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)

Immunosuppressant-induced nephrotoxicity, in particular chronic progressive tubulointerstitial fibrosis/arteriopathy induced by the calcineurin inhibitors cyclosporin and tacrolimus, has become the 'Achilles heel' of immunosuppressive agents. The use of calcineurin inhibitors as primary immunosuppressants in hepatic and cardiac transplantation has led to end-stage renal disease and dialysis. Calcineurin inhibitor-induced acute renal failure may occur as early as a few weeks or months after initiation of cyclosporin therapy. The clinical manifestations of acute renal dysfunction are caused by vasoconstriction of renal arterioles, and include reduction in glomerular filtration rate, hypertension, hyperkalaemia, tubular acidosis, increased reabsorption of sodium and oliguria. The acute adverse effects of calcineurin inhibitors on renal haemodynamics are thought to be directly related to the cyclosporin or tacrolimus dosage and blood concentration. However, new clinical data indicate that calcineurin inhibitor-induced chronic nephropathy can occur independently of acute renal dysfunction, cyclosporin dosage or blood concentration. Several strategies have been evaluated to attenuate cyclosporin-induced nephropathy, but their efficacy remains unknown. Cytokine release syndrome associated with the use of muronomab-CD3 (OKT-3) can also contribute to the pathogenesis of transient acute tubular necrosis and renal dysfunction following renal transplantation. Continued research and clinical experience should provide information regarding the aetiology of cyclosporin-induced chronic progressive tubulointerstitial fibrosis/arteriopathy and its potential treatment.
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PMID:Immunosuppressant-induced nephropathy: pathophysiology, incidence and management. 1061 71

Cyclosporine and tacrolimus are potent inhibitors of the calcineurin-dependent cytokine synthesis in activated lymphocytes. In renal transplant patients tacrolimus is more powerful in preventing severe and refractory rejections, even when compared with the new cyclosporine microemulsion formulation. Both drugs are equally nephrotoxic, but tacrolimus induces less hypertension and less pronounced hyperlipidaemia. Especially in some categories of patients, a higher incidence of de-novo diabetes mellitus is seen with tacrolimus therapy.
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PMID:Which calcineurin inhibitor is preferred in renal transplantation: tacrolimus or cyclosporine? 1063 Aug 11

We have shown that interleukin-1beta (IL-1beta) activates the human brain natriuretic peptide (hBNP) promoter via a transcriptional mechanism. Others have reported that changes in intracellular calcium (Ca(2+)) mediate the action of IL-1beta. We questioned whether Ca(2+) and Ca(2+)-dependent pathways mediate IL-1beta regulation of the hBNP promoter in cardiac myocytes. The hBNP promoter (-1818 to +100) coupled to a luciferase cDNA reporter gene was transferred into neonatal cardiac myocytes. Cells were then treated with agents that modify Ca(2+) levels or inhibit Ca(2+)-dependent kinases, and luciferase activity was measured as an index of hBNP promoter activity. The Ca(2+) ionophore A23187 increased hBNP promoter activity; however, neither EGTA nor nifedipine reduced IL-1beta-stimulated promoter activity. Long-term treatment with thapsigargin, which depletes intracellular Ca(2+) stores, decreased basal promoter activity and blocked the effect of IL-1beta. Inhibition of protein kinase C completely blocked IL-1beta-stimulated hBNP promoter activity, whereas inhibition of Ca(2+)/calmodulin-dependent kinase II decreased promoter activity by 40%. In contrast, inhibition of the Ca(2+)-regulated phosphatase calcineurin by cyclosporin A had no effect. These data suggest that (1) Ca(2+) activates the hBNP promoter; (2) release of Ca(2+) from intracellular stores is important to IL-1beta regulation of the hBNP promoter, but transport via voltage-sensitive Ca(2+) channels is not; (3) protein kinase C and Ca(2+)/calmodulin-dependent kinase II mediate the action of IL-1beta; and (4) the phosphatase calcineurin is not involved in IL-1beta regulation of the hBNP promoter. Thus, Ca(2+) and Ca(2+)-dependent pathways are critical to IL-1beta regulation of the hBNP promoter.
Hypertension 2000 Jan
PMID:Interleukin-1beta regulates the human brain natriuretic peptide promoter via Ca(2+)-dependent protein kinase pathways. 1064 13

