Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to examine the action of endothelin-1 (ET-1) per se, or the combined effects of ET-1 with vasoconstrictor agonists such as acetylcholine (ACh), histamine (His), and 5-hydroxytryptamine (5-HT), all of which have been implicated in the genesis of coronary spasm. Isometric tension development and the cytosolic Ca2+ concentration [( Ca2+]i) in a ring segment of porcine coronary artery loaded with fura-2 were measured simultaneously with a mechanoelectric transducer and a fluorometer, respectively. ET-1 (30-100 pM) specifically potentiated the 5-HT-induced contraction without causing a significant increase in [Ca2+]i. This effect of the peptide seems to be qualitatively similar to that produced by the tumor-promoting phorbol ester, DPB. These results suggest that the combined stimulation of ET-1 and 5-HT augments the Ca2+ sensitivity of the contractile elements through the possible activation of protein kinase C.
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PMID:Synergistic coronary vasoconstriction produced by endothelin-1 in combination with 5-hydroxytryptamine. 172 25

1. In order to elucidate the physiological and potential pathological roles of endothelin-1 (ET-1) in coronary artery contraction and relaxation, we undertook the present study to examine the action of ET-1 itself, and the combined effects of ET-1 with vasoconstrictor agonists such as acetylcholine (ACh), histamine, and 5-hydroxytryptamine (5-HT), all of which have been implicated in the genesis of coronary spasm. 2. Isometric tension and cytosolic Ca2+ concentration ([Ca2+]i) in a ring segment of porcine coronary artery loaded with fura-2 were measured simultaneously. 3. ET-1 contracted the artery in a concentration-dependent manner; and nisoldipine, a Ca2+ channel blocking drug of the 1,4-dihydropyridine type, antagonized the ET-1 action non-competitively. A radio-receptor binding assay also indicated the mutually exclusive binding of ET-1 and (+)-[3H]-PN200-110, a Ca2+ channel ligand, to the membrane fraction of porcine coronary artery. 4. ET-1 (10-100 pM) increased tension and [Ca2+]i in a parallel manner, while at higher concentrations (1-10 nM) it produced further contraction with a small increase in [Ca2+]i. 5. ET-1 (30-100 pM) selectively potentiated the 5-HT-induced contraction 1.5 to 2 times over the control without causing a significant increase in [Ca2+]i, which seems to be qualitatively similar to a tumour promoting phorbol ester, 12-deoxyphorbol 13-isobutylate (DPB). Bay K 8644 (10 nM), on the other hand, potentiated the contraction in response to practically all agonists used and affected a concomitant increase in [Ca2+]i.6. A Ca2+ channel blocking drug such as diltiazem abolished the increase in [Ca2+]i and partially attenuated the mechanical potentiation produced by a small amount of ET-1 in combination with 5-HT.7. The results suggest that ET-1 and 5-HT interact functionally at the cellular or subcellular level and modulate the Ca2 + sensitivity of the contractile elements through the possible activation of protein kinase C.
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PMID:Potentiation by endothelin-1 of 5-hydroxytryptamine-induced contraction in coronary artery of the pig. 181 Jun 5

