term incubation of isolated rat pancreatic islets. Incubation with MBP in the absence of Ca2+ resulted in approx. 11-fold stimulation of insulin and glucagon release. The stimulation dwindled with increasing Ca2+ concentration and was 6.5-fold at 0.5 mM and 2-fold at 2.5 mM Ca2+. When MBP and glucose at various concentrations were simultaneously present in the incubation mixture, stimulation of insulin release was the sum of the stimulation induced by these two agents separately both at the 0.5 and 2.5 mM Ca2+ concentrations. Glucose at concentrations of 10 or 15 mM did not suppress MBP-stimulated glucagon release. Caffeine-evoked increase in intracellular Ca2+ was without effect on MBP-stimulated insulin or glucagon release but enhanced glucose-induced insulin release. The Ca2+ channel blocker diltiazem had no effect on MBP-stimulated insulin release at concentrations where glucose-stimulated release was inhibited. Ruthenium red inhibited both MBP- and glucose-stimulated insulin release as well as MBP-induced glucagon release. Staurosporine (inhibitor of protein kinase C) had no effect on MBP-induced insulin release, although it partially inhibited glucose-stimulated release. Maleylation of MBP abolished its insulin- and glucagon-releasing activity by approx. 90%. These results suggest that MBP exerts its insulin-releasing effect by mechanisms different from those of glucose-stimulated insulin release and does not require Ca2+ channels or protein kinase C. The relation of MBP-induced insulin and glucagon release to Ca2+ concentration is probably explained by enhanced self-aggregation of MBP or by increased ability of MBP to interact with islet cell membranes in the absence of Ca2+, or both. It is concluded that MBP-induced hormone release appears to be mediated by membrane fusion and oligomerization of MBP. The mechanism thus resembles that of various toxins and other cytotoxic agents.
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PMID:Mechanism of the myelin basic protein-induced insulin and glucagon release from isolated rat pancreatic islets. 754 15

Over the past several decades emphasis has been given to the elucidation of mechanisms involved in the onset and progression of cardiovascular disorders. Stroke, hypertension, and atherosclerosis continue to rank as primary causes of death in the western world. In the case of atherosclerosis, the preferential localization of atheroma to large- and medium-sized blood vessels and the sequence of events leading to plaque development have been well defined. Damage to luminal endothelial and/or medial smooth muscle cells, migration of inflammatory cells, diffusion or local delivery of mediators within the vessel wall, proliferation of vascular smooth muscle cells, and cellular accumulation of lipids are now recognized as hallmarks of the pathologic process. Although these events have been established with a fair degree of certainty, the mechanisms responsible for initiation of the atherosclerotic process are not yet completely understood. Environmental chemicals have come under increasing scrutiny as evidence continues to accumulate suggesting that toxic insult plays an important role in the initiation and/or progression of atherosclerotic disorders. This review focuses on various aspects of xenobiotic-induced vascular injury with emphasis on the toxic effects of allylamine and benzo[a]pyrene in smooth muscle cells, the primary cellular component of atherosclerotic lesions. Both of these chemicals modulate growth and differentiation programs in aortic smooth muscle cells and have been implicated in the development of atherosclerotic-like lesions in laboratory animals. The major findings from recent studies examining the cellular and molecular basis of toxicant-induced phenotypic modulation of vascular smooth muscle cells to a proliferative state and the role of oxidative metabolism, phospholipid turnover, protein kinase C, ras-related signal transduction, and matrix interactions in the vasculotoxic response to allylamine and benzo[a]pyrene are discussed.
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PMID:Responses of vascular smooth muscle cells to toxic insult: cellular and molecular perspectives for environmental toxicants. 799 Jan 68

