Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Benzophenanthridines”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources
PubMed2002

Protein kinase C modulators enhance angiotensin II desensitization of guinea pig ileum via maxi-K+ channels.

We investigated the role of protein kinase C in the desensitization of the angiotensin II-induced contraction of guinea pig ileum. In contrast to their antagonistic effects on enzymatic activity, both activator and blockers accelerated the dissipation of the 10(-7) M angiotensin II isometric contractile response. These agents indirectly activated maxi-K+ channels in cell-attached membrane patches from freshly dispersed myocytes bathed in high-K+ solution and clamped at -40 mV. In parallel with the contractile responses, fura 2-loaded myocytes bathed in Tyrode solution showed additive increases in [Ca2+]i in response to both angiotensin II and phorbol dibutyrate (PDB). The PDB-promoted increase of the rate of angiotensin II desensitization was completely abolished by pretreatment of the tissue strips with 93 nM iberiotoxin or 8 mM KCl. Thus, we conclude that protein kinase C modulators promote faster angiotensin II desensitization by recruiting maxi-K+ channels and inducing membrane repolarization rather than by affecting the protein kinase C activity.

Alkaloids↗
PubMed2002

Interaction between alpha2-autoreceptors and receptors mediating the effects of angiotensin II and bradykinin in the heart of newborn rats.

The interaction between alpha2-autoreceptors and receptors for angiotensin II and bradykinin was studied in the heart of newborn rats. The tissues were labelled with [3H]noradrenaline and then superfused with cocaine-containing medium and stimulated electrically. Angiotensin II (10-300 nM) and bradykinin (3-100 nM) enhanced the evoked overflow of tritium, the maximum increase reaching 63.2% and 87.1%, respectively. Blockade of alpha2-adrenoceptors by 100 nM yohimbine reduced, and that by 1 microM abolished, the effect of both angiotensin II and bradykinin. On the contrary, chelerythrine and staurosporine--blockers of protein kinase C--as well as forskolin, an activator of adenylyl cyclase and a blocker of phosphodiesterase, markedly enhanced the facilitatory effect of angiotensin II and bradykinin. We conclude that: (1) alpha2-autoreceptors are present in the heart of newborn rats which interact with prejunctional receptors for angiotensin II and bradykinin also present in the rat heart at that age; (2) the facilitatory influence of chelerythrine and staurosporine on the one hand and that of forskolin on the other hand suggests a link between protein kinase C and cyclicAMP pathways.

Adrenergic alpha-Antagonists↗
PubMed2003

In vitro effect of sanguinarine alkaloid on binding of [3H]candesartan to the human angiotensin AT1 receptor.

The type of interaction of 5-methyl-2,3,7,8-bis(methylenedioxy)benzo[c]phenanthridinium (sanguinarine), an alkaloid isolated from the root of Bocconia frutescens L., with the human angiotensin AT(1) receptor was evaluated in both intact cells and membrane binding of [3H](2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-benzimidazoline-7-carboxylic acid) ([3H]candesartan). The results indicate that the inhibition of [3H]candesartan binding by sanguinarine is independent of cell viability, since the alkaloid inhibited at a similar extent radioligand binding on both intact Chinese hamster ovary (CHO) cells transfected with the human angiotensin AT(1) receptor (hAT(1)) and their cell membranes (K(i)=0.14 and 1.10 microM, respectively). The unsuccessful recovery of [3H]candesartan binding after washing sanguinarine off the cells suggested a nearly irreversible or slow reversible interaction. Saturation binding studies showed a substantial reduction of the B(max) without affecting the K(d). In addition, the presence of 2-n-butyl-4chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole (losartan) could not prevent sanguinarine inhibition of [3H]candesartan binding neither. The present findings indicate that sanguinarine interacts with the receptor in a slow, nearly irreversible and noncompetitive manner.

Alkaloids↗
PubMed2003

Chelerythrine and bisindolylmaleimide I prolong cardiac action potentials by protein kinase C-independent mechanism.

Effects of chelerythrine and bisindolylmaleimide I on action potential duration and on voltage-activated K(+) and Ca(2+) currents in rat ventricular myocytes were studied using perforated patch-clamp technique. The action potentials were markedly prolonged after application of 20 microM chelerythrine or 100 nM bisindolylmaleimide I. Chelerythrine and bisindolylmaleimide I reduced the amplitude of sustained current (I(K,sus)) significantly. Transient K(+) current (I(to)) was inhibited only by chelerythrine. Ca(2+) current was reduced only with highest chelerythrine concentration (50 microM). Application of chelerythrine and bisindolylmaleimide I inhibited outward K(+) currents significantly also in ruptured patch-clamp configuration. Bisindolylmaleimide V, an inactive analogue of bisindolylmaleimide I, decreased I(K,sus) substantially. However, I(to) and I(K,sus) were not affected by calphostin C. Direct protein kinase C activators resulted in decrease of outward K(+) currents. Chelerythrine blocked I(to) in a use-dependent manner and the block did not recover during a 4-min washout. I(K,sus) was not blocked by this mechanism by either inhibitor. We conclude that chelerythrine and bisindolylmaleimide I inhibit outward K(+) currents independently of protein kinase C inhibition.

