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.

Cholinergic stimulation modulates negative inotropic effect of cocaine on ferret ventricular myocardium

1996 ◽  
Vol 270 (2) ◽  
pp. H678-H684
Author(s):  
L. Miao ◽  
Z. Qiu ◽  
J. P. Morgan
Keyword(s):  
Response Curve ◽  
Negative Inotropic Effect ◽  
Ventricular Myocardium ◽  
Inotropic Effect ◽  
Dependent Manner ◽  
Cholinergic Stimulation ◽  
Concentration Dependent Manner ◽  
Cell Shortening ◽  
Inotropic State ◽  
Concentration Response Curve

We tested the hypothesis that the negative inotropic effect (NIE) of cocaine is mediated, at least in part, by cholinergic stimulation and can be correlated with the degree of adenosine 3',5'-cyclic monophosphate (cAMP) dependency of the inotropic state. Cardiac myocytes were isolated from left ventricles of ferrets and loaded with the fluorescent Ca2+ indicator indo 1. Cells were placed in physiological solution containing 2.0 mM Ca2+ and stimulated at 0.5 Hz and 30 degrees C. Cocaine decreased peak cell shortening and peak intracellular Ca2+ in a concentration-dependent manner (10(-8)-10(-4) M). The concentration-response curve of cocaine was shifted significantly downward compared with those of lidocaine and procaine in the same range of concentrations. Atropine (10(-6) M) shifted the concentration-response curve of cocaine, but not those of lidocaine and procaine, rightward, with a pA2 value (7.66) similar to that obtained with carbachol (7.99). With prior addition of isoproterenol (ISO, 10(-8) M) or increased Ca2+ (4.0 mM) to increase cell shortening to the same degree (approximately 60%), cocaine and carbachol decreased contractility to a significantly greater extent in ISO-stimulated myocytes. To clarify whether these treatments changed responsiveness of the contractile elements to Ca2+, the effect of 2,3-butanedione monoxime, an agent that interferes with the interaction of myosin and actin, was tested with previous addition of ISO or increased Ca2+, and no differential effect occurred. Therefore, we postulate that 1) the NIE of cocaine on myocytes is caused by decreased Ca2+ availability; 2) this effect is due to specific stimulation of cholinergic receptors in addition to other direct myocardial (probably local anesthetic) effects; and 3) the NIE correlates with the level of cAMP dependence of the inotropic state.

gamma-Aminobutyric acid-induced response in rat dissociated paratracheal ganglion cells

1992 ◽  
Vol 67 (5) ◽  
pp. 1367-1374 ◽  
Author(s):  
S. Itabashi ◽  
K. Aibara ◽  
H. Sasaki ◽  
N. Akaike
Keyword(s):  
Response Curve ◽  
Ganglion Cells ◽  
Aminobutyric Acid ◽  
Equilibrium Potential ◽  
Induced Response ◽  
Dependent Manner ◽  
Gamma Aminobutyric Acid ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Concentration Response Curve

1. The pharmacologic properties of gamma-aminobutyric acid (GABA)-induced Cl- current (ICl) were studied in the paratracheal ganglion cells freshly dissociated from 7- to 10-day-old rat trachea in a whole-cell recording mode by the use of a conventional patch-clamp technique. 2. GABA- and muscimol-induced currents increased sigmoidally in a concentration-dependent manner, and both currents reversed at approximately -3 mV, which was close to the Cl- equilibrium potential (ECl). 3. Strychnine (STR) at low concentration and bicuculline (BIC) inhibited GABA response competitively, whereas STR at the higher concentrations, benzylpenicillin (PCG), or picrotoxin (PTX) inhibited noncompetitively. Inhibition of GABA response by PCG but not other antagonists was voltage dependent, indicating that PCG acts as a Cl- channel blocker. 4. The concentration-response curve of pentobarbital sodium (PB)-induced ICl was bell shaped. At concentrations higher than 10(-3) M, both the peak and plateau currents decreased, and a transient "hump" current appeared immediately after washing out PB. In the presence of PB, the concentration-response curve of GABA shifted toward left without changing the maximum response. 5. Although diazepam (DZP) at concentration used did not induce a response, it potentiated the GABA response in a concentration-dependent manner between 10(-8) and 10(-6) M. DZP also caused a parallel shift toward left in the concentration-response curve of GABA. 6. PB or DZP further enhanced the GABA response in the presence of the other agent. 7. It is concluded that the properties of GABAA receptors in the paratracheal ganglion cells are essentially similar to those reported in other preparations.