Calcineurin inhibitors are a mainstay of transplant immunosuppression and commonly induce hypertension. They are highly lipid soluble and penetrate vascular smooth muscle cell membranes readily. Changes in vascular tone are universally observed during administration of these agents, particularly within the kidney, leading to diminished glomerular filtration and enhanced sodium retention. Disturbances of endothelial function are prevalent in many tissues, including stimulation of endothelin and impaired nitric oxide synthesis. Multiple additional pathways produce increased vasoconstriction, leading to an increase in arterial pressure. Clinical manifestations include disturbances in circadian blood pressure patterns, left ventricular hypertrophy, and acceleration of atherosclerotic and renal injury. Rapid increases in pressure occasionally produce accelerated hypertension and microangiopathic tissue damage. Principles of therapy require recognition of hazards of changing arterial pressures during calcineurin use and preferential use of vasodilating drugs, particularly dihydropyridine calcium channel blocking agents. Attention must be paid to interactions between antihypertensive agents and calcineurin inhibitor blood levels.
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PMID:Posttransplantation hypertension related to calcineurin inhibitors. 1098 50

Inhibition of calcineurin-mediated signaling in T lymphocytes is a major mechanism of cyclosporine A (CsA)-induced immunosuppression, and previous rat studies have suggested that inhibition of calcineurin-mediated signaling in central neuronal pools involved in blood pressure regulation plays an important role in causing acute CsA-induced hypertension. However, a central neural mechanism is difficult to reconcile with other data suggesting that CsA-induced hypertension is due to activation of renal and other subdiaphragmtic visceral afferents that reflexively increase efferent sympathetic nerve activity. Accordingly, we now have revised our hypothesis to suggest that CsA stimulates renal afferents by a calcineurin-dependent process. To test this new hypothesis, in anesthetized rats we recorded arterial pressure and multifiber afferent renal nerve activity from the cut distal end of the renal nerve before, during, and after intravenous infusion of either CsA (5 mg/kg over 20 min, n = 8), FK506 (0.15 mg/kg, n = 7), another potent calcineurin inhibitor that is structurally unrelated to CsA, or rapamycin (0.15 mg/kg, n = 4), a structural analog of FK506 that has no effect on calcineurin. We found that renal afferent discharge was increased markedly by intravenous FK506, as well as CsA, but unaffected by rapamycin (or vehicle), indicating calcineurin mediation. After infusion of either calcineurin inhibitor, afferent renal nerve activity remained elevated for up to 2 h, paralleling the prolonged increase in blood pressure. Thus, the major new conclusion of this study is that, in contrast to what has been assumed previously, calcineurin inhibitors enhance sympathetic neurotransmission by a novel action localized to visceral sensory nerve endings rather than to nerve cell bodies or central synapses. In the rat, calcineurin-dependent activation of renal afferents appears to be the primary mechanism producing the large blood-pressure-raising effect of CsA. Because the data suggest that the major side-effect of CsA and FK506--hypertension--is inexorably linked to calcineurin inhibition in extralymphoid tissue, development of agents that selectively inhibit calcineurin only in T lymphocytes could eliminate this important secondary form of hypertension.
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PMID:Calcineurin inhibitors cause renal afferent activation in rats: a novel mechanism of cyclosporine-induced hypertension. 1098 50

Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca(2+)/calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.
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PMID:Calcineurin blockade prevents cardiac mitogen-activated protein kinase activation and hypertrophy in renovascular hypertension. 1101 40

Despite recent advances in the prolongation of patient and graft survival, transplant patients continue to die prematurely of accelerated cardiovascular disease. Arterial hypertension is a well-known risk factor for cardiovascular disease morbidity and mortality in the general population and a frequent complication following transplantation. The pathogenesis of posttransplant hypertension in renal transplant recipients is multifactorial and includes pretransplant hypertension in the recipient, donor hypertension, uncontrolled renin secretion from the remaining native kidney, hypertension as a consequence of graft dysfunction, recurrent or de novo renal disease, and, nowadays more rarely, transplant artery stenosis. The strong impact of an immunosuppressive regimen consisting of calcineurin inhibitors and steroids must also be considered. Calcineurin inhibitors and corticosteroids induce hypertension in renal, cardiac, liver, bone marrow, and lung transplant recipients. Posttransplant hypertension appears to be a major risk factor for graft and patient survival. Recent controlled studies support the opinion that posttransplant hypertension must be treated as strictly as in a population with essential hypertension, diabetes mellitus, or chronic renal failure.
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PMID:Management strategies for posttransplant hypertension. 1115 34