Action Potentials↗
PubMed1997

Chelerythrine, a protein kinase C inhibitor, interacts with cyclic nucleotide phosphodiesterases.

Chelerythrine, a potent inhibitor of protein kinase C, was evaluated for its effect on cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta. Chelerythrine activated basal PDE2 and inhibited activated PDE2, PDE4 and PDE5. The effect of chelerythrine (10 microM) was also investigated on vasorelaxation induced by a beta-adrenoceptor agonist or a PDE3 inhibitor. Chelerythrine attenuated the isoprenaline-mediated relaxation whereas it potentiated the relaxation induced by SK & F 94120 (5-(4)acetamidophenyl)pyrazin-2(1 H)-one, a PDE3 inhibitor). The present study demonstrates that chelerythrine, at a concentration generally reported in the literature to inhibit protein kinase C, interacts with cyclic nucleotide phosphodiesterases and consequently modulates vasorelaxation. These results cast some doubt on the use of chelerythrine as a specific inhibitor of protein kinase C.

Adrenergic beta-Agonists↗
PubMed1999

Cocaine decreases the glycine-induced Cl- current of acutely dissociated rat hippocampal neurons.

The effects of cocaine on glycine-induced Cl- current (I(GLY)) of single neurons, freshly isolated from the rat hippocampal CA1 area, were studied with conventional whole-cell recording under voltage-clamp conditions. Cocaine depressed I(GLY) in a concentration-dependent manner, with an IC50 of 0.78 mM. Preincubation with 1 mM cocaine alone had no effect on I(GLY), suggesting that resting glycine channels are insensitive to cocaine. The depression of I(GLY) by cocaine was independent of membrane voltage. Internal cell dialysis with 1 mM cocaine failed to modify I(GLY). Because the depression of I(GLY) was noncompetitive, cocaine may act on the glycine receptor-chloride ionophore complex at a site distinct from that to which glycine binds. The cocaine suppression of I(GLY) was unaffected by 1 microM tetrodotoxin and 1 microM strychnine. Blockers of protein kinase C (Chelerythrine), kinase A (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide HCl, (H-89)) and Ca-calmodulin-dependent kinase (1-[N,O-bis(5-isoquinoline-sulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperaz ine (KN-62)) were also ineffective, which suggests that these phosphorylating mechanisms do not modulate cocaine-induced suppressant action on I(GLY). This extracellular, strychnine-independent depression of I(GLY) may contribute to cocaine-induced seizures.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

Reduction of myocardial injury by the EP3 receptor agonist TEI-3356. Role of protein kinase C and of K(ATP)-channels.

The effects of the prostanoid EP3 receptor agonist TEI-3356 on either protein kinase C or ATP-sensitive (K(ATP)) K+ channels and on the infarct size caused by regional myocardial ischaemia and reperfusion in the rat were investigated. Male Wistar rats (n = 72) were subjected to 25 min occlusion of the left anterior descending coronary artery followed by 2 h of reperfusion. TEI-3356 (1 microg/kg/min i.v., n = 6) caused a significant reduction in infarct size from 60+/-3% (control, n = 8) to 38+/-3% of the area at risk. Pretreatment of rats with 5-hydroxydecanoate (5 mg/kg i.v., n = 6), a specific inhibitor of K(ATP)-channels, attenuated the cardioprotective effects of TEI-3356. The reduction in infarct size afforded by TEI-3356 was also abolished by the protein kinase C inhibitors staurosporine (1 microg/kg i.v., n = 6) and chelerythrine (0.7 mg/kg i.v., n = 5). Thus, TEI-3356 reduces myocardial infarct size in the rat by a mechanism(s) which involves the activation of protein kinase C and the opening of K(ATP)-channels.

Adenosine Triphosphate↗
PubMed1999

The difference between methadone and morphine in regulation of delta-opioid receptors underlies the antagonistic effect of methadone on morphine-mediated cellular actions.

