Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of cyclosporin A on induction of nitric oxide synthase in rat aortic smooth muscle cells was examined. A combination of interleukin-1 alpha (100 U/mL) and tumor necrosis factor--alpha (5000 U/mL) induced accumulation of nitrite/nitrate, the stable end products of nitric oxide, in culture media within 48 hours. Cyclosporin A inhibited this nitrite/nitrate accumulation in a concentration-dependent manner with an IC50 of 4 x 10(-7) mol/L when applied simultaneously with the cytokines. The expression of inducible nitric oxide synthase messenger RNA (mRNA) induced by the combination of interleukin-1 alpha and tumor necrosis factor-alpha was inhibited by the cyclosporin A cotreatment. Cyclosporin A did not decrease inducible nitric oxide synthase mRNA stability in the presence of transcription inhibitor actinomycin D (5 micrograms/mL). Induction of nitrite/nitrate production by the combination of tumor necrosis factor-alpha and bacterial lipopolysaccharide or that of interleukin-1 alpha and interferon gamma (100 U/mL) was also inhibited by cyclosporin A cotreatment. Another inhibitor of calcineurin, FK506 (up to 10(-6) mol/L), had no effect on the induction of nitrite/nitrate production, suggesting the possibility that the inhibitory effect of cyclosporin A may be exerted by means of a novel pathway other than inhibition of calcineurin. These results indicate that cyclosporin A inhibits inducible nitric oxide synthase induction at the mRNA level and that inducible nitric oxide synthase in vascular smooth muscle cells can be a target for cyclosporin A, providing a possible mechanism for the interference of the drug with the balance of vasoactive substances.
Hypertension 1995 Apr
PMID:Cyclosporin A inhibits nitric oxide synthase induction in vascular smooth muscle cells. 753 14

Cyclosporine A (CsA)-induced hypertension appears to be caused in part by neurogenic vasoconstriction, but the mechanism by which CsA activates the sympathetic nervous system is unknown. In T lymphocytes, the cellular target of CsA and the macrolide immunosuppressant FK506 (as complexes with their endogenous cytoplasmic receptors, or immunophilins) is the Ca(2+)-calmodulin-dependent phosphatase calcineurin. The presence of calcineurin and its colocalization with immunophilin in the brain led us to hypothesize that the phosphatase also mediates CsA-induced sympathetic activation. We now report that sympathetic activity and arterial pressure in rats are increased not only by CsA but also by FK506, which is structurally unrelated to CsA but inhibits the same calcineurin-sensitive T-cell signaling pathway. In contrast, sympathetic activity and blood pressure are not increased by rapamycin, which forms an immunophilin complex that does not bind calcineurin. Furthermore, CsA- and FK506-induced sympathetic activation is attenuated for drug analogues possessing modest changes in molecular structure in a way that closely parallels the ability of each analogue to inhibit calcineurin-mediated T-cell signaling. These results implicate an important role for extralymphoid (ie, neuronal) calcineurin in mediating immunosuppressive drug toxicity.
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PMID:Cyclosporine- and FK506-induced sympathetic activation correlates with calcineurin-mediated inhibition of T-cell signaling. 768 70

The catecholamines dopamine and norepinephrine, play a central role in the regulation of sodium homeostasis and blood pressure. Dopamine inhibits tubular Na+, K(+)-ATPase activity and increases sodium excretion. Norepinephrine stimulates Na+, K(+)-ATPase activity and decreases urinary sodium excretion. The signaling pathway by which these two opposite first messengers regulate Na+, K(+)-ATPase activity involves the dopamine-specific protein phosphatase-1 inhibitor, DARPP-32, and the norepinephrine-activated protein phosphatase-2B, calcineurin. Aberrations in the renal dopamine/norepinephrine system may be the cause of alterations in the regulation of sodium excretion during ontogeny and in salt-sensitive hypertension.
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PMID:Molecular mechanisms involved in catecholamine regulation of sodium transport. 838 80

