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 Spasmolytic Action of the Methanol Extract and Isojuripidine from Solanum asterophorum Mart. (Solanaceae) Leaves in Guinea-Pig Ileum

2006 ◽  
Vol 61 (11-12) ◽  
pp. 799-805 ◽  
Author(s):  
Rita de Cassia Meneses Oliveira ◽  
Julianeli T. Lima ◽  
Luciano A. A. Ribeiro ◽  
Joelmir L. V. Silva ◽  
Fabio S. Monteiro ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Methanol Extract ◽  
Calcium Influx ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Guinea Pig Ileum ◽  
Response Curves ◽  
Concentration Dependent Manner ◽  
Control Curve ◽  
Spasmolytic Action

Abstract Solanum asterophorum Mart. (Solanaceae) is a shrub popularly known as “jurubeba-defogo” in the northeast of Brazil. In the present work, the methanol extract (SA-MeOH, 3-750 μg/mL) and isojuripidine (10-7 - 3 x 10-4 ᴍ), a steroidal alkaloid obtained from S. asterophorum Mart. leaves, inhibited phasic contractions induced by both 1 μᴍ histamine [IC50 = (225.8 ± 47.4) μg/mL and (3.5 ± 0.8) x 10-5 ᴍ] or 1μᴍ acetylcholine [IC50 = (112.5 ± 20.6) μg/mL and (2.3 ± 0.4) \ 10-5 ᴍ] in guinea-pig ileum, respectively. The extract and isojuripidine also relaxed the ileum (SA-MeOH, 1-750 μg/mL, and isojuripidine, 10-9 - 3 x 10-4 ᴍ) pre-contracted with 1 μᴍ histamine [EC50 = (101.1 ± 17.4) μg/mL and (1.2 ± 0.3) x 10-6 ᴍ] or 1 μm acetylcholine [EC50 = (136.8 ± 21.1) μg/mL and (1.9 ± 0.4) x 10-6 ᴍ] or 40 mᴍ KCl [EC50 = (149.4 d 19.5) μg/mL and (1.8 ± 0.7) x 10-6 ᴍ], respectively, in an equipotent and concentration-dependent manner. This effect is probably due to inhibition of calcium influx through voltage-operated calcium (Cav) channels. To confirm this hypothesis, we evaluated their effect on cumulative CaCl2 curves in depolarizing medium nominally without Ca2+. SA-MeOH (27, 243, 500, and 750 μg/mL) and isojuripidine (3 x 10-8, 10-6, 3 x 10-5, and 3 x 10-4 m) inhibited the contractions induced by CaCl2, in a concentrationdependent manner. The concentration-response curves to CaCl2, in the presence of SAMeOH and isojuripidine, were shifted downward in relation to a control curve in a nonparallel manner resulting in reduction of the maximum effect [Emax = (71.2 ± 9.2); (57.4 ± 9.2); (43.8 ± 3.4); (41.5 ± 2.4) and (90.6 ± 4.8); (74.7 ± 8.7); (66.4 ± 3.9); (31.3 ± 4.1)%, respectively]. SA-MeOH and isojuripidine present spasmolytic action in guinea-pig ileum due to a partially blockade of calcium influx through Cav channels.

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.

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>

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.

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.

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.

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.

Effects of estrogen on cerebral blood flow and pial microvasculature in rabbits

2000 ◽  
Vol 279 (3) ◽  
pp. H1208-H1214 ◽  
Author(s):  
M. T. Littleton-Kearney ◽  
D. M. Agnew ◽  
R. J. Traystman ◽  
P. D. Hurn
Keyword(s):  
Blood Flow ◽  
Estrogen Receptor ◽  
Cerebral Blood Flow ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Dependent Manner ◽  
Pial Arteries ◽  
Concentration Dependent Manner ◽  
Cranial Window ◽  
Pial Arterioles

We tested the hypothesis that intracarotid estrogen infusion increases cerebral blood flow (CBF) in a concentration-dependent manner and direct application of estrogen on pial arterioles yields estrogen receptor-mediated vasodilation. Rabbits of both genders were infused with estrogen via a branch of the carotid artery. Estrogen doses of 20 or 0.05 μg · ml−1 · min−1 were used to achieve supraphysiological or physiological plasma estrogen levels, respectively. CBF and cerebral vascular resistance were determined at baseline, during the infusion, and 60-min postinfusion, and effects on pial diameter were assessed via a cranial window. Pial arteriolar response to estrogen alone and to estrogen after administration of tamoxifen (10−7), an antiestrogen drug that binds to both known estrogen receptor subtypes, was tested. No gender differences were observed; therefore, data were combined for both males and females. Systemic estrogen infusion did not increase regional CBF. Estradiol dilated pial arteries only at concentrations ranging from 10−4–10−7 M ( P ≤ 0.05). Pretreatment with tamoxifen alone had no effect on arteriolar diameter but inhibited estrogen-induced vasodilation ( P < 0.001). Our data suggest that estrogen does not increase CBF under steady-state conditions in rabbits. In the pial circulation, topically applied estradiol at micromolar concentrations dilates vessels. The onset is rapid and dependent on estrogen receptor activation.

Vasodilation induced by substance P in guinea pig carotid arteries

1994 ◽  
Vol 266 (3) ◽  
pp. H1132-H1137
Author(s):  
G. Zhang ◽  
Y. Yamamoto ◽  
K. Miwa ◽  
H. Suzuki
Keyword(s):  
Substance P ◽  
Guinea Pig ◽  
Carotid Arteries ◽  
Smooth Muscles ◽  
Peak Amplitude ◽  
Resting Potential ◽  
Dependent Manner ◽  
Similar Form ◽  
Concentration Dependent Manner ◽  
High K

In the guinea pig carotid artery with an intact endothelium, substance P (SP, 10(-10)-10(-7) M) relaxed the norepinephrine- (NE) contracted smooth muscles transiently, in a concentration-dependent manner. Acetylcholine (ACh, 10(-6) M) produced a sustained relaxation. SP and ACh also relaxed muscles contracted with high-K (29.6 mM) solution, with a similar form but with a reduced amplitude compared with findings in NE-contracted muscles. In the presence of nitroarginine (10(-5) M) and NE, the ACh-induced relaxation was transient, with a reduced amplitude, whereas the SP-induced relaxation was not significantly changed. In muscles contracted with high-K solution containing nitroarginine, neither SP nor ACh produced relaxation. SP (> 10(-11) M) transiently hyperpolarized the membrane, but only when this peptide was applied from the intimal side of the intact vessel, and the peak amplitude reached approximately 20 mV from the resting potential at 10(-8) M. ACh transiently hyperpolarized the membrane (the peak amplitude being approximately 10 mV), in both the adventitial and intimal applications. In high-K solution, neither SP nor ACh produced hyperpolarization. The amplitude of hyperpolarizations produced by SP did not significantly change in the presence of nitroarginine, oxyhemoglobin, or indomethacin. Thus, SP-induced relaxation seems to be produced mainly by endothelium-derived hyperpolarizing factor-induced hyperpolarization.

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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