scholarly journals Aristoteline, an Indole-Alkaloid, Induces Relaxation by Activating Potassium Channels and Blocking Calcium Channels in Isolated Rat Aorta

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2748 ◽  
Author(s):  
Fernando Romero ◽  
Javier Palacios ◽  
Ignacio Jofré ◽  
Cristian Paz ◽  
Chukwuemeka R. Nwokocha ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Vascular Reactivity ◽  
Soluble Guanylate Cyclase ◽  
Indole Alkaloid ◽  
Soluble Guanylyl Cyclase ◽  
Rat Aorta ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cav1.2 Channels ◽  
Aristotelia Chilensis

Alkaloids derived from plants have shown great medicinal benefits, and are often reported for their use in cardiovascular disease management. Aristotelia chilensis (Molina) Stuntz (Maqui) has shown important medicinal properties in traditional useage. In this study, we evaluated the effect of the indole-alkaloid aristoteline (ARI), isolated from leaves of Maqui, on vascular reactivity of isolated aortic rings from normotensive rats. ARI induced relaxation (100%) in a concentration-dependent manner in intact or denuded-endothelium aortic rings pre-contracted with phenylephrine (PE; 1 μM). However, a specific soluble guanylyl cyclase inhibitor (ODQ; 1 μM) significantly reduced the relaxation to ARI in aortic rings pre-contracted with PE. In the presence of ARI, the contraction induced by KCl or PE was significantly (p < 0.05) decreased. Interestingly, the potassium channel blockade with 10 μM BaCl2 (Kir), 10 μM glibenclamide (KATP), 1 mM tetraethylammonium (TEA; KCa1.1), or 1 mM 4-aminopyridine (4-AP; Kv) significantly (p < 0.05) reduced the ARI-induced relaxation. ARI significantly (p < 0.05) reduced the contractile response to agonist of CaV1.2 channels (Bay K8644; 10 nM), likely reducing the influx of extracellular calcium through plasma membrane. The mechanisms associated with this process suggest an activation of the potassium channels, a calcium-induced antagonism and endothelium independent vasodilation that possibly involves the nitric oxide-independent soluble guanylate cyclase pathway.

Vasorelaxing Activity of Stilbenoid and Phenanthrene Derivatives from Brasiliorchis porphyrostele: Involvement of Smooth Muscle CaV1.2 Channels

Planta Medica ◽  
2020 ◽  
Vol 86 (09) ◽  
pp. 631-642
Author(s):  
Watcharee Waratchareeyakul ◽  
Fabio Fusi ◽  
Miriam Durante ◽  
Amer Ahmed ◽  
Walter Knirsch ◽  
...  
Keyword(s):  
Channel Blocker ◽  
Antihypertensive Agents ◽  
Dependent Manner ◽  
Vascular Effects ◽  
Concentration Dependent Manner ◽  
Spasmolytic Activity ◽  
Depth Analysis ◽  
Cav1.2 Channels ◽  
Vasorelaxant Activity

AbstractFive compounds, 3,4′-dihydroxy-3′,5,5′-trimethoxydihydrostilbene, 1; 3,4′-ihydroxy-3′,5′-dimethoxydihydrostilbene, 2; 3,4′-dihydroxy-5,5′-dimethoxydihydrostilbene, 3; 9,10-dihydro-2,7-dihydroxy-4,6-dimethoxyphenanthrene, 4; and the previously unreported 1,2,6,7-tetrahydroxy-4-methoxyphenanthrene, 5 were isolated from the South American orchid, Brasiliorchis porphyrostele. An in-depth analysis of their vascular effects was performed on in vitro rat aorta rings and tail main artery myocytes. Compounds 1 – 4 were shown to possess vasorelaxant activity on rings pre-contracted by the α 1 receptor agonist phenylephrine, the CaV1.2 stimulator (S)-(−)-Bay K 8644, or depolarized with high K+ concentrations. However, compound 5 was active solely on rings stimulated by 25 mM but not 60 mM K+. The spasmolytic activity of compounds 1 and 4 was significantly affected by the presence of an intact endothelium. The KATP channel blocker glibenclamide and the KV channel blocker 4-aminopyridine significantly antagonized the vasorelaxant activity of compounds 4 and 1, respectively. In patch-clamp experiments, compounds 1 – 4 inhibited Ba2+ current through CaV1.2 channels in a concentration-dependent manner, whereas neither compound 4 nor compound 1 affected K+ currents through KATP and KV channels, respectively. The present in vitro, comprehensive study demonstrates that Brasiliorchis porphyrostele may represent a source of vasoactive agents potentially useful for the development of novel antihypertensive agents that has now to be validated in vivo in animal models of hypertension.

