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Results for “Calcium Channels”

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PubMed1986

Effects of calcium channel blockers on urinary tract smooth muscle.

Influx of calcium from the extracellular medium seems to be important for spontaneous as well as agonist-induced contractile activity in urinary tract smooth muscle. To a various extent this calcium influx occurs through pathways which can be blocked by calcium channel blockers. These drugs effectively suppress spontaneous ureteral activity in vitro. Whether they affect ureteral motility in vivo or whether they can counteract ureteral spasm associated with ureteral stones have not been established. Calcium channel blockers partially block electrically as well as agonist-induced detrusor contractions. Some of these drugs abolish even atropine-resistant contractile responses induced by electrical stimulation in detrusor muscle. Drugs with combined antimuscarinic and calcium channel blocking effect therefore have an attractive effect profile. Experiences with calcium channel blockers in the treatment of patients with 'unstable bladder' are limited, but results obtained with terodiline seem promising. Even if calcium channel blockers reduce agonist-induced contraction in isolated urethral muscle, their clinical effect on urethral function seems to be small. The effects of calcium blockers on urinary tract smooth muscle may be clinically useful and deserve further study.

Animals↗

PubMed1994

Developmental and tissue-specific regulation of rabbit skeletal and cardiac muscle calcium channels involved in excitation-contraction coupling.

Two types of calcium channels signal excitation-contraction (E-C) coupling in striated muscle: dihydropyridine receptors (DHPRs, voltage-gated L-type calcium channels on the transverse tubule) and ryanodine receptors (RyRs, calcium release channels on the sarcoplasmic reticulum). Sarcolemmal depolarization activates the DHPR; subsequently, the RyR is activated and releases calcium that activates muscle contraction. We show in the present study that expression of the E-C coupling calcium channels is upregulated during myogenic development in the rabbit. Skeletal and cardiac muscle isoforms of the following genes were examined: the DHPR alpha 1, alpha 2, beta, and gamma subunits and the RyR. Distinct cardiac and skeletal muscle-specific cDNAs were isolated, encoding each of the DHPR subunits and the RyR. The skeletal muscle DHPR alpha 1, alpha 2, beta, and gamma subunits and the cardiac DHPR alpha 1 subunit mRNA levels increased on the day of birth and at the adult stage compared with fetal levels. The skeletal and cardiac RyR mRNA levels increased on the day of birth and at adult stages compared with fetal levels. Ryanodine binding sites increased in both skeletal and cardiac muscle. We now provide a molecular explanation for the physiological "maturation" of the E-C coupling apparatus observed at the day of birth and during early postnatal development in both skeletal and cardiac muscles. Low levels of calcium channel expression in fetal cardiac and skeletal muscle make these tissues more sensitive to pharmacological therapy with calcium channel blockers, a phenomenon that has been reported in human neonates.

Aging↗

PubMed1999

Calcium channels involved in synaptic transmission from reticulospinal axons in lamprey.

The pharmacology of calcium channels involved in glutamatergic synaptic transmission from reticulospinal axons in the lamprey spinal cord was analyzed with specific agonists and antagonists of different high-voltage activated calcium channels. The N-type calcium channel blocker omega-conotoxin GVIA (omega-CgTx) induced a large decrease of the amplitude of reticulospinal-evoked excitatory postsynaptic potentials (EPSPs). The P/Q-type calcium channel blocker omega-agatoxin IVA (omega-Aga) also reduced the amplitude of the reticulospinal EPSPs, but to a lesser extent than omega-CgTx. The dihydropyridine agonist Bay K and antagonist nimodipine had no effect on the amplitude of the reticulospinal EPSP. Combined application of omega-CgTx and omega-Aga strongly decreased the amplitude the EPSPs but was never able to completely block them, indicating that calcium channels insensitive to these toxins (R-type) are also involved in synaptic transmission from reticulospinal axons. We have previously shown that the group III metabotropic glutamate receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) mediates presynaptic inhibition at the reticulospinal synapse. To test if this presynaptic effect is mediated through inhibition of calcium influx, the effect of L-AP4 on reticulospinal transmission was tested before and after blockade of N-type channels, which contribute predominantly to transmitter release at this synapse. Blocking the N-type channels with omega-CgTx did not prevent inhibition of reticulospinal synaptic transmission by L-AP4. In addition, L-AP4 had no affect on the calcium current recorded in the somata of reticulospinal neurons or on the calcium component of action potentials in reticulospinal axons. These results show that synaptic transmission from reticulospinal axons in the lamprey is mediated by calcium influx through N-, P/Q- and R-type channels, with N-type channels playing the major role. Furthermore, presynaptic inhibition of reticulospinal transmission by L-AP4 appears not to be mediated through inhibition of presynaptic calcium channels.