To investigate the cellular and molecular basis for using methadone in substitution therapy for morphine addiction, the difference between methadone and morphine in causing desensitization of delta-opioid receptors was examined, and the effects of methadone pretreatment on opiate-induced inhibition of forskolin-stimulated cAMP accumulation was studied. Methadone substantially attenuated the ability of [D-Ala2,D-Leu5]enkephalin (DADLE), morphine and methadone to inhibit forskolin-stimulated cAMP accumulation. Methadone was able to block the morphine-induced compensatory increase in intracellular cAMP levels and naloxone-precipitated cAMP overshoot after chronic exposure to morphine. The protein kinase inhibitor (1-5-isoquinolinesulfony)-2-methylpiperazine) (H7) could significantly block the chronic methadone treatment-induced loss of the ability of DADLE to inhibit adenylate cyclase. The protein kinase inhibitor chelerythrine was able to block the acute methadone treatment-induced loss of the ability of DADLE to inhibit adenylate cyclase. In contrast, morphine did not cause a substantial desensitization of the delta-opioid receptor. These results indicate that methadone is different from morphine in its regulation of the delta-opioid receptor. In addition, these results also indicate that the mechanisms of delta-opioid receptor desensitization induced by acute and chronic methadone treatment are different.

Adenylyl Cyclases↗
PubMed2003

Protein kinase C inhibition induces DNA fragmentation in COLO 205 cells which is blocked by cysteine protease inhibition but not mediated through caspase-3.

Enhancing apoptosis to remove abnormal cells has potential in reversing cancerous processes. Caspase-3 activation generally accompanies apoptosis and its substrates include enzymes responsible for DNA fragmentation and isozymes of protein kinase C (PKC). Recent data, however, question its obligatory role in apoptosis. We have examined whether modulation of PKC activity induces apoptosis in COLO 205 cells and the role of caspase-3. Proliferation ([3H]thymidine) and apoptosis (DNA fragmentation and FACS) of COLO 205 cells were measured in response to PKC activation and inhibition. Caspase-3 activity was assayed and the effects of its inhibition with Ac-DEVD-cmk, and the effect of other protease inhibitors, on apoptosis were determined. PKC activation and inhibition both reduced DNA synthesis and induced DNA fragmentation. As PKC inhibitors induced DNA fragmentation more rapidly than PKC activators and failed to block activator effects, we conclude that it is PKC down-regulation (i.e., inhibition) after activator exposure that mediates apoptosis. Increases in caspase-3 activity occurred during apoptosis but apoptosis was not blocked by caspase inhibition. By contrast, the cysteine protease inhibitor, E-64d, blocked apoptosis. Cysteine proteases not of the caspase family may either act more closely to the apoptotic process than caspases or lie on an alternative, more active pathway.

Aged↗
PubMed1995

Regulation of retinal glial cell proliferation by antiproliferative molecules.

Glial cells normally do not proliferate in the adult retina despite the presence of glial mitogens. In this study, we examined the hypothesis that endogenous antiproliferative molecules inhibit the effects of glial mitogens. Using cultures of glial cells obtained from the adult human retina, we found that transforming growth factor beta 2 (TGF beta 2) and a metabotrophic glutamate agonist (t-ACPD) inhibit the mitogenic effects of basic fibroblast growth factor, platelet-derived growth factor, epidermal growth factor and insulin-like growth factor-1. These antiproliferative effects may involve activation of protein kinase C (PKC) since chelerythine, a specific PKC inhibitor, blocks the antiproliferative effects of TGF beta 2 and t-ACPD. Furthermore, exposure of the glia to a phorbol ester mimics the inhibitory effects of TGF beta 2 or t-ACPD. Although TGF beta 2 and t-ACPD markedly inhibit a number of mitogens, they do not alter the mitogenic response of retinal glia to thrombin and glutamate. A common characteristic of the mitogens sensitive to TGF beta 2 or t-ACPD is activation of tyrosine kinase-linked receptors. In contrast, thrombin acts at a G-protein-linked receptor, and glutamate stimulates retinal glial proliferation via activation of an NMDA receptor. It appears that TGF beta 2 and t-ACPD may selectively inhibit retinal glial mitogenesis mediated by activation of tyrosine kinase-linked receptors. Our experiments support the idea that endogenous antiproliferative molecules play a role in preventing glial proliferation in the retina.

Alkaloids↗
PubMed1997

Isoform specificity of activators and inhibitors of protein kinase C gamma and delta.

Expression of certain mammalian protein kinase C (PKC) isoforms inhibits the proliferation of Schizosaccharomyces pombe (Goode et al., Mol. Biol. Cell 5 (1994) 907-920). We have taken advantage of this fact to determine the in vivo isoform preference of a number of PKC inhibitors, using a microtitre plate assay which allows rapid screening. This in vivo model has revealed previously unreported preferences; calphostin C is a more efficient inhibitor of the novel PKCS than chelerythrine chloride whereas the efficiencies are reversed for inhibition of the classical PKCgamma. We have also shown that the anti-leukaemic agent bryostatin 1 inhibits or activates in vivo in an isoform-specific manner.