Allosteric modulation of GABAA receptors in acutely dissociated neurons of the suprachiasmatic nucleus

1996 ◽  
Vol 270 (6) ◽  
pp. C1726-C1734 ◽  
Author(s):  
M. Shimura ◽  
N. Harata ◽  
M. Tamai ◽  
N. Akaike
Keyword(s):  
Gabaa Receptor ◽  
Suprachiasmatic Nucleus ◽  
Gabaa Receptors ◽  
Response Curve ◽  
Equilibrium Potential ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Gabaa Receptor Antagonist ◽  
Inward Currents ◽  
Concentration Response Curve

The gamma-aminobutyric acid (GABA)-induced response was investigated in acutely dissociated suprachiasmatic nucleus (SCN) neurons of 11- to 14-day-old rats, under the voltage-clamp condition of nystatin-perforated patch recording. At a holding potential of -40 mV, application of GABA induced inward currents in a concentration-dependent manner. Pentobarbital and 5 beta-pregnan-3 alpha-ol-20-one (pregnanolone) similarly induced inward currents. GABA-induced inward currents were suppressed in a concentration-dependent manner by pretreating neurons with a GABAA receptor antagonist, bicuculline. Bicuculline (3 x 10(-6) M) shifted the concentration-response curve of GABA to the left in a competitive manner. Reversal potential of the GABA response (EGABA) was -3.4 +/- 0.7 mV, close to the theoretical Cl- equilibrium potential of -4.1 mV. Pretreating SCN neurons with diazepam, pentobarbital, and pregnanolone enhanced the 3 x 10(-6) M GABA response. Diazepam (3 x 10(-8) M), pentobarbital (3 x 10(-5) M), and pregnanolone (10(-7) M) shifted the concentration-response curve of GABA to the left without changing the maximal amplitude of GABA responses. EGABA in the presence of diazepam, pentobarbital, or pregnanolone was the same as that in their absence. These results show that the GABA response in acutely dissociated SCN neurons is mediated by the GABAA receptor. Because the GABAA receptor of SCN neurons is allosterically augmented by diazepam, pentobarbital, and pregnanolone, similarly as in other regions of the central nervous system, the present study opens up ways to functionally modulate the GABAA receptors in SCN.

gamma-Aminobutyric acid-induced response in acutely isolated nucleus solitarii neurons of the rat

1991 ◽  
Vol 260 (4) ◽  
pp. C745-C749 ◽  
Author(s):  
T. Nakagawa ◽  
M. Wakamori ◽  
T. Shirasaki ◽  
T. Nakaye ◽  
N. Akaike
Keyword(s):  
Response Curve ◽  
Aminobutyric Acid ◽  
Equilibrium Potential ◽  
Induced Response ◽  
Dependent Manner ◽  
Gamma Aminobutyric Acid ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Voltage Dependent ◽  
Concentration Response Curve

The gamma-aminobutyric acid (GABA)-induced macroscopic Cl- current (ICl) was investigated in acutely isolated nucleus tractus solitarii (NTS) neurons by a conventional patch-clamp technique combined with a rapid drug application method. The GABA- and muscimol-induced ICl increased in a concentration-dependent manner. The reversal potentials were close to the Cl- equilibrium potential. Pentobarbital sodium (PB) itself elicited a current. Bicuculline (BIC), strychnine (STR), picrotoxin, benzylpenicillin (PCG), Cd2+, and Zn2+ suppressed the GABA response in a concentration-dependent manner. Both BIC and STR shifted the concentration-response curve for GABA response to the right, whereas PCG suppressed the maximum response without affecting the threshold, indicating that BIC and STR antagonized competitively and PCG noncompetitively. The inhibitory action of PCG on GABA response was in a highly voltage-dependent manner. PB shifted the concentration-response curve for GABA response to the left. The augmentatory effect of PB was voltage dependent.

scholarly journals Ex vivo Inhibitory Activity of the Ethanol Root Extract of Senna occidentalis (Labaceae) on Isolated Rat Uterus

2020 ◽  
Vol 27 (1) ◽  
pp. 59-66
Author(s):  
Z.A.M. Nworgu ◽  
S.O. Oyiana ◽  
E.E. Bafor
Keyword(s):  
Response Curve ◽  
Ex Vivo ◽  
Root Extract ◽  
Dependent Manner ◽  
Free Medium ◽  
Rat Uterus ◽  
Concentration Dependent Manner ◽  
Uterine Contractions ◽  
Concentration Response Curve ◽  
Isolated Rat