Animals↗

PubMed1991

Dependency of hypoxic chemotransduction in cat carotid body on voltage-gated calcium channels.

The hypothesis that the entry of extracellular calcium ions into some compartment, quite possibly the type I cells, through voltage-gated calcium channels (VGCC) is essential for hypoxic chemotransduction in the cat carotid body was tested using an in situ perfusion technique. The neural output of the carotid body of anesthetized, paralyzed, and artificially ventilated cats in response to perfusions with Krebs-Ringer bicarbonate solution (KRB), calcium-free KRB, KRB containing calcium channel blockers, or KRB containing BAY K 8644 was recorded. Selective perfusion of the carotid body with hypoxic calcium-free KRB significantly decreased carotid chemoreceptor activity, suggesting that extracellular calcium is essential for hypoxic chemotransduction. Selective perfusion of the carotid body with hypoxic KRB containing verapamil (10-100 microM), diltiazem (10-100 microM), or nifedipine (10-100 microM) dose dependently attenuated the increase in chemoreceptor activity produced by hypoxia, suggesting that VGCC need to be activated for hypoxic chemotransduction. The carotid body response to hyperoxic KRB containing the calcium channel agonist BAY K 8644 (10 microM) was 267 +/- 87% of hyperoxic control KRB, suggesting that an enhanced influx of calcium ions through VGCC stimulates carotid chemoreceptor activity. Selective perfusion of the carotid body with severely hypoxic KRB containing BAY K 8644 did not increase chemoreceptor activity above that produced by severe hypoxia alone. This suggests that severe hypoxia increases intracellular calcium in some compartment of the carotid body to achieve stimulatory maximum response and that further increase in intracellular calcium does not produce further elevation of neural activity.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1998

Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation.

High voltage calcium channels are implicated in nociceptive transmission after nerve injury, capsaicin or formalin injection. The purpose of this study was to investigate the role of calcium channels in secondary heat hyperalgesia associated with acute joint inflammation. After induction of acute inflammation (knee joint injection of kaolin and carrageenan), decreased paw withdrawal latency (PWL) to radiant heat (i.e., secondary heat hyperalgesia), increased guarding of the limb and increased joint circumference occurs. Spinal administration (through a microdialysis fiber placed in dorsal horn) of an N-type calcium channel blocker (MVIIA, SNX 111, ziconotide, 0.001-0.1 mM), before induction of inflammation, prevents the decrease in PWL. Treatment with SNX 111 4 hr after inflammation reverses heat hyperalgesia. A small reduction in spontaneous pain-related behaviors (guarding of the limb) occurs after pre- or post-treatment with SNX 111. Spinal blockade of P/Q-type calcium channels (with omega-agatoxin IVA) had no effect on the decrease in PWL to radiant heat when administered after induction of inflammation. However, pre-treatment with omega-agatoxin IVA prevents secondary heat hyperalgesia. omega-Agatoxin IVA has no effect on spontaneous pain-related behaviors whether administered before or after induction of inflammation. In contrast, pre or post-treatment with nifedipine (L-type calcium channel blocker, 0.01-1.0 mM), had no effect on heat hyperalgesia or spontaneous pain-related behaviors induced by acute inflammation. There were no differences in joint circumference between groups with any treatment. Thus, N-type calcium channels contribute to both the development and maintenance of secondary heat hyperalgesia while P-type calcium channels are only involved during development of hyperalgesia.