1. The major side effects of the immunosuppressive drug cyclosporin A (CsA) are hypertension and nephrotoxicity. It is likely that both are caused by local vasoconstriction. 2. We have shown previously that 20 h treatment of rat vascular smooth muscle cells (VSMC) with therapeutically relevant CsA concentrations increased the cellular response to [Arg8]vasopressin (AVP) by increasing about 2 fold the number of vasopressin receptors. 3. Displacement experiments using a specific antagonist of the vasopressin V1A receptor (V1AR) showed that the vasopressin binding sites present in VSMC were exclusively receptors of the V1A subtype. 4. Receptor internalization studies revealed that CsA (10(-6) M) did not significantly alter AVP receptor trafficking. 5. V1AR mRNA was increased by CsA, as measured by quantitative polymerase chain reaction. Time-course studies indicated that the increase in mRNA preceded cell surface expression of the receptor, as measured by hormone binding. 6. A direct effect of CsA on the V1AR promoter was investigated using VSMC transfected with a V1AR promoter-luciferase reporter construct. Surprisingly, CsA did not increase, but rather slightly reduced V1AR promoter activity. This effect was independent of the cyclophilin-calcineurin pathway. 7. Measurement of V1AR mRNA decay in the presence of the transcription inhibitor actinomycin D revealed that CsA increased the half-life of V1AR mRNA about 2 fold. 8. In conclusion, CsA increased the response of VSMC to AVP by upregulating V1AR expression through stabilization of its mRNA. This could be a key mechanism in enhanced vascular responsiveness induced by CsA, causing both hypertension and, via renal vasoconstriction, reduced glomerular filtration.
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PMID:Upregulation of vasopressin V1A receptor mRNA and protein in vascular smooth muscle cells following cyclosporin A treatment. 1118 32

Cyclosporin and tacrolimus have improved survival figures in organ transplantation. However, both drugs are potentially nephrotoxic. The immunosuppressive and nephrotoxic effects of both drugs appear to depend on the inhibition of calcineurin. Cyclosporin and tacrolimus cause acute (functional changes) and chronic nephrotoxicity (structural lesions in the kidney). These last important lesions include arteriolar hyalinosis, stripped interstitial fibrosis and tubular atrophy. It is possible that repeated episodes of renal ischaemia contribute to the development of chronic nephrotoxicity and then chronic allograft nephropathy. Cyclosporin and tacrolimus also induce arterial hypertension. Therefore, the beneficial effects of immunosuppression have been limited due to nephrotoxicity and arterial hypertension. Rapamycin, a novel immunosuppressive agent, that does not inhibit calcineurin, provides immunosuppression without nephrotoxicity. In fact, in the trials performed in Europe, sirolimus-treated immunosuppression patients exhibited a much better renal function than cyclosporin-treated patients. However, sirolimus can potentiate the nephrotoxic effect of cyclosporin. Therefore, when cyclosporin and sirolimus are used in combination, a reduction of the cyclosporin dose is desirable.
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PMID:Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation. 1136 39

During the last two decades, owing to advances in immunosuppressive pharmacotherapy, liver transplantation has been increasingly accepted by the medical community as an effective treatment for patients with end-stage liver disease. Successful transplantation of the liver, however, requires frequent monitoring. Most of the serious infectious complications and allograft dysfunction occur during the early post-transplantation period (i.e., first six months). Blood levels of cyclosporine or tacrolimus, the two major calcineurin inhibitors currently in use, need to be frequently checked. Drug dosage is adjusted in order to maintain target serum concentrations and the patients free of side-effects. In the time, the risk of acute allograft rejection decreases considerably, whereas the proportion of patients with fibrosis or cirrhosis increases, particularly among hepatitis C virus carriers. Graft loss may occur, secondary to recurrent disease or chronic rejection. Patients with well-functioning grafts may still be affected by significant comorbidities, such as hypertension, diabetes, obesity, hyperlipidemia and osteoporosis, which appear to be related to long-term immunosuppression. The incidence of lymphoma, skin and colorectal cancers in liver transplantation recipients exceeds those found in the general population and requires early detection. The principles of the management of medical problems after liver transplantation are a careful clinical assessment of the patient and a judicious use of laboratory tests, radiological evaluation and liver biopsy.
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PMID:[Periodic clinical monitoring after liver transplantation]. 1141 96


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