The ex vivo activity of the ethanol root extract of Senna occidentalis (Labaceae) on isolated rat uterus was examined in order to determine its potential in the therapy of uterine related pathologies. The ethanol root extract of S. occidentalis was investigated on the isolated uterus of rats primed with diethyl stilboestrol (0.1 mg/kg) 24 h prior to the experiment. The extract (2.5 and 7.5 mg/mL) effect on ACh (0.1 – 1.0 μg/mL)– induced contractility, in the presence of atropine (0.12 μg/mL), propranolol (8 μg/mL), CaCl2 (in Ca2+-free medium) and in the presence of 100 mM KCl was examined. The extract significantly inhibited ACh-induced uterine contractions (P< 0.05) and CaCl2- induced uterine contractions (in Ca2+-free medium) (P<0.05) in a non-competitive but concentration-dependent manner. A rightward shift of the concentration-response curve was observed in all cases. However, a bell- shaped concentration-response curve was observed for CaCl2. The inhibitory effect of the extract on ACh-induced uterine contractions was unaffected by propranolol. The extract (0.1 - 0.4 mg/mL) also inhibited KCl- induced uterine contractions. The root extract of S. Occidentalis was shown to inhibit agonist-induced uterine contractions probably through interaction with voltage-operated calcium channels. Keywords: Acetylcholine; Calcium; Propranolol; Ex vivo uterine activity; Senna occidentalis; Uterus

scholarly journals Rapid nitric oxide–induced desensitization of the cGMP response is caused by increased activity of phosphodiesterase type 5 paralleled by phosphorylation of the enzyme

2001 ◽  
Vol 155 (2) ◽  
pp. 271-278 ◽  
Author(s):  
Florian Mullershausen ◽  
Michael Russwurm ◽  
W. Joseph Thompson ◽  
Li Liu ◽  
Doris Koesling ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Rapid Decline ◽  
Aortic Tissue ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Activity Increase ◽  
Phosphodiesterase Type ◽  
Increased Activity

Most of the effects of the signaling molecule nitric oxide (NO) are mediated by cGMP, which is synthesized by soluble guanylyl cyclase and degraded by phosphodiesterases. Here we show that in platelets and aortic tissue, NO led to a biphasic response characterized by a tremendous increase in cGMP (up to 100-fold) in less than 30 s and a rapid decline, reflecting the tightly controlled balance of guanylyl cyclase and phosphodiesterase activities. Inverse to the reported increase in sensitivity caused by NO shortage, concentrating NO attenuated the cGMP response in a concentration-dependent manner. We found that guanylyl cyclase remained fully activated during the entire course of the cGMP response; thus, desensitization was not due to a switched off guanylyl cyclase. However, when intact platelets were incubated with NO and then lysed, enhanced activity of phosphodiesterase type 5 was detected in the cytosol. Furthermore, this increase in cGMP degradation is paralleled by the phosphorylation of phosphodiesterase type 5 at Ser-92. Thus, our data suggest that NO-induced desensitization of the cGMP response is caused by the phosphorylation and subsequent activity increase of phosphodiesterase type 5.

Older versus newer antidepressants: Substance P or calcium antagonism?

2007 ◽  
Vol 85 (10) ◽  
pp. 1004-1011 ◽  
Author(s):  
C. Boselli ◽  
M. Santagostino Barbone ◽  
A. Lucchelli
Keyword(s):  
Substance P ◽  
Receptor Subtypes ◽  
Dependent Manner ◽  
Depression And Anxiety ◽  
Guinea Pig Ileum ◽  
Response Curves ◽  
Concentration Dependent Manner ◽  
Calcium Antagonism ◽  
Blocking Activity ◽  
Concentration Response Curve

Substance P (SP) is possibly involved in the pathophysiology of depression and anxiety. We investigated interactions between antidepressants on SP-induced effects and their potential calcium-blocking activity in the isolated guinea pig ileum. All the antidepressants tested, except pargyline, moclobemide, mianserin, and reboxetine, were able to inhibit in a concentration-dependent manner the contraction induced by 100 nmol/L SP. Clomipramine, fluoxetine, maprotiline, and amitriptyline (all at 3 μmol/L) flattened the concentration–response curves to SP, resulting in a reduction of up to 59%, 63%, 32%, and 23%, respectively, of the maximum contractile effect. All the antidepressants tested (3 μmol/L), except pargyline, moclobemide, and mianserin, produced a rightward parallel shift of the concentration–response curve to CaCl2. The L-type selective calcium blocker nifedipine and the T-type selective mibefradil showed similar behaviour against both agonists used, SP and CaCl2. The relative order of potency was nifedipine (pA2, 7.6 ± 0.1) > clomipramine (pA2, 7.0 ± 0.1) > fluoxetine (pKB, 6.5 ± 0.1) = mibefradil (pKB, 6.6 ± 0.1) > amitriptyline (pKB, 6.3 ± 0.1) = maprotiline (pKB, 6.2 ± 0.1) > fluvoxamine (pKB, 5.9 ± 0.1). The data reported in the present study suggest that the antidepressants tested did not behave as competitive antagonists versus NK1-receptor subtypes, but their inhibitory action seems to be related to their calcium-blocking properties.