In the present study, we investigate the possible role of protein kinase C (PKC)-dependent smooth muscle contraction in cerebral vasospasm following subarachnoid hemorrhage (SAH), employing the beagle "two-hemorrhage" model. The occurrence of chronic vasospasm was angiographically confirmed on day 7 in the basilar artery, which was exposed via the transclival approach. The artery was superfused with aerated Krebs-Henseleit solution containing various agents, and the subsequent changes in the basilar artery diameter were recorded by successive angiography. The preexisting spasm was not ameliorated by local application of neurotransmitter antagonists (atropine, methysergide, phentolamine, and diphenhydramine), calmodulin inhibitors (R24571 and W-7), or a calcium antagonist, nicardipine. However, the application of PKC inhibitors such as H-7 and staurosporine induced significant dilation of the artery. In another experiment, an intrinsic PKC activator, 1,2-diacylglycerol (DAG), in the basilar artery, the CSF, and the cisternal clot of beagles exposed to two hemorrhages was measured on days 1, 2, 4, 7, and 14 using the DAG kinase method. On days 2, 4, and 7, the DAG content of the basilar artery showed a significant and prolonged increase (150-190% of control), whereas it was unchanged on days 1 and 14. Throughout the experimental period, there was a significant linear correlation between the DAG content and the angiographical diameter of the basilar artery. The above results indicate that SAH leads to an increase in the DAG level within the cerebral artery through an as yet unknown mechanism and that subsequent activation of the PKC-dependent contractile system participates in the occurrence of chronic vasospasm.
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PMID:Possible role of protein kinase C-dependent smooth muscle contraction in the pathogenesis of chronic cerebral vasospasm. 198 98

The effect of phorbol myristate acetate (PMA) was compared with that of histamine on the guinea-pig lung parenchymal strip. PMA, 10(-5) M, caused a slowly developing sustained contraction which had approximately the same magnitude as the maximal histamine contraction. Isoprenaline, at 10(-5) M, caused 86% relaxation of the histamine contraction but only 22% relaxation of the PMA contraction. Forskolin, at 10(-5) M had a similar action to isoprenaline on the effects of both spasmogens while aminophylline, 5 X 10(-4) M, was considerably less effective. Sodium nitroprusside had little effect on the histamine contraction and actually increased the PMA spasm. It is suggested that protein kinase C may have a role in the tonic phase of the contraction of bronchiolar smooth muscle. These findings could have relevance for the delayed phase of asthma, which is known to be insensitive to beta-agonists.
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PMID:Phorbol myristate acetate causes in guinea-pig lung parenchymal strip a maintained spasm which is relatively resistant to isoprenaline. 404 98

Papaverine (PPV) is a nonspecific vasodilator with widespread clinical uses in the treatment of arterial spasm. It has also been utilized in an attempt to reverse cerebral vasospasm. Recent angiographic results have demonstrated significant reversal of vasospasm in large vessels after selective intra-arterial application of PPV; however, these impressive results lacked good clinical correlation. In this study, phorbol dibutyrate was used to stimulate protein kinase C in an in vitro model of cerebral microvessels. Papaverine was found to elicit a dose-dependent exacerbation of phorbol dibutyrate-induced microvascular constriction in this model system. Because protein kinase C is thought to play a key role in the development of cerebral vasospasm, PPV-induced vasoconstriction represents a potentially important deleterious effect that may not be apparent on angiography. Such a constrictor response may compromise the beneficial vasodilatory effect seen with intra-arterial injection of PPV.
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PMID:The effects of papaverine on phorbol dibutyrate-induced vasoconstriction in brain slice microvessels. 793 91

The plasma membrane plays an important role in the pathogenesis of acute cell injury. This brief review outlines the role of the plasma membrane in the cellular response to two clostridial toxins, the botulinum C2 toxin and the tetanus toxin. These two toxins belong to the same family of toxins as botulinum toxin type A and type F, those used clinically for the treatment of facial spasm. The actions of C2 toxin on cultured cells give rise to an acute injury characterized by a dissociation of the actin filaments of the cell cytoskeleton. While this toxin can be lethal to intact organisms, the acute cellular response need not necessarily result in cell death. In the case of tetanus toxin, the toxin appears to perturb the plasma membrane so that the function of one important cell second messenger system, protein kinase C, is altered.
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PMID:Cellular responses to acute injury: the role of the plasma membrane in cell response to two clostridial toxins. 816 89