scholarly journals Tumor necrosis factor alpha activates soluble guanylate cyclase in bovine glomerular mesangial cells via an L-arginine-dependent mechanism.

1990 ◽  
Vol 172 (6) ◽  
pp. 1843-1852 ◽  
Author(s):  
P A Marsden ◽  
B J Ballermann
Keyword(s):  
Guanylate Cyclase ◽  
Mesangial Cell ◽  
Soluble Guanylate Cyclase ◽  
Mesangial Cells ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Concentration Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Factor Alpha

Endothelium-derived nitric oxide (NO) causes vasodilatation by activating soluble guanylate cyclase, and glomerular mesangial cells respond to NO with elevations of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). We explored whether mesangial cells can be stimulated to produce NO and whether NO modulates mesangial cell function in an autocrine or paracrine fashion. Tumor necrosis factor alpha (TNF-alpha) raised mesangial cell cGMP levels in a time- and concentration-dependent manner (threshold dose 1 ng/ml, IC50 13.8 ng/ml, maximal response 100 ng/ml). TNF-alpha-induced increases in mesangial cGMP content were evident at 8 h and maximal at 18-24 h. The TNF-alpha-induced stimulation of mesangial cell cGMP production was abrogated by actinomycin D or cycloheximide suggesting dependence on new RNA or protein synthesis. Hemoglobin and methylene blue, both known to inhibit NO action, dramatically reduced TNF-alpha-induced mesangial cell cGMP production. Superoxide dismutase, known to potentiate NO action, augmented the TNF-alpha-induced effect. Ng-monomethyl-L-arginine (L-NMMA) decreased cGMP levels in TNF-alpha-treated, but not vehicle-treated mesangial cells in a concentration-dependent manner (IC50 53 microM). L-arginine had no effect on cGMP levels in control or TNF-alpha-treated mesangial cells but reversed L-NMMA-induced inhibition. Interleukin 1 beta and lipopolysaccharide (LPS), but not interferon gamma, also increased mesangial cell cGMP content. Transforming growth factor beta 1 blunted the mesangial cell response to TNF-alpha. TNF-alpha-induced L-arginine-dependent increases in cGMP were also evident in bovine renal artery vascular smooth muscle cells, COS-1 cells, and 1502 human fibroblasts. These findings suggest that TNF-alpha induces expression in mesangial cell of an enzyme(s) involved in the formation of L-arginine-derived NO. Moreover, the data indicate that NO acts in an autocrine and paracrine fashion to activate mesangial cell soluble guanylate cyclase. Cytokine-induced formation of NO in mesangial and vascular smooth muscle cells may be implicated in the pathogenesis of septic shock.

Effects of potassium channel modulators on myotropic responses of aortic rings of pregnant rats

2000 ◽  
Vol 278 (2) ◽  
pp. H567-H576 ◽  
Author(s):  
C. Cadorette ◽  
B. Sicotte ◽  
M. Brochu ◽  
J. St-Louis
Keyword(s):  
Membrane Potential ◽  
Potassium Channels ◽  
Basal Membrane ◽  
Maximal Response ◽  
Dependent Manner ◽  
Response Curves ◽  
Concentration Dependent Manner ◽  
Pregnant Rats ◽  
Potassium Channel Modulators ◽  
High Conductance