This article reviews the current state of knowledge concerning cyclosporine A-induced hypertension after heart transplantation, its pathophysiology and management. The hypothesis is presented that a common molecular mechanism mediates both the immunosuppressive and the hypertensive actions of cyclosporine. The calcium-calmodulin dependent phosphatase, calcineurin, is the common cellular target mediating the salient immunosuppressive effects of both cyclosporine A and FK506. Calcineurin is even more plentiful in nonlymphoid tissues such as the nervous system, muscle, and kidney. Because these are the main target sites for cyclosporine A-induced toxicity, it has been hypothesized recently that inhibition of calcineurin mediates cyclosporine A-induced toxicity. This hypothesis is supported by increasing experimental evidence, at both the whole animal and cellular levels, indicating that the toxicity profile of cyclosporine A is duplicated by FK506 but not by rapamycin, a structural analog of FK506 which is a potent immunosuppressive agent but has no effect on calcineurin. Recent multicenter trials demonstrate that in the clinical setting the hypertensive and other side effects of cyclosporine A are duplicated by FK506. The clinical toxicity of rapamycin is as yet unknown.
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PMID:Hypertension after cardiac transplantation: pathophysiology and management. 856 50

1. The full therapeutic potential of the main immunosuppressive drug, cyclosporin A (CsA), is limited because of its side effects, namely nephrotoxicity and hypertension. Several lines of evidence suggest that the origin of both side effects could be CsA-induced vasoconstriction. However, the underlying molecular mechanisms are not well understood. 2. Diameter measurements of rat isolated mesenteric arteries showed an increase in noradrenaline- and [Arg]8vasopressin-induced vasoconstriction when arteries were pretreated with CsA. 3. Measurements in cultured vascular smooth muscle cells (VSMC) of either cytosolic calcium concentration or of 45Ca2+ efflux showed that CsA potentiated the calcium influx to several vasoconstrictor hormones: [Arg]8vasopressin, angiotensin II, endothelin-1 and 5-hydroxytryptamine. On the other hand, 45Ca2+ efflux in response to thapsigargin, which depletes calcium from intracellular pools, was not potentiated by CsA. 45Ca2+ uptake was not altered by CsA or by any of the analogues tested. 4. Time-course studies in cultured VSMC showed that maximal CsA-induced Ca2+ potentiation occurred after ca. 20 h and this effect was reversed over approximately the next 20 h. 5. To investigate the possible role played by the known intracellular targets of CsA, namely cyclophilin and calcineurin, CsA derivatives with variable potencies with respect to their immunosuppressive activity, were tested on the calcium influx to [Arg]8vasopressin. Derivatives devoid of immunosuppressive activity (cyclosporin H, PSC-833) potentiated calcium signalling, while the potent immunosuppressant, FK520, a close derivative of FK506, and MeVal4CsA, an antagonist of the immunosuppressive effect of CsA did not. The latter compound was unable to reverse the calcium potentiating effect of CsA. 6. Our results show that CsA increases the calcium influx to vasoconstrictor hormones in smooth muscle cells, which presumably increases vasoconstriction. Loading of the intracellular calcium pools appears not to be involved. Experiments with derivatives of CsA and FK520 suggest that interactions with cyclophilins and calcineurin are not the mechanism involved. This indicates, for the first time, that the immunosuppressive activity can be dissociated from the calcium potentiating effect of CsA in vascular smooth muscle.
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PMID:Effect of cyclosporin A and analogues on cytosolic calcium and vasoconstriction: possible lack of relationship to immunosuppressive activity. 879 58

The immunosuppressant drug cyclosporine A (CsA) has emerged as an important new cause of hypertension in both organ transplant recipients and patients with autoimmune diseases. Despite the clinical importance of this hypertension, the underlying mechanisms have been enigmatic. This article presents a conceptual framework for understanding the pathophysiologic basis of CsA-induced hypertension and focuses on the hypothesis that a common molecular mechanism is involved in mediating the immunosuppressive and the hypertensive effects of CsA. This mechanism involves the binding of CsA to a newly discovered class of cytoplasmic receptors (termed "immunophilins") not only in T lymphocytes but also in the kidney, vascular smooth muscle, and central nervous system, which are the main target tissues mediating CsA-induced hypertension. Binding of CsA to its receptor leads to inhibition of calcineurin, the Ca2+/calmodulin-dependent protein phosphatase. Evidence is reviewed to support the hypothesis that calcineurin inhibition plays a pivotal role in mediating both CsA-induced immunosuppression and hypertension, the latter being produced at least in part by sympathetic neural activation. The elucidation of novel CsA-sensitive cellular signaling pathways has lead to the search for the ideal immunosuppressant drug, one which retains CsA's immunosuppressive efficacy but without its toxicity.
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PMID:Sympathetic neural mechanisms of cyclosporine-induced hypertension. 893 45