Animals↗

PubMed1999

Role of N-type calcium channels in autonomic neurotransmission in guinea-pig isolated left atria.

1. Calcium entry via neuronal calcium channels is essential for the process of neurotransmission. We investigated the calcium channel subtypes involved in the operation of cardiac autonomic neurotransmission by examining the effects of selective calcium channel blockers on the inotropic responses to electrical field stimulation (EFS) of driven (4 Hz) guinea-pig isolated left atria. In this tissue, a previous report (Hong & Chang, 1995) found no evidence for N-type channels involved in the vagal negative inotropic response and only weak involvement in sympathetic responses. 2. The effects of cumulative concentrations of the selective N-type calcium channel blocker, omega-conotoxin GVIA (GVIA; 0.1-10 nM) and the non-selective N-, P/Q-type calcium channel blocker, omega-conotoxin MVIIC (MVIIC; 0.01-10 nM) were examined on the positive (with atropine, 1 microM present) and negative (with propranolol, 1 microM and clonidine, 1 microM present) inotropic responses to EFS (eight trains, each train four pulses per punctate stimulus). 3. GVIA caused complete inhibition of both cardiac vagal and sympathetic inotropic responses to EFS. GVIA was equipotent at inhibiting positive (pIC50 9.29+/-0.08) and negative (pIC50 9.13+/-0.17) inotropic responses. MVIIC also mediated complete inhibition of inotropic responses to EFS and was 160 and 85 fold less potent than GVIA at inhibiting positive (pIC50 7.08+/-0.10) and negative (pIC50 7.20+/-0.14) inotropic responses, respectively. MVIIC was also equipotent at inhibiting both sympathetic and vagal responses. 4. Our data demonstrates that N-type calcium channels account for all the calcium current required for cardiac autonomic neurotransmission in the guinea-pig isolated left atrium.

Animals↗

PubMed1991

Nicotine-induced release of noradrenaline and neuropeptide Y in guinea-pig heart: role of calcium channels and protein kinase C.

The role of calcium, calcium influx through calcium channels, and activation of protein kinase C for the nicotine-induced release of noradrenaline and of the sympathetic co-transmitter neuropeptide Y (NPY) was investigated in the guinea-pig isolated perfused heart. In the coronary venous overflow noradrenaline and NPY were determined by high-pressure liquid chromatography and radioimmunoassay, respectively. In the presence of extracellular calcium (1.85 mmol/l) nicotine (1-100 mumol/l) evoked a concentration-dependent overflow of both transmitters with a molar ratio of approximately 1500 (noradrenaline):1 (NPY). The nicotine-induced (100 mumol/l) overflow of noradrenaline and NPY was in a linear manner related (r = 0.79 and 0.90, respectively; p less than 0.05) to the extracellular calcium concentration (0-1.85 mmol/l), and it was prevented by calcium-free perfusion. The L-type calcium channel blocker felodipine (100 nmol/l) did not affect the nicotine-induced (100 mumol/l) transmitter overflow. On the other hand, the neuronal (N-type) calcium channel blockers omega-conotoxin (100 nmol/l) and cadmium chloride (50 mumol/l) reduced the nicotine-induced (100 mumol/l) transmitter overflow to 20% of the control value, suggesting a role of N-type calcium channels in mediating the calcium influx for the nicotine-induced transmitter release. The nicotine-induced (30 mumol/l) overflow of both transmitters was two- to three-fold increased by activation of protein kinase C (phorbol 12-myristate 13-acetate; 100 nmol/l). The transmitter overflow was unaffected by 4 alpha-phorbol 12,13-didecanoate (100 nmol/l), a phorbol ester which does not stimulate protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Effects of calcium channel blocking agents on membrane microviscosity and calcium in the liver of the carbon tetrachloride treated rat.