The contribution of potassium channels [ATP-sensitive potassium (KATP) and high-conductance calcium-activated potassium (BKCa) channels] in the resistance of aortic rings of term pregnant rats to phenylephrine (Phe), arginine vasopressin (AVP), and KCl was investigated. Concentration-response curves to tetraethylammonium (TEA), a nonselective K+ channel inhibitor, were obtained in the absence or presence of KCl. TEA induced by itself concentration-dependent responses only in aortic rings of nonpregnant rats. These responses to TEA could be modulated in both groups of rings by preincubation with different concentrations of KCl. Concentration-response curves to Phe, AVP, and KCl were obtained in the absence or presence of cromakalim or NS-1619 (KATP and BKCa openers, respectively) and glibenclamide or iberiotoxin (KATPand BKCa inhibitors, respectively). Cromakalim significantly inhibited the responses to the three agonists in a concentration-dependent manner in both groups of rats. Alternatively, in the pregnant group of rats, glibenclamide increased the sensitivity to all three agonists. NS-1619 also inhibited the response to all agonists. With AVP and KCl, its effect was greater in aortic rings of pregnant than nonpregnant rats. Finally, iberiotoxin increased the sensitivity to all three agents. This effect was more important in aortic rings of nonpregnant rats and was accompanied by an increase of the maximal response to Phe and AVP. These results suggest that potassium channels are implicated in the control of basal membrane potential and in the blunted responses to these agents during pregnancy.

Activation of endothelin ETB receptors increases glomerular cGMP via an L-arginine-dependent pathway

1992 ◽  
Vol 263 (6) ◽  
pp. F1020-F1025 ◽  
Author(s):  
R. M. Edwards ◽  
M. Pullen ◽  
P. Nambi
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Binding Sites ◽  
Soluble Guanylate Cyclase ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
High Affinity ◽  
Dependent Pathway ◽  
Stimulation Of

The effects of endothelins (ET) on guanosine 3',5'-cyclic monophosphate (cGMP) levels in intact rat glomeruli were examined. ET-3 produced a rapid approximately fivefold increase in cGMP levels with the maximum effect occurring at 1 min. The ET-3-induced increase in cGMP accumulation occurred in the absence and presence of 3-isobutyl-1-methylxanthine. ET-1, ET-2, ET-3, and the structurally related toxin, sarafotoxin S6c, all increased glomerular cGMP levels in a concentration-dependent manner and with similar potencies (EC50 approximately 15-30 nM). The L-arginine analogue, N omega-nitro-L-arginine (L-NNA), reduced basal levels of cGMP and also totally inhibited ET-induced increases in cGMP as did methylene blue, an inhibitor of soluble guanylate cyclase. The effect of L-NNA was attenuated by L-arginine but not by D-arginine. The stimulation of cGMP accumulation by ET-3 was dependent on extracellular Ca2+ and was additive to atriopeptin III but not to acetylcholine. The ETA-selective antagonist, BQ 123, had no effect on ET-3-induced formation of cGMP. Glomerular membranes displayed high-affinity (Kd = 130-150 pM) and high-density (approximately 2.0 pmol/mg) binding sites for 125I-ET-1 and 125I-ET-3. ET-1, ET-3, and sarafotoxin S6c displaced 125I-ET-1 binding to glomerular membranes with similar affinities. BQ 123 had no effect on 125I-ET-1 binding. We conclude that ET increases cGMP levels in glomeruli by stimulating the formation of a nitric oxide-like factor that activates soluble guanylate cyclase. This effect of ET appears to be mediated by activation of ETB receptors and may serve to modulate the contractile effects of ET.

Potentiation of angiotensin II-stimulated vascular contraction by lithium

1995 ◽  
Vol 268 (5) ◽  
pp. H2009-H2016
Author(s):  
M. E. Ullian ◽  
L. G. Walsh ◽  
K. C. Wong ◽  
C. J. Allan
Keyword(s):  
Angiotensin Ii ◽  
Inositol Phosphate ◽  
Cytosolic Calcium ◽  
Rat Aorta ◽  
Dependent Manner ◽  
Ang Ii ◽  
Concentration Dependent Manner ◽  
Adrenergic Agents ◽  
Phosphoinositide Signaling ◽  
Protein Kinase C Inhibitor