The use of the immunosuppressant cyclosporin A (CsA) is frequently associated with hypertension. Drug-induced local vasoconstriction appears to be responsible for this effect. Using fura-2 and 45Ca2+ efflux techniques, we have examined variations in the cytosolic calcium concentration ([Ca2+]c) in rat aortic smooth muscle cells and have shown that increases in [Ca2+]c after [Arg8]vasopressin, serotonin, endothelin-1 or angiotensin II stimulation were potentiated after preincubation of cells with CsA. This effect was independent of cyclophilin or calcineurin inhibition by CsA. Measurements of inositol phosphates (InsPn) after agonist stimulation showed that CsA also potentiated their formation. As for 45Ca2+ efflux this effect was not related to cyclophilin or calcineurin inhibition. Direct stimulation of G proteins with aluminium tetrafluoride induced an increase in InsPn formation and 45Ca2+ efflux. Neither of these responses was potentiated by CsA. These results indicate that CsA acts on a target upstream of G protein activation, possibly at the receptor level, resulting in a potentiation of InsPn formation and subsequent calcium increase.
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PMID:Cyclosporin A potentiates receptor-activated [Ca2+]c increase. 902 87

Ciclosporine-A (CSA) has been in clinical use as an immunosuppressive drug in transplant recipients for over a decade. Unfortunately, CSA also has major side-effects (including nephrotoxic ones). In an attempt to find safer agents, tacrolimus (TAC) has been introduced recently. Despite major differences in the chemical structure, TAC and CSA seem to have many effects in common. This phenomenon can be explained by the inhibition of the calcineurin pathway characteristic for both drugs. The aim of our brief review was to compare personal observations regarding side-effects encountered under CSA or TAC therapy with data reported previously. We found that the profile of side-effects both under CSA and TAC was nearly identical. In particular, morphologic changes associated with toxic drug effects in the kidney were indistinguishable from one another, i.e. tubular lesions, arteriolopathy, HUS-like changes in glomeruli and vessels. The prevalence of defined nephrotoxic lesions was very similar. Some differences were found regarding the prevalence of clinical side effects. Hypertension, hypertrichosis and gingival hyperplasia were less pronounced in the TAC group and an elevated blood glucose level in the CSA group. We conclude that TAC and CSA are closely related immunosuppressive drugs with regard to adverse effects.
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PMID:The side-effects of ciclosporine-A and tacrolimus. 969 31

We report 4 cases of central neurocytoma removed by a transfrontal approach with no recurrence after a mean follow up of 3 years. This uncommon lesion of the supratentorial ventricles (150 cases reported) occurs in young adults, and often induces intracranial hypertension secondary to an obstructive hydrocephalus. The CT scan, MRI and histopathological features are related. This neuronal origin tumor is difficult to distinguish from other intraventricular processes as oligodendroglioma or ependymoma. However, the immunopositivity for the neuronal markers as synaptophysin, calcineurin and microtubul associated protein 2, and the negativity for the glial fibrillary acidic protein, allow the diagnosis of this neuropathological entity. The prognosis is favorable though some cases of recurrence (14 cases) and cerebrospinal dissemination (2 cases) has been reported in the literature.
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PMID:[Central neurocytoma. A report of 4 cases]. 1037 33

Cardiac hypertrophy is an increase in the mass of the heart. It is a major risk factor for the development of myocardial infarction and congestive heart failure, diseases that afflict millions of patients worldwide. Hypertrophy can be caused by intrinsic defects of the proteins of the contractile apparatus of the heart, or by extrinsic stimuli such as hypertension. In this review, we will focus on the cytosolic signal transduction pathways that mediate the hypertrophic response to extrinsic stimuli. Although a large number of signaling molecules have been implicated in the hypertrophic response, we will review data that, we believe, suggest there may be only a few molecules that serve as signaling funnels through which many hypertrophic signals must pass on their way to the nucleus. These include the stress response protein kinases (the stress-activated protein kinases or SAPKs, and, possibly, the p38 kinases) and calcineurin. These molecules have as their primary targets transcription factors, many of which have been implicated in the complex yet stereotypic genetic response to hypertrophic stress. In most cases, it is not possible at present to complete the link from hypertrophic stimulus through a specific signaling molecule and a specific transcription factor to the induction of a specific gene that initiates a particular biologic response. We will attempt to identify some of the most important areas where major questions remain in the hopes of stimulating further research into this major cause of death and disability.
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PMID:Signaling pathways mediating the response to hypertrophic stress in the heart. 1044 Feb 34


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