Membrane microviscosity was determined from the polarized fluorescence of diphenylhexatriene in plasma membranes and microsomes prepared from the liver of carbon tetrachloride treated rats. It was greatly depressed between 12 and 24 hr after the administration of the carbon tetrachloride. Depression of microviscosity was also seen in the liposomes which were prepared from these membranes. There were decreases in phospholipid content and phospholipid methyltransferase activity, but these changes did not appear to explain the decreased microviscosity. A large accumulation of calcium occurred in the liver cells between 12 and 24 hr after the administration of carbon tetrachloride. Chlorpromazine, verapamil and nifedipine, when administered prior to the carbon tetrachloride, partially reduced the later accumulation of calcium and reduced the degree of histological damage observed. When these agents were administered 12 hr after the administration of carbon tetrachloride, they did not reduce the subsequent accumulation of calcium. When administered prior to and 7 hr after carbon tetrachloride, they had a small but potentially significant effect on the microviscosity change. It is suggested that at low levels of microviscosity a critical threshold may exist below which entry of calcium into the cell is poorly controlled and that calcium channel blocking agents may be ineffective if administered at a time when membrane microviscosity is very low. Tissue calcium accumulation was associated with visible cell damage.

Animals↗

PubMed1997

Relative contributions of G protein, channel, and receptor to voltage-dependent inhibition of neuronal N-type and P/Q-type calcium channels in HEK 293 cell lines.

The voltage-dependent modulation of neuronal voltage-gated calcium channels by heterotrimeric G protein-coupled receptors potentially provides a means for activity-dependent modulation of synaptic efficacy. Recent attention has focused upon the molecular mechanisms by which such G proteins influence the biophysical properties of calcium channels. We have used an HEK 293-based heterologous system which stably expresses human neuronal calcium channels to address the relative contributions of receptor, G protein, and channel to voltage-dependent inhibition. We find that the receptor and channel subtype only insignificantly influence the time it takes to re-establish modulation following voltage-dependent relief of inhibition. In contrast, the G protein subtype mediating inhibition appears to play a significant part in this process. These results emphasize the importance of G protein subtype in the modulation of neuronal calcium channels.

Calcium Channels↗

PubMed1994

Mercury (Hg2+) and zinc (Zn2+): two divalent cations with different actions on voltage-activated calcium channel currents.

1. We examined the actions of mercury (Hg2+) and zinc (Zn2+) on voltage-activated calcium channel currents of cultured rat dorsal root ganglion (DRG) neurons, using the whole-cell patch clamp technique. 2. Micromolar concentrations of both cations reduced voltage-activated calcium channel currents. Calcium channel currents elicited by voltage jumps from a holding potential of -80 to 0 mV (mainly L- and N-currents) were reduced by Hg2+ and Zn2+. The threshold concentration for Hg2+ effects was 0.1 microM and that for Zn2+ was 10 microM. Voltage-activated calcium channel currents were abolished (> 80%) with 5 microM Hg2+ or 200 microM Zn2+. The peak calcium current was reduced to 50% (IC50) by 1.1 microM Hg2+ or 69 microM Zn2+. While Zn2+ was much more effective in reducing the T-type calcium channel current--activated by jumping from -80 to -35 mV--Hg2+ showed some increased effectiveness in reducing this current. 3. The effects of both cations occurred rapidly and a steady state was reached within 1-3 min. While the action of Zn2+ was not dependent on an open channel state, Hg2+ effects depended partially on channel activation. 4. While both metal cations reduced the calcium channel currents over the whole voltage range, some charge screening effects were detected with Hg2+ and with higher concentrations (> 100 microM) of Zn2+. 5. As Zn2+ in the concentration range used had no influence on resting membrane currents, Hg2+ caused a clear inward current at concentrations > or 2 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

Mammalian voltage-gated calcium channels are potently blocked by the pyrethroid insecticide allethrin.