Previous studies have suggested that lithium prolongs or enhances vascular contractions stimulated by alpha-adrenergic agents. The present study was performed to determine whether a similar phenomenon occurs with angiotensin II (ANG II)-stimulated contractions and whether this phenomenon results from interactions with the phosphoinositide signaling system. Contractions of rat aortic rings with 100 nM ANG II were 38% greater in the presence of 20 mM LiCl than in its absence (0.47 +/- 0.07 vs. 0.34 +/- 0.05 g tension/mg dry tissue wt, P < 0.01). The effects of lithium on inositol phosphate responses, diacylglycerol responses, and intracellular calcium concentration on single or repeated stimulations with ANG II were then examined in vascular smooth muscle cells cultured from rat aorta. Cells exposed twice to 100 nM ANG II contained 50% lower inositol trisphosphate levels (InsP3) and 10% lower diacylglycerol levels than cells exposed to ANG II only once. LiCl or lithium acetate abolished these desensitizations in a concentration-dependent manner. Similarly, InsP3 and diacylglycerol responses to a single exposure of ANG II were heightened by lithium (by 75 and 25%, respectively), and the duration of the responses was prolonged by lithium (5- and 2-fold, respectively). In contrast, ANG II-stimulated calcium transients were not enhanced or prolonged by lithium, nor was desensitization of ANG II-stimulated cytosolic calcium mobilization upon serial exposures abolished by lithium. When ring contraction studies were repeated in the presence of the protein kinase C inhibitor staurosporine (150 nM), lithium no longer potentiated ANG II contractions [0.38 +/- 0.03 (control) vs. 0.35 +/- 0.06 g tension/mg dry tissue wt (lithium)].(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Ca2+ entry in the modulation of airway tone by hypoxia

1993 ◽  
Vol 264 (3) ◽  
pp. L284-L289 ◽  
Author(s):  
L. B. Fernandes ◽  
K. Stuart-Smith ◽  
T. L. Croxton ◽  
C. A. Hirshman
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Muscle Tone ◽  
Maintenance Phase ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Concentration Dependent Manner ◽  
Initiation Phase ◽  
Airway Tone

To evaluate the cellular mechanisms involved in hypoxic relaxation of airway smooth muscle, we investigated the effects of hypoxia on the behavior of third- and fourth-order porcine bronchial rings contracted with either carbachol or KCl. In one series of experiments, hypoxia (95% N2-5% CO2) was imposed and rings were then exposed to increasing concentrations of carbachol or KCl. In separate experiments, rings were first contracted with carbachol (10(-6) M) or KCl (40 mM) and were then exposed to solutions bubbled with decreasing concentrations of O2. The CO2 concentration was maintained constant at 5% in all experiments. The initial magnitude of KCl-induced but not carbachol-induced contractions was profoundly reduced by 95% N2-5% CO2. The sensitivity of the airway to carbachol was unchanged. In rings precontracted with either carbachol or KCl, hypoxia caused similar losses of airway smooth muscle tone in a reversible and concentration-dependent manner. The effects of hypoxia were independent of the presence of an intact epithelium and were not inhibited by the cyclooxygenase inhibitor indomethacin (5 microM), the soluble guanylate cyclase inhibitor methylene blue (50 microM), or the beta-adrenoceptor antagonist propranolol (1 microM). The impairment by hypoxia of the initiation phase of KCl-induced contractions and of the maintenance phase of both KCl- and carbachol-induced contractions, but not the initiation phase of carbachol-induced contractions, suggests that changes in O2 tension modulate airway tone by altering the entry of extracellular calcium into the airway smooth muscle.

scholarly journals Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs

2012 ◽  
Vol 58 (1) ◽  
pp. 32-42 ◽  
Author(s):  
N.V. Pyatakova ◽  
I.S. Severina
Keyword(s):  
Sodium Nitroprusside ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Human Platelet ◽  
Dependent Manner ◽  
Therapeutic Action ◽  
Rat Lung ◽  
Concentration Dependent Manner ◽  
No Donors ◽  
Stimulation Of