Blood platelets interact with a variety of soluble agonists such as epinephrine and adenosine diphosphate (ADP); many insoluble cell matrix components, including collagen and laminin, and biomaterials used for construction of invasive medical devices. These interactions stimulate specific receptors and glycoprotein-rich domains (integrins and nonintegrin) on the plasma membrane and lead to the activation of intracellular effector enzymes. The majority of regulatory events appear to require free calcium. Ionized calcium is the primary bioregulator, and a variety of biochemical mechanisms modulate the level and availability of free cytosolic calcium. Major enzymes that regulate the free calcium levels via second messengers include phospholipase C, phospholipase A2, and phospholipase D, together with adenylyl and guanylyl cyclases. Activation of phospholipase C results in the hydrolysis of phosphatidyl inositol 4,5-bisphosphate and formation of second messengers 1,2-diacylglycerol and inositol 1,4,5-trisphosphate (IP3). Diglyceride induces activation of protein kinase C, whereas IP3 mobilizes calcium from internal membrane stores. Elevation of cytosolic calcium stimulates phospholipase A2 and liberates arachidonic acid. Free arachidonic acid is transformed to a novel metabolite, thromboxane A2, by fatty acid synthetases. Thromboxane A2 is the major metabolite of this pathway and plays a critical role in platelet recruitment, granule mobilization and secretion. Up-regulation in signalling pathways will increase the risk for clinical complications associated with thromboembolic episodes. Down-regulation of signal transduction mechanisms may precipitate bleeding diathesis or stroke.
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PMID:Physiology of blood platelet activation. 811 2

Intracellular free Ca2+, [Ca2+]i, levels were measured in platelets from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY) using fura-2AM. In the presence of extracellular Ca2+ (1 mM), [Ca2+]i levels in unstimulated platelets of 2- and 9-month-old SHRSP were both significantly higher than those of the age matched WKY. In the absence of extracellular Ca2+, the levels in platelets from 9-month-old SHRSP were also higher than any other groups examined. Receptor-linked Ca2+ influxes of old SHRSP were smaller when thrombin or collagen was given to the platelets. Phorbol 12-myristate 13-acetate (TPA) enhanced more prominently the Ca2+ influx into old SHRSP platelets than into old WKY platelets. These results strongly suggest that the Ca2+ permeability across plasma membrane is increased in young as well as old SHRSP platelets, where the resting [Ca2+]i level is highly sustained because of an impaired Ca2+ uptake mechanism and possible enhancement of protein kinase C activity.
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PMID:Changes in Ca2+ mobilization in platelets from stroke-prone spontaneously hypertensive rats. 813 78

The accumulation of inositol 1,4,5-trisphosphate (IP3) after hormonal stimulation has a physiological role, possibly by alteration of Ca2+ levels in cardiac myocyte. However, this accumulation has not been studied under pathophysiological conditions. In this report, we examine phosphatidylinositol metabolism during cellular response to norepinephrine in pressure-overloaded hypertrophic rat heart. After stimulation with norepinephrine, the accumulations of IP3 and diacylglyceride significantly increased in isolated myocytes from stroke-prone spontaneously hypertensive rat (SHRSP) heart, indicating phosphatidylinositol-specific phospholipase C activity increased in SHRSP heart cells. Protein kinase C activity was also enhanced in SHRSP, with a marked increase in particulate activity. We determined the intracellular calcium concentration and found it to be higher in SHRSP than in Wistar-Kyoto (WKY) rats at 30-40 weeks of age. Ca2+ influx was also elevated in SHRSP stimulated by norepinephrine. In SHRSP heart, cytosolic Ca2+ concentration may rise quickly in response to some stimuli, such as alpha 1-adrenergic stimulation, which is shown to be one of the pathways that increases cytosolic Ca2+ levels in hypertrophied rat heart. These data suggest that a part of the phosphatidylinositol-turnover pathway, such as the phosphatidylinositol 4,5-bisphosphate-IP3-Ca2+ pathway or the diacylglyceride-protein kinase C pathway, may play an important role in the development of hypertrophy in SHRSP heart.
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PMID:Phosphatidylinositol metabolism in hypertrophic rat heart. 847 30