Pyrethroids are commonly used insecticides for both household and agricultural applications. It is generally reported that voltage-gated sodium channels are the primary target for toxicity of these chemicals to humans. The phylogenetic and structural relatedness between sodium channels and voltage-gated calcium (Ca) channels prompted us to examine the effects of the type 1 pyrethroid allethrin on the three major classes of mammalian calcium channels exogenously expressed in human embryonic kidney 293 cells. We report that all classes of mammalian calcium channels are targets for allethrin at concentrations very similar to those reported for interaction with sodium channels. Allethrin caused blockade with IC(50) values of 7.0 microM for T-type alpha(1G) (Ca(v)3.1), 6.8 microM for L-type alpha(1C) (Ca(v)1.2), and 6.7 microM for P/Q-type alpha(1A) (Ca(v)2.1) channels. Mechanistically, the blockade of calcium channels was found to be significantly different than the prolonged opening of mammalian sodium channels caused by pyrethroids. In all calcium channel subtypes tested, allethrin caused a significant acceleration of the inactivation kinetics and a hyperpolarizing shift in the voltage dependence of inactivation. The high-voltage-activated P/Q- and L-type channels showed a frequency of stimulation-dependent increase in block by allethrin, whereas the low-voltage-activated alpha(1G) subtype did not. Allethrin did not significantly modify the deactivation kinetics or current-voltage relationships of any of the calcium channel types. Our study indicates that calcium channels are another primary target for allethrin and suggests that blockade of different types of calcium channels may underlie some of the chronic effects of low-level pyrethroid poisoning.

Allethrins↗

PubMed1992

Modulation of dihydropyridine-sensitive gastric mucosal calcium channels by GM1-ganglioside.

1. A dihydropyridine-sensitive calcium channel complex was solubilized from gastric mucosal cell membranes and purified by affinity chromatography on wheat germ agglutinin. 2. The calcium channel complex labeled with [3H]PN200-110, when reconstituted into phosphatidylcholine vesicles, exhibited active 45Ca2+ uptake into intravesicular space as evidenced by La3+ displacement and osmolarity studies. The channel complex responded in a dose-dependent manner to dihydropyridine calcium antagonist, PN200-110, which at 0.5 microM exerted maximal inhibitory effect of 66% in 45Ca2+ uptake. 3. The uptake of 45Ca2+ into vesicle-reconstituted gastric mucosal calcium channel complex was inhibited by GM1-ganglioside. Maximum inhibitory effect was achieved at 10-15 nM GM1, at which point a 74% decrease in 45Ca2+ uptake occurred. Furthermore, GM1 also inhibited dihydropyridine binding to gastric mucosal membranes, indicating the extracellular orientation of calcium channel domains for GM1. 4. The ability of GM1 to modulate the intracellular calcium levels may be an important feature in gastric mucosal protection by this ganglioside.

Animals↗

PubMed1998

Proliferation of human peripheral blood mononuclear cells during calcium channel blockade.

To evaluate the role of intracellular calcium and particularly Ca2+ uptake in the initiation of lymphocyte mitogenesis, the effect of mibefradil--which blocks both L- and T-type calcium channels with a more selective blockade of T-type channels--on the proliferation of human peripheral blood mononuclear cells (PBMC) is compared with the effect of nifedipine, which blocks only the L-type calcium channel. The rate of 3H-thymidine, 3H-uridine, and 3H-leucine incorporation into control and concanavalin A-stimulated PBMC in the presence or absence of the calcium channel blockers mibefradil or nifedipine (1, 10, or 50 micromol/L), and of the intracellular calcium antagonist TMB-8 or the calmodulin antagonist W-7 (1, 10, 25, or 50 micromol/L) was assayed in cells cultured for 3 days. The cellular cytotoxicity and the cell number in growing cultures was also determined in mibefradil- or nifedipine-treated control or stimulated cells. Mibefradil and nifedipine reduced the cell number and the 3H-thymidine, 3H-uridine, or 3H-leucine incorporation or the de novo DNA, RNA, or protein synthesis in control and concanavalin A-stimulated human PBMC in a concentration-dependent manner. Mibefradil exhibited a more pronounced inhibition than nifedipine. The inhibitory effect of mibefradil or nifedipine on DNA synthesis was dependent upon the timing of treatment with the drugs. The inhibitory effect of mibefradil or nifedipine on the lymphoproliferative response was nearly abolished if the drugs were added 20 h after cell stimulation. A markedly reduced inhibitory effect was found when mibefradil or nifedipine were added 1 to 7 h after cell stimulation. However, regardless of time of addition, TMB-8 and W-7 caused a persistent inhibition of the proliferation of human PBMC. Our data show that mibefradil had a more pronounced inhibitory effect on the proliferation of human PBMC than nifedipine and that this inhibitory effect on de novo DNA synthesis was dependent upon the timing of treatment with both drugs. Mibefradil and nifedipine also reduce RNA and protein synthesis in human PBMC. Therefore, administration of these calcium channel blockers to inhibit cellular proliferation might be most beneficial at anatomic sites where cellular proliferation is not already an active process, while being ineffective in the presence of ongoing active proliferation, as suggested by some prospective studies.