The spasmogenic activity of methylxanthines was evaluated in guinea-pig isolated trachea treated with indomethacin (2.8 microM) and cooled to 20 degrees C. The contraction elicited by caffeine or theophylline (10 mM) was reduced in the presence of ouabain (10 microM), amiloride (100 microM), staurosporine (1 microM), H-7 (50 microM), polymyxin B (500 microM), K(+)-free solution, low Na+ (25 mM) medium or Ca(2+)-free (EGTA 0.1 mM) solution but was unaltered in the presence of verapamil (10 microM) or vanadate (10-100 microM). These results suggest that tracheal spasm to methylxanthines predominantly involves Ca2+ release from intracellular stores with a minor component due to extracellular Ca2+ entry through verapamil-insensitive pathways. A Na+/Ca2+ exchange process and the activation of protein kinase C may be also involved.
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PMID:Pharmacological modulation of the spasmogenic response to methylxanthines in guinea-pig trachea. 843 29

1. Subarachnoid haemorrhage (SAH) is a unique disorder and a major clinical problem that most commonly occurs when an aneurysm in a cerebral artery ruptures, leading to bleeding and clot formation. Subarachnoid haemorrhage results in death or severe disability of 50-70% of victims and is the cause of up to 10% of all strokes. Delayed cerebral vasospasm, which is the most critical clinical complication that occurs after SAH, seems to be associated with both impaired dilator and increased constrictor mechanisms in cerebral arteries. Mechanisms contributing to development of vasospasm and abnormal reactivity of cerebral arteries after SAH have been intensively investigated in recent years. In the present review we focus on recent advances in our knowledge of the roles of nitric oxide (NO) and cGMP, endothelin (ET), protein kinase C (PKC) and potassium channels as they relate to SAH. 2. Nitric oxide is produced by the endothelium and is an important regulator of cerebral vascular tone by tonically maintaining the vasculature in a dilated state. Endothelial injury after SAH may interfere with NO production and lead to vasoconstriction and impaired responses to endothelium-dependent vasodilators. Inactivation of NO by oxyhaemoglobin or superoxide from erythrocytes may also occur in the subarachnoid space after SAH. 3. Nitric oxide stimulates activity of soluble guanylate cyclase in vascular muscle, leading to intracellular generation of cGMP and relaxation. Subarachnoid haemorrhage appears to cause impaired activity of soluble guanylate cyclase, resulting in reduced basal levels of cGMP in cerebral vessels and often decreased responsiveness of cerebral arteries to NO. 4. Endothelin is a potent, long-lasting vasoconstrictor that may contribute to the spasm of cerebral arteries after SAH. Endothelin is present in increased levels in the cerebrospinal fluid of SAH patients. Pharmacological inhibition of ET synthesis or of ET receptors has been reported to attenuate cerebral vasospasm. Production of and vasoconstriction by ET may be due, in part, to the decreased activity of NO and formation of cGMP. 5. Protein kinase C is an important enzyme involved in the contraction of vascular muscle in response to several agonists, including ET. Activity of PKC appears to be increased in cerebral arteries after SAH, indicating that PKC may be critical in the development of cerebral vasospasm. Recent evidence suggests that PKC activation may occur in cerebral arteries after SAH as a result of decreased negative feedback influence of NO/cGMP. 6. Cerebral arteries are depolarized after SAH, possibly due to decreased activity of potassium channels in vascular muscle. Decreased basal activation of potassium channels may be due to several mechanisms, including impaired activity of NO (and/or cGMP) or increased activity of PKC. Vasodilator drugs that produce hyperpolarization, such as potassium channel openers, appear to be unusually effective in cerebral arteries after SAH. 7. Thus, endothelial damage and reduced activity of NO may contribute to cerebral vascular dysfunction after SAH. Potassium channels may represent an important therapeutic target for the treatment of cerebral vasospasm after SAH.
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PMID:Subarachnoid haemorrhage: what happens to the cerebral arteries? 980 57