Acetophenones↗
PubMed1997

Metal-induced metallothionein gene expression can be inactivated by protein kinase C inhibitor.

The effects of protein kinase C (PKC) inhibitors on the metallothionein (MT) gene expression induced by metals were investigated. When PKC inhibitor (H7 or chelerythrine) was administered to Cd resistant, MT gene-amplified Chinese hamster ovary (CdR) cells, the induction of MT mRNA by Cd or Zn was blocked. Treating the CdR cells with a PKA-specific inhibitor, HA1004, did not cause an inhibition of metal-induced MT gene transcription. The inhibitory effect was effectuated by adding inhibitors within 40 min of exposing the cells to Cd. Apparently, AP1 was not involved in this down-regulatory effect of PKC inhibitor on MT gene expression since the inducibility of MT promoter was blocked by H7 even in the absence of the AP1-binding sequence. For Cd-treated cells, Cd accumulation in the cell was similar with or without H7 treatment. However, H7 markedly reduced cellular Zn accumulation when the cells were treated with Zn. Cycloheximide treatment increased the level of MT mRNA. This elevation can also be blocked by treating the cell with PKC inhibitor. Results in this study suggest that PKC participates in the process of metal-induced MT gene expression.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

Phosphatidylinositol 3-kinase and protein kinase C are required for the inhibition of caspase activity by epidermal growth factor.

The mechanism by which growth factors exert an anti-apoptotic function on many cell types is not well understood. This issue is addressed in relation to epidermal growth factor (EGF) which inhibits apoptosis induced by staurosporine or wortmannin in an epithelial tumour cell line (CNE-2). The presence of EGF substantially reduced the in vitro Ac-DEVD-AMC hydrolytic activity and almost completely suppressed the intracellular cleavage of poly(ADP-ribose) polymerase in staurosporine- or wortmannin-treated cells. Staurosporine but not wortmannin caused the intracellular proteolytic processing of pro-caspase-3 and this event was transiently inhibited by EGF. Staurosporine-induced apoptosis was not inhibited by EGF in the presence of wortmannin or LY294002. Similarly, EGF failed to inhibit wortmannin-induced apoptosis in the presence of staurosporine, chelerythrine chloride or Gö6850. These results suggest that phosphatidylinositol 3-kinase and protein kinase C play a role in the survival function of EGF but the reduction of cellular caspase activity cannot be satisfactorily explained by a lack of pro-caspase-3 activation.

Alkaloids↗
PubMed1999

Activation of Ras by phorbol esters in cardiac myocytes. Role of guanine nucleotide exchange factors.

The relationship between protein kinase C (PKC) activation and Ras function was investigated in cardiac cells. Ras function was required for ERK activation by phorbol esters in cardiac myocytes, but not in cardiac fibroblasts. Accordingly, treatment with phorbol esters resulted in GTP loading of Ras in cardiac myocytes, but not fibroblasts. Ras activation by phorbol esters was abolished by a PKC specific inhibitor, but was insensitive to tyrosine kinase inhibitors. Ras activation was mediated by stimulation of guanine nucleotide exchange. These results suggest the existence of a novel pathway for Ras activation, specific to cardiac myocytes, with implications for myocardial hypertrophy.

Alkaloids↗
PubMed2001

Investigation of the inhibitory effects of chelerythrine chloride on the translocation of the protein kinase C betaI, betaII, zeta in human neutrophils.

The protein kinase C (PKC) is a serine/threonine kinase, consisting of different isoforms, implicated in numerous processes of signal transduction. To understand this enzyme well, different pharmacological tools were developed. To activate PKC specifically, phorbol esters were previously used but recent research has shown that these compounds are able to stimulate other proteins. Our model is the respiratory burst in the polymorphonuclear neutrophils. A decrease in the inflammatory process was measured using chelerythrine chloride. Action on PKC was proved by a binding study and by showing the absence of translocation of this enzyme from the cytoplasm to the plasmic membrane during stimulation.

Alkaloids↗
PubMed1999

Separation, identification and determination of sanguinarine in argemone and other adulterated edible oils by reversed-phase high-performance liquid chromatography.

A simple, rapid and reliable reversed-phase high-performance liquid chromatographic method for the separation and determination of sanguinarine in argemone and other edible oils has been developed. The separation has been achieved on a C18 column with CH3OH-CH3CN-tetrahydrofuran-water as mobile phase using diode array detection at 280 nm. The minimum detection limit of sanguinarine in the adulterated edible oils is 5 microg/g.

Alkaloids↗