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.

scholarly journals Short fungal fractions of β-1,3 glucans affect platelet activation

2016 ◽  
Vol 311 (3) ◽  
pp. H725-H734 ◽  
Author(s):  
Hélène Vancraeyneste ◽  
Rogatien Charlet ◽  
Yann Guerardel ◽  
Laura Choteau ◽  
Anne Bauters ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Atp Release ◽  
Human Platelets ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Platelet Activity ◽  
Concentration Dependent Manner ◽  
Wide Range ◽  
Invasive Infections ◽  
Life Threatening

Platelets are capable of binding, aggregating, and internalizing microorganisms, which enhances the elimination of pathogens from the blood. The yeast Candida albicans is a pathobiont causing life-threatening invasive infections. Its cell wall contains β-1,3 glucans that are known to trigger a wide range of host cell activities and to circulate during infection. We studied the effect of β-1,3 glucan fractions (BGFs) consisting of diglucosides (Glc2), tetraglucosides (Glc4), and pentaglucosides (Glc5) on human platelets, their mechanisms of action, and their possible impact on host defenses. The effect of BGFs on the coagulation process was determined by measuring thrombin generation. Platelets pretreated with BGFs were analyzed in terms of activation, receptor expression, aggregation, and adhesion to neutrophils and to C. albicans. The results show that BGFs affected the endogenous thrombin potential in a concentration-dependent manner. For platelet activation, BGFs at a low concentration (2 μmol/l) reduced ATP release and prevented the phosphorylation of protein kinase C. BGFs diminished the expression of P-selectin and the activation of αIIbβ3. BGFs decreased platelet aggregation and the interaction between thrombin-stimulated platelets and neutrophils, fibrinogen, and C. albicans. GLc5 decreased ATP release and TGF-β1 production in response to TLR4 upregulation in thrombin-stimulated platelets, but TLR4 blockage abolished the effect of BGFs on platelets. This study provides evidence that fungal pentaglucosides modulate platelet activity mediated via TLR4 stimulation and reduce platelet-neutrophil interaction.

scholarly journals Modification of human placental alkaline phosphatase by periodate-oxidized 1,N6-ethenoadenosine monophosphate

1990 ◽  
Vol 272 (3) ◽  
pp. 683-690 ◽  
Author(s):  
G G Chang ◽  
M S Shiao ◽  
K R Lee ◽  
J J Wu
Keyword(s):  
Alkaline Phosphatase ◽  
Dependent Manner ◽  
Placental Alkaline Phosphatase ◽  
Phosphate Binding ◽  
Hydrophobic Region ◽  
Concentration Dependent Manner ◽  
General Chemical ◽  
Wide Range ◽  
Human Placental Alkaline Phosphatase ◽  
Activity Loss

Oxidation of 1,N6-ethenoadenosine monophosphate (epsilon AMP) with periodate cleaved the cis-diol of the ribose ring and resulted in the formation of a dialdehyde derivative (epsilon AMP-dial). At room temperature epsilon AMP-dial was unstable and underwent beta-elimination to give 4′,5′-anhydro-1,N6-ethenoadenosine dialdehyde acetal (A epsilon Ado-dial). These nucleotide analogues were found to inactivate human placental alkaline phosphatase in a time- and concentration-dependent manner. epsilon AMP-dial was shown to be an affinity label for the enzyme on the basis of the following criteria. (a) Kinetics of the enzyme activity loss over a wide range of epsilon AMP-dial concentration showed a saturating phenomenon. Removal of the phosphate group made the reagent (A epsilon Ado-dial) become a general chemical modifying reagent. (b) The artificial substrate p-nitrophenyl phosphate gave substantial protection of the enzyme against inactivation. (c) epsilon AMP-dial was a substrate and a partial mixed-type inhibitor for the enzyme. Results of the inhibition and protection studies indicated that the reagent and substrate could combine with the enzyme simultaneously. Besides the phosphate-binding domain, an induced hydrophobic region is proposed for the substrate-binding site for human placental alkaline phosphatase.

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