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.

Responsiveness of individual airways to methacholine in adult rat lung explants

1993 ◽  
Vol 75 (1) ◽  
pp. 364-372 ◽  
Author(s):  
R. J. Dandurand ◽  
C. G. Wang ◽  
N. C. Phillips ◽  
D. H. Eidelman
Keyword(s):  
Video Camera ◽  
Maximal Response ◽  
Dependent Manner ◽  
Response Curves ◽  
Concentration Dependent Manner ◽  
Lung Inflation ◽  
Adult Rat ◽  
Computerized Image Processing ◽  
Before And After ◽  
Area X

We used a modified adult lung explant technique to directly measure the area of individual airways before and after methacholine (MCh) administration. Lungs were removed from 12-wk-old male Lewis rats under sterile conditions, filled with an agarose-containing solution at 37 degrees C, and cooled to 4 degrees C. Transverse slices (0.5–1.0 mm thick) were cut and cultured overnight. Concentration-response curves to MCh were determined for explant airways from lungs inflated to 25, 50, 75, and 100% total lung capacity (TLC) with a 1.0% agarose solution and to 75% TLC with 0.5 and 2.0% agarose solutions. MCh was added to the medium to achieve final concentrations ranging from 10(-9) to 10(-2) M. Airways were imaged before and 10 min after each increase in MCh concentration with an inverted microscope and video camera, and airway area was determined by computerized image processing. The maximal response (MR) ([1-(minimal area/baseline area)] x 100) and concentration of MCh resulting in 50% MR (EC50) were determined. A total of 217 airways from 3–12 explants per rat constricted in a concentration-dependent manner. Baseline area was larger with both higher lung volumes and agarose concentrations. MR was greatest in the airways from the 25% TLC and 0.5% agarose explants. Although there was considerable heterogeneity toward MCh within rats (EC50 varied up to 5.46 x 10(5)-fold), the median EC50 was similar among all rats (range 1.96 x 10(-6)-5.87 x 10(-4) M). Lung inflation volume and agarose concentration affected baseline area and MR, suggesting that airway-parenchymal interdependence mechanisms are operative in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Calcium channels blocked activity: Providing the basis for medicinal use of Abies pindrow in diarrhea and bronchitis

2015 ◽  
Vol 10 (2) ◽  
pp. 430 ◽  
Author(s):  
Sohaib Mushtaq ◽  
Mueen Ahmad Chaudhry ◽  
Hafiz Muhammad Abdul Rahman
Keyword(s):  
Calcium Channels ◽  
Crude Extract ◽  
Dependent Manner ◽  
Response Curves ◽  
Traditional Practice ◽  
Concentration Dependent Manner ◽  
Medicinal Uses ◽  
High K ◽  
Medicinal Use ◽  
Abies Pindrow

<p><em>Abies pindrow</em> is widely used in traditional practice for the treatment of diarrhea and bronchitis and the present study was designed to validate its folkloric uses. The crude extract of <em>A. pindrow</em> inhibit spontaneously contracting (1-10 mg/mL) and high K<sup>+</sup> (80 mM)-induced pre-contracted rabbit jejun-um (3 mg/mL) in concentration dependent manner. A rightward shift in Ca<sup>+2</sup> concentration response curves was seen in the presence of crude extract (0.1-0.3), similar to verapamil. In isolated tracheal tissue, <em>A. pindrow</em> inhibited, high K<sup>+</sup> and carbachol (1 µM)-induced contractions, at 3 mg/mL and 10 mg/mL respectively, similar to that caused by verapamil. These results indicate the presence of calcium channels blocked activity in crude extract of <em>A. pindrow</em>, which provide sound basis for medicinal uses of<em> A. pindrow</em> in diarrhea and bronchitis.   </p><p> </p>

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 1289. Pravibismane is a Potent, Broad Spectrum Anti-Infective Small Molecule that Rapidly Disrupts Bacterial Bioenergetics and Halts Bacterial Growth

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S660
Author(s):  
Brett Baker
Keyword(s):  
Membrane Potential ◽  
Cell Growth ◽  
Protein Expression ◽  
Broad Spectrum ◽  
Time Lapse ◽  
Luciferase Assay ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Time Lapse Microscopy ◽  
Atp Levels

