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

The role of Ca2(+)-calmodulin-dependent protein kinase II (CaM kinase II) in the central nervous system has been studied with special reference to the effect of CaM kinase II inhibitor on gamma-aminobutyric acid (GABA) release. We have used two different selective inhibitors of Ca2(+)-calmodulin-dependent enzymes such as a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), and a newly synthesized selective inhibitor of CaM kinase II, 1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpipe raz ine (KN-62). N-[1-[P-(5-Isoquinolinesulfonyl)benzyl]-2-(4- phenylpiperazinyl)ethyl]-5-isoquinolinesulfonamide (KN-04), a derivative of KN-62, which has a much lower inhibitory activity on the enzyme, was also synthesized for use as a control. Although i.v. injection of the drugs did not produce any effect, infusion of W-7 or KN-62 into the 4th ventricle produce any effect, infusion of W-7 or KN-62 into the 4th ventricle of the rat caused hypertension and tachycardia, associated with the diminished rate of GABA release in cerebrospinal fluid. The ability of KN-62 to produce these effects was more potent than that of W-7. Intracisternal infusion of KN-04 influenced neither systemic blood pressure nor GABA release at the concentration up to 100 microM. The same order of potencies of three agents (KN-62 greater than W-7 much greater than KN-04) has been obtained in their effects on either in vitro CaM kinase II activity, the in vivo autonomic nervous system or the rate of GABA release.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effect of a new Ca2(+)-calmodulin-dependent protein kinase II inhibitor on GABA release in cerebrospinal fluid of the rat. 238 87

An established intermediate phenotype of human hypertension and diabetic nephropathy is an elevation of Na+/H+ exchanger (NHE) activity, but the mechanism for this is unclear. This phenotype is maintained in vascular myocytes from the spontaneously hypertensive rat (SHR) compared with the normotensive Wistar Kyoto rat (WKY). Since intracellular calcium levels ([Ca2+]i) following agonist stimulation were elevated in cells from both hypertensive humans and SHR, we have examined the role of calcium-calmodulin (CaM) in the mechanism of increased NHE activity in vascular myocytes of SHR by determining the activity and phosphorylation state of NHE isoform-1 (NHE-1) in cells from SHR and WKY when [Ca2+]i was elevated by the ionophores A23187 or ionomycin. NHE activity was measured using fluorometry and NHE-1 phosphorylation by immunoprecipitating the exchanger from 32P-orthophosphate-labeled cells with a polyclonal NHE-1-specific antibody. The ionophore A23187 increased [Ca2+]i in both cell types to approximately 700 to 800 nmol x L(-1), and led to stimulation of NHE-1 activity only in WKY myocytes, with no effect on SHR cells. An inhibitor of CaM kinase II (KN-62) failed to abolish stimulation of NHE-1 by A23187 in WKY cells, and had no effect on unstimulated NHE-1 activity in both cell types. Ionomycin also elevated [Ca2+]i in both cell types to approximately 1,000 nmol x L(-1) and activated NHE-1 activity in only WKY cells. Activation of NHE-1 in WKY cells by an increased [Ca2+]i was not mediated by an increase in NHE-1 phosphorylation, whether in the presence or absence of KN-62. The elevated NHE-1 phosphorylation in SHR cells was not affected by elevated [Ca2+]i or KN-62. Calmodulin-agarose beads bound NHE-1 extracted from SHR cells to a lesser extent than that from WKY cells. We conclude that calcium-induced NHE-1 activation in WKY cells was not mediated by CaM kinase II. The elevated NHE-1 activity and phosphorylation of SHR cells was not further modulated by increased [Ca2+]i, and was also independent of CaM kinase II. Non-phosphorylation-dependent mechanisms of activation of NHE-1 may therefore be responsible for alterations of NHE-1 activity in these cells, such as the direct binding of CaM to NHE-1. This direct binding of CaM to NHE-1 may be impaired in SHR compared with WKY cells.
 ...
PMID:Calcium-induced activation of the rat vascular myocyte Na+/H+ exchanger isoform-1. 905 65