Glutamate is a ubiquitous neurotransmitter which causes excess neuronal excitotoxicity and neurodegenerative insults such as stroke, trauma and seizures. A salient feature of the activation of glutamate receptors is the induction of oxidative burst. Moreover, glutamate stimulates Ca2+ influx and translocates protein kinase C (PKC). PKC mediates cellular processes mediated via phosphorylations which may be essential for oxidative burst in many cells. Subsequent oxidative stress may be a causal factor of neurodegenerative diseases. Increased glutamate release and oxidative burst may thus both be essential in the cascade of events leading to neuronal damage. Glutamate may also mediate neurotoxic effects of environmental toxic agents such as lead which amplify glutamate excitotoxicity. In these interactions, excessive activation of glutamate receptors and oxidative burst may converge into a common pathway leading to cell death through a cascade involving PKC or other protein important in oxidative burst in neurons.
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PMID:Amplification of glutamate-induced oxidative stress. 859 84

Thrombin-induced phosphorylation of 47 kDa protein (P47) in platelets, a substrate of protein kinase C (PKC), was defective in stroke-prone spontaneously hypertensive rats (SHRSP) (Hypertens. 14, 304-315, 1989). Platelet PKC from SHRSP and Wistar Kyoto rats (WKY) was partially purified and Ca(2+)-sensitivity of PKC activity was examined to understand the defect in the protein phosphorylation. When the platelets from SHRSP and WKY were homogenized in a buffer containing 10 mM EGTA and 2 mM EDTA, approx. 80% of PKC was in the cytosol fraction. PKC in this fraction was purified by DE52 and hydroxyapatite column chromatography. Both platelet PKC preparations contained only PKC-alpha, and there was no significant difference in the Ca(2+)-dependency of activity between them. When the platelets from SHRSP and WKY were homogenized in a buffer containing 10 microM CaCl2, 90% of PKC was found to be bound to the membrane. PKC was extracted from the membrane with a buffer containing 2.5 mM EGTA and 2.5 mM EDTA, and purified by DE52 column chromatography. PKC from WKY platelets eluted as a single peak whereas that from SHRSP platelets eluted as two peaks (peak 1 and peak 2). Ca(2+)-sensitivity of peak 1 PKC was much lower than that of WKY PKC. In contrast, the Ca(2+)-sensitivity of peak 2 PKC appeared to be slightly higher than that of WKY PKC. The specific activity of peak 2 PKC was 4% to 5% of that of peak 1 and WKY PKC. These results suggest that there are two different types of PKC, normal and low Ca(2+)-sensitive in SHRSP platelets. Defective P47 phosphorylation in SHRSP platelets might be attributable to the occurrence of this low Ca(2+)-sensitive PKC.
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PMID:The differences in Ca(2+)-sensitivity of protein kinase C in platelets from Wistar Kyoto rat and stroke-prone spontaneously hypertensive rat. 877 2

1. Hypofunction of stroke-prone spontaneously hypertensive rat (SHRSP) platelets at developmental ages of hypertension is due to the defective protein (p47) phosphorylation which is mediated by protein kinase C. This study was undertaken to examine the genetic association of platelet functions and vascular reactivity with hypertension using male WKY, SHRSP, F1 and backcross generations at 16-18 weeks of age. 2. The distribution of blood pressure was continuous in each generation. 3. Contraction of mesenteric vascular bed with norepinephrine was positively correlated with blood pressure in the five generations (r = 0.77, n = 128). 4. Thrombin-induced platelet aggregation was inversely correlated with blood pressure (r = -0.87, n = 127). 5. The distribution of platelet aggregation and contraction was continuous in each generation, and backcross generations were not likely to have 1:1 segregation. 6. These results suggest the possibility that platelet hypoaggregability and peripheral vascular resistance are due to the pleiotropic effect of hypertensive genes, or that genes controlling these three characters are closely linked each other.
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PMID:Correlation analysis of blood pressure and platelet aggregation/vascular reactivity in SHRSP, WKY, F1 and backcross generations. 907 15


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