Abstract Background The rise in resistance to existing antimicrobials has prompted a need for the development of novel antibiotics. Microbion has identified a novel compound, pravibismane, with potent broad spectrum anti-infective and anti-biofilm activity. Methods Here we used a variety of assays, including Bacterial Cytological Profiling (BCP), to analyze pravibismane in E.coli to gain insight into its likely mechanism of action (MOA). The BCP profile of pravibismane suggested it rapidly shut down cell growth, potentially by turning off cellular gene or protein expression. This was confirmed using a plasmid based GFP induction assay in E.coli tolC that showed pravibismane strongly reduced expression of GFP. The kinetics, reversibility and MOA of pravibismane was further characterized by using time-lapse microscopy, wash out experiments and measurements of both membrane potential and relative intracellular ATP levels. Results We found that pravibismane acts rapidly (within 30 mins) to completely halt cell growth rather than causing immediate cell lysis such as that observed with non-specific cell damaging agents bleach or detergent. Inhibitor wash out experiments in which cells were exposed to pravibismane for 2 hours, washed to remove the compound, and then observed using time-lapse microscopy revealed that the effect of pravibismane is reversible and that cells recovered 8-12 hrs after removing the compound. Wash out experiments with an E.coli tolC strain carrying a plasmid with an IPTG inducible GFP demonstrated that transcription and translation ultimately resumed in most cells after washout. The bioenergetics of the membrane was measured using DiBAC 4(5), a membrane potential sensitive dye which can enter depolarized cells, which revealed that pravibismane caused depolarization of the membrane within 30 mins of exposure in a concentration dependent manner. Finally, a luciferase assay determined pravibismane reduced ATP levels (resulting in decreased luminescence) within 15 mins of exposure in a concentration dependent manner unlike antibiotic controls that had modest or no effect on luminescence. Conclusion Our results suggest that pravibismane acts rapidly to disrupt cellular bioenergetics, resulting in the immediate cessation of cell growth and protein expression. Disclosures Brett Baker, M.Sc., D.C., Microbion Corporation (Board Member, Employee)

Abstract 16939: Metabolic and Electrophysiological Alterations Underlie Proarrhythmic Properties of Highly Reactive Isolevuglandins in Atrial Cardiomyocytes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tuerdi Subati ◽  
Zhenjiang Yang ◽  
Isis L Christopher ◽  
Joseph C Van Amburg ◽  
Matthew B Murphy ◽  
...  
Keyword(s):  
Membrane Potential ◽  
High Throughput Screening ◽  
Cell Metabolism ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Atp Production ◽  
Atrial Cardiomyocytes ◽  
Extracellular Flux ◽  
Mitochondrial Transition Pore

Background: Hypertension is one of the most common risk factors for atrial fibrillation (AF), although the precise cellular and molecular mechanism(s) by which hypertension leads to AF are not well understood. Isolevuglandins (IsoLGs) are highly reactive dicarbonyl products of lipid peroxidation responsible for a major component of oxidative stress-related injury. In a mouse model of hypertension, we recently demonstrated that IsoLGs are elevated in hypertensive mouse atria and that an IsoLG scavenger reduced both IsoLG burden and AF susceptibility. Hypothesis: In this study, we hypothesized that IsoLGs can promote AF by inducing proarrhythmic metabolic and electrophysiologic (EP) changes in atrial cardiomyocytes. Methods and Results: Using standard patch clamp methods, we found significant changes in action potential properties of isolated mouse atrial cardiomyocytes exposed to IsoLGs (1μM, n=15 cells), including elevation of resting membrane potential, shortening of APD and reduction of V max . Acute IsoLG treatment led to a reduction of intracellular ATP production in atrial HL-1 cardiomyocytes, as measured by using a luminescence assay. Employing TMRM and Mitotracker Green staining for confocal and high-throughput screening (HTS) live-cell imaging assays, we also found that IsoLGs decreased mitochondrial membrane potential (compared to control, TMRM fluorescence decreased by 23%, 28%, 36% and 42%, respectively, when exposed to 0.01, 0.1, 0.5 and 1μM concentrations of IsoLG) accompanied by increased apoptosis (Cell Event Caspase-3/7 Green Detection Reagent) in a concentration-dependent manner, suggesting a prolonged mitochondrial transition pore opening. Moreover, cell metabolism assays performed using Agilent’s Seahorse XF96 extracellular flux analyzer revealed that IsoLGs exert a concentration dependent decrease in basal oxygen consumption rate and ATP production in HL-1 atrial cardiomyocytes. Conclusion: Together, these findings indicate that IsoLGs promote proarrhythmic EP and mitochondrial effects in atrial cells and thus may provide a novel therapeutic target for AF.