Coronary artery spasm plays an important role in the pathogenesis of a wide variety of ischemic heart diseases, especially in the Japanese population. Because coronary artery spasm can be induced by a variety of stimuli with different mechanisms of action, the occurrence of the spasm appears to be due to the local hyperreactivity of the coronary artery rather than to an enhanced stimulation with a single mechanism of action. Several lines of evidence indicate that coronary artery spasm is caused primarily by smooth muscle hypercontraction whereas the contribution of endothelial dysfunction may be minimal. In order to elucidate the cellular and molecular mechanisms of the spasm, porcine models of the spasm were developed. In the first model with balloon injury and high-cholesterol feeding, a close topological correlation between the early atherosclerotic lesions and the spastic sites was noted, whereas in the second model with an inflammatory cytokine the potential importance of coronary inflammatory changes, especially at the adventitia, was noted. Subsequent studies in vivo and in vitro demonstrated that protein kinase C (PKC) and Rho-kinase are substantially involved in the intracellular mechanism of the spasm, resulting in increases in the mono- and diphosphorylations of myosin light chain (MLC). Furthermore, molecular biological analyses demonstrated that Rho-kinase is upregulated at the spastic site (at all levels, including mRNA, protein, and activity), resulting in the inhibition of MLC phosphatase through the phosphorylation of its myosin binding subunit and thereby causing the increase in MLC phosphorylations. Preliminary results also suggest that the long-term inhibition of Rho-kinase is effective in inhibiting the development of arteriosclerotic vascular lesions in several porcine models. Thus, Rho-kinase could be regarded as a novel therapeutic target for coronary arteriosclerosis in general and coronary artery spasm in particular.
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PMID:Cellular and molecular mechanisms of coronary artery spasm: lessons from animal models. 1065 Nov 99

This study was designed to test the hypothesis that the sphingomyelin-ceramide signaling pathway may be important in proinflammatory-like responses in the intact brain. Effects of neutral sphingomyelinase (N-SMase), ceramide analogs, phosphorylcholine and ceramide metabolites were studied on rat brain cerebral (cortical) venule lumen sizes, leukocyte rolling, velocity and endothelial cell wall adhesion, microvessel permeability, microvessel rupture and focal hemorrhages using in vivo high resolution TV microscopy. Perivascular and close intra-arterial administration of N-SMase, C(2)-, C(8)-, and C(16)-ceramide, but not either phosphorylcholine, C(6)-ceramide, nervonic (C(24):1) ceramide, lignoceric (C(24):0) ceramide, C(8)-ceramide-1-phosphate, glucosylceramide or 1-0-acylceramide, resulted in potent, concentration-dependent constriction (and spasm) of cortical venules, followed by increased leukocyte rolling, decreased leukocyte velocities, increased leukocyte-endothelial wall adhesion, increased venular wall permeability, postcapillary venule rupture and, often, micro-hemorrhaging at high concentrations; angiotensin II, serotonin and PGF(2alpha) didn't demonstrate these characteristics. Pretreatment with either one of three different antioxidants, including inhibitors of NF-kappaB activation, or two different Ca(2+) channel blockers either prevented or attenuated the adverse venular effects of N-SMase and the ceramides. Likewise, pretreatment with either a PKCalpha-beta antagonist or a MAP kinase antagonist also attenuated the adverse venular effects. These results suggest that N-SMase and several ceramides can result in potent venular cerebrovasospasm, leukocyte-endothelial chemoattraction, and microvessel wall permeability changes in the intact rat brain. These proinflammatory-like actions suggest that N-SMase and ceramides could produce brain-vascular damage by reperfusion injury triggering lipid peroxidation, release of reactive oxygen species and activation of diverse signaling pathways: PKCalpha-beta isozymes, MAP kinase and NF-kappaB.
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PMID:Sphingomyelinase and ceramide analogs induce vasoconstriction and leukocyte-endothelial interactions in cerebral venules in the intact rat brain: Insight into mechanisms and possible relation to brain injury and stroke. 1212 52


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