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

Myocardial hypertrophy is characterized by abnormal intracellular Ca2+ handling and decreased contractile performance. Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylates numerous Ca2+ handling proteins and thus can regulate intracellular Ca2+ homeostasis directly. We therefore investigated whether differential expression of CaMKII isoforms occurs with cardiac hypertrophy which might promote an abnormal intracellular Ca2+ homeostasis. We further investigated the potential influence of angiotensin (Ang) II on CaMKII expression levels. Hearts from adult Spontaneously Hypertensive Rats (SHR) and hearts from two transgenic rat models with Ang II-dependent hypertension were studied. The expression of the cardiac CaMKII isoforms delta2, delta3, delta4 and delta9 was determined by RT-PCR and immunoblot methods. Rats transgenic for the mouse Ren-2 gene (mrTGR), SHR and controls were studied at the age of 6 months and rats transgenic for the human renin-angiotensin system (hrTGR) from postnatal day 1 to week 8. SHR and mrTGR had an increased heart/body weight ratio (26 and 25%) compared with controls (p < 0.05). SHR hearts showed significantly increased mRNA levels of delta4 and delta9 (p < 0.05) with no change for delta2 and delta3. mrTGR hearts had a significantly increased delta4 and a significantly decreased delta3 transcript level (p < 0.05) with no change for delta2 and delta9. hrTGR hearts developed severe hypertrophy (42%) after postnatal day 14. The neonatal delta2, delta3 and delta4 isoform expression levels were higher (30-100%) compared with SD controls. The levels decreased with increasing age and equalized to controls at week 8, except for delta4 which started to increase after week 4 (p < 0.05). CaMKIIdelta protein levels of all cardiac hypertrophy models were increased in sarcoplasmic reticulum preparations (50-120%) compared with controls (p < 0.05) while the cytosolic levels remained unchanged. Thus, CaMKIIdelta isoforms are differentially expressed in cardiac hypertrophy. The fetal delta4 isoform was constantly expressed. CaMKIIdelta adopts the fetal phenotype independent of the type of hypertrophic stimulus. The observed alterations of CaMKIIdelta isoform patterns may affect intracellular Ca2+ homeostasis and thus contribute to the abnormal contractile phenotype of cardiac hypertrophy.
 ...
PMID:Expression of Ca2+/calmodulin-dependent protein kinase II delta-subunit isoforms in rats with hypertensive cardiac hypertrophy. 1145 85

Angiotensin II (Ang II) plays an important role in the central control of blood pressure and baroreflexes. These effects are initiated by stimulation of Ang II type 1 (AT(1)) receptors on neurons within the hypothalamus and brain stem, and involve increasing the activity of noradrenergic, substance P, and glutamatergic pathways. The goal of this study is to investigate the intracellular signaling molecules, which are involved in mediating the Ang II-induced increases in neuronal activity. Using neurons in primary culture from newborn rat hypothalamus and brain stem, we have previously determined that Ang II elicits an AT(1) receptor-mediated inhibition of delayed rectifier K(+) current, a stimulation of Ca(2+) current, and a consequent increase in firing rate. In the present study we have demonstrated that this chronotropic action of Ang II in neuronal cultures involves activation of Ca(2+)-dependent signaling molecules. The Ang II-induced increase in firing rate was abolished by inhibition of phospholipase C with U73122 (10 micromol/L), and was attenuated by the protein kinase C inhibitor calphostin C (10 micromol/L) or by the calcium/calmodulin-dependent kinase II (CaMKII) inhibitor KN-93 (10 micromol/L). A combination of calphostin C and KN-93 completely inhibited this Ang II action. These results indicate that the AT(1) receptor-mediated increase in neuronal firing rate involves activation of both PKC and CaMKII, and suggest that these enzymes are potential targets for manipulating the central actions of Ang II.
Hypertension 2002 Feb
PMID:Chronotropic action of angiotensin II in neurons via protein kinase C and CaMKII. 1188 8