Neural and myogenic effects of cyclooxygenase products on canine bronchial smooth muscle

1995 ◽  
Vol 268 (1) ◽  
pp. L47-L55 ◽  
Author(s):  
A. P. Abela ◽  
E. E. Daniel
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Electrical Field Stimulation ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Ach Release ◽  
Concentration Dependent Manner ◽  
Excitatory Junction Potentials ◽  
Pg E2 ◽  
Large Contraction

In canine bronchi bathed in 10(-6) M indomethacin (IDM), prostaglandin (PG) E2 inhibited electrical field stimulation (EFS)- and acetylcholine (ACh)-mediated contractions and excitatory junction potentials (EJP) in a concentration-dependent manner without altering the resting membrane potential. EFS-induced EJPs were abolished at 10(-7) M PGE2, which shifted responses to ACh 10-fold rightward. Thus PGE2 predominantly inhibited the release of ACh and secondarily decreased smooth muscle response to ACh. U-46619, an analogue of thromboxane A2 (TxA2), initiated tetrodotoxin- and atropine-insensitive contractions in a concentration-dependent manner. U-46619 (10(-9) M) did not alter significantly EFS- or ACh-stimulated contractions and potentiated EFS amplitude of EJPs without depolarizing muscle cells. Either prejunctional activation of ACh release by TxA2 or postjunctional potentiation of the response to ACh can explain these findings. U-46619 (<or = 10(-8) M) depolarized the membrane potential, initiating oscillations accompanied by a large contraction. Addition of 10(-8) M nitrendipine, but not tetraethylammonium (25 mM), blocked the oscillations selectively. Other prostanoids (PGD2, PGI2, and PGF2 alpha) had no significant effects on canine bronchi. In the absence of IDM, PGE2 accumulated, EFS contractions decreased with time, and EJPs disappeared. We conclude that in canine bronchi PGE2 predominantly inhibits ACh release and endogenous PGE2 acts similarly, whereas TxA2 excites, probably at postjunctional sites.

Effects of ω-hydroxylase product on distal human pulmonary arteries

2008 ◽  
Vol 294 (3) ◽  
pp. H1435-H1443 ◽  
Author(s):  
Caroline Morin ◽  
Christelle Guibert ◽  
Marco Sirois ◽  
Vincent Echave ◽  
Marcio M. Gomes ◽  
...  
Keyword(s):  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Dependent Manner ◽  
Response Curves ◽  
Inhibitory Protein ◽  
Concentration Dependent Manner ◽  
Intracellular Process ◽  
Free Arachidonic Acid ◽  
Kinase Pathway

The aim of the present study was to provide a mechanistic insight into how 20-hydroxyeicosatetraenoic acid (20-HETE) relaxes distal human pulmonary arteries (HPAs). This compound is produced by ω-hydroxylase from free arachidonic acid. Tension measurements, performed on either fresh or 1 day-cultured pulmonary arteries, revealed that the contractile responses to 1 μM 5-hydroxytryptamine were largely relaxed by 20-HETE in a concentration-dependent manner (0.01–10 μM). Iberiotoxin pretreatments (10 nM) partially decreased 20-HETE-induced relaxations. However, 10 μM indomethacin and 3 μM SC-560 pretreatments significantly reduced the relaxations to 20-HETE in these tissues. The relaxing responses induced by the eicosanoid were likely related to a reduced Ca2+ sensitivity of the myofilaments since free Ca2+ concentration ([Ca2+])-response curves performed on β-escin-permeabilized cultured explants were shifted toward higher [Ca2+]. 20-HETE also abolished the tonic responses induced by phorbol-ester-dibutyrate (a PKC-sensitizing agent). Western blot analyses, using two specific primary antibodies against the PKC-potentiated inhibitory protein CPI-17 and its PKC-dependent phosphorylated isoform pCPI-17, confirmed that 20-HETE interferes with this intracellular process. We also investigated the effect of 20-HETE on the activation of Rho-kinase pathway-induced Ca2+ sensitivity. The data demonstrated that 20-HETE decreased U-46619-induced Ca2+ sensitivity on arteries. Hence, this observation was correlated with an increased staining of p116Rip, a RhoA-binding protein. Together, these results strongly suggest that the 20-hydroxyarachidonic acid derivative is a potent modulator of tone in HPAs in vitro.