The influence of ambroxol - a mucolytic drug - on the activity of human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase and activation of both enzymes by NO-donors (sodium nitroprusside and Sin-1) were investigated. Ambroxol in the concentration range from 0.1 to 10 μM had no effect on the basal activity of both enzymes. Ambroxol inhibited in a concentration-dependent manner the sodium nitroprusside-induced human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase with the IC50 values 3.9 and 2.1 μM, respectively. Ambroxol did not influence the stimulation of both enzymes by protoporphyrin IX.The influence of artemisinin - an antimalarial drug - on human platelet soluble guanylate cyclase activity and the enzyme activation by NO-donors were investigated. Artemisinin (0.1-100 μM) had no effect on the basal activity of the enzyme. Artemisinin inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet guanylate cyclase with an IC50 value 5.6 μM. Artemisinin (10 μM) also inhibited (by 71±4.0%) the activation of the enzyme by thiol-dependent NO-donor the derivative of furoxan, 3,4-dicyano-1,2,5-oxadiazolo-2-oxide (10 μM), but did not influence the stimulation of soluble guanylate cyclase by protoporphyrin IX. It was concluded that the sygnalling system NO-soluble guanylate cyclase-cGMP is involved in the molecular mechanism of the therapeutic action of ambroxol and artemisinin.

scholarly journals Potentiation of NO-dependent activation of soluble guanylyl cyclase by 5-nitroisatin and antiviral preparatation arbidol

2013 ◽  
Vol 59 (3) ◽  
pp. 295-304
Author(s):  
I.S. Severina ◽  
A.Yu. Schegolev ◽  
A.E. Medvedev
Keyword(s):  
Guanylyl Cyclase ◽  
Response Curve ◽  
Physiological Activity ◽  
Soluble Guanylyl Cyclase ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Leftward Shift ◽  
Wide Range ◽  
Concentration Response Curve ◽  
Synergistic Increase

Isatin (indole-dione) is an endogenous indole that exibits a wide range of biological and physiological activity. The influence of isatin derivatives 5-nitroisatin and arbidol (an antiviral preparatation) on spermine NONO-induced activation of human platelet soluble guanylyl cyclase was investigated. 5-nitroistnin and arbidol had no effect on basal activity, but synergistically increased in a concentration-dependent manner the spermine NONO-induced activation of this enzyme. 5-Nitroisatin and arbidol, like YC-1, sensitized guanylyl cyclase towards nitric oxide (NO) and produced a leftward shift of the spermine NONO concentration response curve. At the same time both compounds used did not influence the activation of guanylyl cyclase by YC-1 and did not change the synergistic increase of spermine NONO-induced activation of soluble guanylyl cyclase in the presence of YC-1. This suggests that 5-nitroisanin and arbidol did not compete with YC-1. Addition of isatin did not change the synergistic increase in the spermine NONO-induced guanylyl cyclase activation by 5-nitroisatin and arbidol and did not influence a leftward shift of spermine NONO concentration response curve produced by these compounds. These data suggest lack of competitive interaction between isatin and both its derivatives used.

scholarly journals Anti-proliferation of Melanoma Cells and Immune Stimulation by the Cyanobacterial Indole-alkaloid Scytonemin

Fine Focus ◽  
2021 ◽  
Vol 7 (1) ◽  
pp. 54-63
Author(s):  
Jadon Evans ◽  
Aaron Jones ◽  
Elliott Blumenthal ◽  
Tanya Soule
Keyword(s):  
Tritiated Thymidine ◽  
Indole Alkaloid ◽  
Melanoma Cells ◽  
Thymidine Uptake ◽  
Dependent Manner ◽  
Spleen Cells ◽  
Concentration Dependent Manner ◽  
Proliferative Effect

Under the stress of ultraviolet radiation some cyanobacteria synthesize scytonemin, a protective pigment against DNA photodamage. In addition to photoprotection, scytonemin has been shown to have an anti-proliferative effect on various types of malignant cells. In this study the effect of scytonemin on melanoma and spleen cells was assessed both in vitro using tissue cultures and in vivo in mice models. Melanoma and spleen cells were exposed to 0.08 to 10 μM of scytonemin, and cell proliferation was measured using tritiated thymidine uptake. The data suggest that scytonemin acts as an inhibitor for melanoma cells in a concentration-dependent manner while enhancing the proliferation of spleen cells, suggesting that it can potentially augment the immune response. Furthermore, mice injected with melanoma cells and scytonemin produced fewer tumors than mice that did not receive scytonemin, although the data were not significant. This study adds to the growing body of research that scytonemin may be beneficial as a future anticancer agent to prevent tumor cell growth.

Sign in / Sign up

Export Citation Format

Share Document