We have reported that norepinephrine (NE) and angiotensin II (Ang II) increase CaM kinase II activity, which, in turn, activates cytosolic phospholipase A(2) (PLA(2)) and releases arachidonic acid. The products of arachidonic acid generated via cytochrome P-450 and lipoxygenase contribute to the development of hypertension and vascular smooth muscle cell (VSMC) hyperplasia. The purpose of this study was to investigate whether CaM kinase II contributes to VSMC proliferation elicited by NE and Ang II and to hypertension induced by Ang II. NE (1 micromol/L) and Ang II (1 micromol/L) increased proliferation of rabbit aortic VSMC as measured by increased [(3)H]-thymidine incorporation; this effect of NE and Ang II was attenuated 88 +/- 10% and 64 +/- 11% by the CaM kinase II inhibitor KN-93, respectively. Infusion of Ang II with miniosmotic pumps (350 ng/min for 6 days) in rats elevated mean arterial pressure (MABP), which was reduced by simultaneous infusion of KN-93 (578 ng/min, for 6 days) (Ang II alone: MABP =174 +/- 3 mm Hg, n=12 versus Ang II + KN-93: MABP 123 +/- 5 mm Hg, n=4, P<0.05). Administration of KN-93 as a single bolus injection (16 mg/Kg), but not its vehicle, in Ang II--infused hypertensive animals also decreased MABP from 179 +/- 9 mm Hg to 109 +/- 6 mm Hg (n=5, P<0.05). CaM kinase II activity was increased in the kidney of Ang II--infused hypertensive animals compared with normotensive controls. Treatment with KN-93 reduced CaM kinase II activity and ameliorated the intravascular injury in the kidneys of Ang II--infused hypertensive rats. Our data indicate that CaM kinase activation represents an important component of the mechanism(s) initiating VSMC proliferation and the development and maintenance of Ang II--induced hypertension in rat.
Hypertension 2002 Feb
PMID:Functional significance of activation of calcium/calmodulin-dependent protein kinase II in angiotensin II--induced vascular hyperplasia and hypertension. 1188 35

We studied the early pathophysiological response of lenticulostriate arterioles in rats in three models of human conditions associated with stroke: (a) chronic angiotensin II-hypertension; (b) chronic nicotine administration; (c) oxidative endothelial injury. In all three models, quantitative patch clamp analysis of freshly isolated vascular smooth muscle cells from lenticulostriate arterioles and posterior cerebral arteries showed significant increases in activity of functional L-type calcium channels that were due to an increase in open channel probability, with no change in other biophysical properties or in channel expression. In addition, all three models showed evidence of endothelial dysfunction, but of a different nature in the three. With chronic angiotensin II-hypertension, but not in the other two models, endothelial nitric oxide synthase (eNOS) was dysfunctional, was mislocalized away from its normal abluminal location, and was accumulated in peri-nuclear Golgi. By contrast, the other two models showed no mislocalization of eNOS, but instead showed evidence of oxidative stress in endothelium, with up-regulation of superoxide dismutase and hexose kinase. All three models showed significant up-regulation of expression of proliferative cell nuclear antigen (PCNA) (PCNA index, 70-80%) in arterioles in situ, which is associated with increased activation of the nuclear transcription factor, phospho-cAMP response element binding protein (phospho-CREB). In addition, calmodulin-dependent protein (CaM) kinase II was activated, in concert with the activation of L-type calcium channels. Furthermore, blockers of either L-type calcium channels (amlodipine) or of CaM kinase II (KN-93) completely prevented the activation of CREB and the up-regulation of PCNA in arterioles. Our findings demonstrate that abnormal regulation of L-type calcium channels is directly responsible for abnormal proliferative responses in vascular smooth muscle in various forms of cerebral arteriolar injury associated with endothelial dysfunction.
 ...
PMID:Early pathophysiological changes in cerebral vessels predisposing to stroke. 1472 53