Responsiveness to D-glucose in neurosecretory cells of crustaceans

1993 ◽  
Vol 70 (2) ◽  
pp. 758-764 ◽  
Author(s):  
E. Garcia ◽  
A. Benitez ◽  
C. G. Onetti
Keyword(s):  
Membrane Potential ◽  
Action Potentials ◽  
Electrophysiological Study ◽  
Reversal Potential ◽  
Neurosecretory Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Long Time ◽  
Glucose Sensitivity ◽  
Discharge Patterns

1. An electrophysiological study of the D-glucose sensitivity of X-organ (XO) neurosecretory cell bodies in crayfish was carried out with the use of microelectrodes, perforated, and cell-attached patch-clamp techniques. 2. Glucose depolarizes the membrane potential of XO cells in a concentration-dependent manner. 3. Depolarization produced by glucose initiates a change in the pattern of electrical activity. Silent cells began to discharge action potentials. When bursting cells are depolarized by glucose, their action potentials are no longer grouped in bursts or disappear entirely. 4. Although the membrane potential returns to its initial value after removing glucose from the bath, discharge patterns of the cells may remain different. This suggests that besides the depolarizing effect, once the cells have been exposed to glucose, the sugar switches on a process that is maintained for a long time. 5. Glucose produced a reduction of membrane steady-state conductance, and a shift of reversal potential of membrane currents to a more positive value. 6. Depolarization induced by D-glucose appears to be related with a closure of potassium channels. 7. Glucose effect was thought to be generated by a product of metabolism that would act as intracellular mediator.

Pharmacological properties of endothelin receptor subtypes mediating positive inotropic effects in rabbit heart

1994 ◽  
Vol 266 (6) ◽  
pp. H2220-H2228 ◽  
Author(s):  
H. Kasai ◽  
M. Takanashi ◽  
C. Takasaki ◽  
M. Endoh
Keyword(s):  
Partial Agonist ◽  
Ventricular Myocardium ◽  
Rabbit Heart ◽  
Maximal Response ◽  
Second Phase ◽  
Receptor Subtypes ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Inotropic Effects ◽  
Rabbit Ventricular Myocardium

The positive inotropic effect (PIE) of endothelin (ET) isoforms, ET-1 and ET-3, was similar in that 1) the PIE was associated with prolongation of isometric contractions, 2) the maximal response was approximately 60% of that to isoproterenol (Isomax), 3) the PIE was associated with acceleration of PI hydrolysis, and 4) it was selectively antagonized by phorbol 12,13-dibutyrate. Because the concentration-response curve for ET-1 was biphasic (whereas that for ET-3 was monophasic), ET-1 had a PIE greater than ET-3 up to 10(-8) M. ET-1 induced a PIE at 3 x 10(-14) M and higher, which reached a plateau of 10-20% of Isomax at 10(-12) M (first phase); the curve became steeper at 10(-9) M and higher (second phase), achieving the maximal response at 10(-7) M to 3 x 10(-7) M. An ETA-selective antagonist, BQ-123, did not affect the PIE of ET-1 up to 10(-7) M; it abolished the first phase at 10(-6) M but did not affect the second phase. BQ-123 at 10(-8) to 10(-6) M antagonized the PIE of ET-3, [Thr2]sarafotoxin S6b, and [Glu9]sarafotoxin S6b in a concentration-dependent manner. The PIE of ET-3 was abolished by 10(-6) M BQ-123. An ETB-selective partial agonist IRL-1620 neither elicited a PIE nor affected the PIE of ET-3. These findings indicate that the PIE of ET receptor agonists on rabbit ventricular myocardium cannot be totally explained by occupancy of the ETA or ETB receptor.

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