Obese Zucker rat (OZR) is a genetic model of obesity with noninsulin-dependent diabetes and hypertension. The OZR exhibit hyperinsulinemia, hyperlipidmia, and high circulating glucocorticoid levels. We have shown previously that long-term potentiation (LTP) is impaired in the CA1 region of the hippocampus of OZR. In the present work, although electrophysiological recording from anesthetized OZR hippocampus showed impaired LTP in the CA1, an intact LTP was recorded in the dentate gyrus (DG) region of the hippocampus of the same OZR. Thus, LTP is differentially impaired in the CA1 compared with the DG region of OZR hippocampus. Immunoblotting was used to investigate the molecular mechanism responsible for impairment of LTP in the CA1 but not in the DG region. Analysis revealed reduction in the levels of phosphorylated calcium-dependent calmodulin kinase II (P-CaMKII) and total CaMKII in the CA1 region of OZR. However, in the DG region, reduction was observed only in the levels of total CaMKII, with no change in P-CaMKII levels. The ratio of P-CaMKII to total CaMKII was increased in the DG but not in the CA1 area of hippocampus of OZR. Although unchanged in the CA1, calcineurin levels were significantly reduced in the DG of OZR. These findings suggest that the DG might possess a compensatory mechanism whereby calcineurin levels are reduced to allow sufficient P-CaMKII to produce an apparently normal LTP in the DG area of OZR hippocampus.
 ...
PMID:Impairment of long-term potentiation in the CA1, but not dentate gyrus, of the hippocampus in Obese Zucker rats: role of calcineurin and phosphorylated CaMKII. 1628 Jun 4

Physiological hemodynamic stress, such as aerobic exercise, is intermittent and requires an increase in Ca2+ -dependent contractility through sympathetic nervous system activation. Pathological hemodynamic stress, such as hypertension, is persistent and requires sustained increases in cardiac function. Over time, this causes left ventricular hypertrophy (LVH)-reduced responsiveness to sympathetic stimulation. In this study, we examined the hypothesis that blunted in vivo adrenergic contractile responsiveness in pressure overload (PO)-induced cardiac hypertrophy is caused by abnormalities in the abundance and/or basal phosphorylation state of Ca2+ regulatory proteins. PO, induced by aortic constriction, caused concentric LVH or dilated LVH. Only animals with dilation exhibited a decrease in baseline left ventricle function [fractional area change (FAC); measured with echocardiography]. All PO animals had a reduced contractile response to adrenergic agonists (increase in FAC with 40 microg.kg(-1).min(-1) dobutamine, control 0.30 +/- 0.04, n = 5 vs. banded 0.10 +/- 0.03, n = 10; P < 0.01). PO animals had reduced phospholamban (PLB) protein abundance (P = 0.07, not significant) and increased PLB phosphorylation at the calmodulin-dependent kinase II (CaMKII)-specific site (PLB-Thr17, P < 0.05) but not at the protein kinase A-specific site (PLB-Ser16). PLB-Thr17 phosphorylation was inversely correlated with dobutamine-induced increases in contractility in PO animals (r2 = 0.81, P < 0.05). Continuous induction of Ca2+ transients in isolated ventricular myocytes for 24 h increased phosphorylation at PLB-Thr17 and diminished inotropic responsiveness and PLB-Ser16 phosphorylation after exposure to isoproterenol (P < 0.05). These data show that reduced adrenergic responsiveness in feline PO hypertrophy and failure involves increases in basal PLB-Thr17 phosphorylation, suggesting that activation of CaMKII in PO hypertrophy contributes to defective adrenergic reserve in compensated LVH and early heart failure.
 ...
PMID:Phosphorylation of phospholamban at threonine-17 reduces cardiac adrenergic contractile responsiveness in chronic pressure overload-induced hypertrophy. 1656 14

In response to pathologic stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is characterized by myocyte hypertrophy, myocyte death and fibrosis, resulting in impaired cardiac function and heart failure. Cardiac remodeling is associated with derepression of genes that contribute to disease progression. This review focuses on evidence linking members of the Ca(2+)/calmodulin-dependent protein kinase (CaMK) superfamily, specifically CaMKII, protein kinase D (PKD) and microtubule associated kinase (MARK), to stress-induced derepression of pathological cardiac gene expression through their effects on class IIa histone deacetylases (HDACs).
 ...
PMID:Derepression of pathological cardiac genes by members of the CaM kinase superfamily. 1721 38


1 2 3 4 Next >>