Adult↗

PubMed1995

Norepinephrine modulates high voltage-activated calcium channels in freshly dissociated rat nucleus tractus solitarii neurons.

The effects of norepinephrine on the low- and high-voltage-activated calcium channels in the neurons acutely dissociated from the nucleus tractus solitarius of 2- to 3-week-old rats were investigated in the nystatin perforated patch recording configuration under voltage-clamp conditions. The norepinephrine had no effect on the low voltage-activated calcium channel but inhibited the high voltage-activated calcium channel in a concentration-, time- and voltage-dependent manner. The norepinephrine slowed the activation phase of the high voltage-activated calcium channel current and the maximum inhibition was 30% of the total current amplitude measured 10 ms after the current activation. The inhibitory effect was eliminated by applying larger depolarizing prepulses. The pretreatment with pertussis toxin completely blocked the norepinephrine effect on high-voltage activated calcium channels, suggesting the contribution of pertussis toxin-sensitive Gi/Go-proteins to the norepinephrine-induced inhibition. Yohimbine but not prazosin nor propranolol antagonized the norepinephrine-induced inhibition, suggesting the involvement of alpha 2-adrenoceptor in norepinephrine-induced inhibition of the high voltage-activated calcium channels. omega-Conotoxin-GVIA, omega-agatoxin-IVA, nicardipine and omega-conotoxin-MVIIC blocked the high voltage-activated calcium channel current by 26, 9, 36 and 11% of the total current respectively, suggesting the existence of N-, P-, L- and Q-type calcium channels in the nucleus tractus solitarii neurons. The current being insensitive to these calcium channel antagonists, termed R-type calcium channel current, also existed. This residual R-type calcium channel was completely blocked by adding 200 microM CD2+. The norepinephrine significantly inhibited N- and P-type calcium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Further thoughts on mast cells, calcium channels and histamine release.

Calcium movements across membranes of mast cells represent a major target for effective anti-allergic drugs, as these are essential events linking stimulation to secretion. Using isolated peritoneal mast cells from two types of genetically different rats and a blocker of the entry of calcium ions into cells, histamine release induced by antigen, calcium ionophore and potassium (in a lowered calcium medium) has been followed. Lower concentrations of the calcium entry blocker were required to inhibit potassium-induced release than those needed for release induced by allergic and other non-allergic stimuli, suggesting that different specialised calcium channels are involved in histamine release from rat mast cells.

Animals↗

PubMed1997

G-protein regulation of an L-type calcium channel current in canine jejunal circular smooth muscle.

Calcium entry into smooth muscle cells is essential to maintain contractility. In canine jejunal circular smooth muscle cells the predominant calcium entry pathway is through L-type calcium channels. The aim of this study was to determine the G-protein regulation of L-type calcium channel current (ICaL) in isolated canine jejunal circular smooth muscle cells. Barium (80 mM) was used as the charge carrier. GTP-gamma S and GTP increased maximal inward current from 118.7 +/- 12 pA to 227.5 +/- 21.5 pA (n = 8) and 174.6 +/- 10.1 pA (n = 6) respectively. The increase in inward current was blocked by nifedipine suggesting it was through L-type calcium channels. Pertussis toxin did not alter baseline ICaL while cholera toxin increased ICaL from 125 +/- 19 pA in controls (n = 6) to 347 +/- 30 pA (n = 4). Staurosporine inhibited the increase in current evoked by GTP-gamma S and calyculin further increased ICaL over the increase evoked by GTP-gamma S. The results suggest that cholera toxin sensitive G-proteins activate L-type calcium channels in isolated canine jejunal circular smooth muscle cells through protein phosphorylation.

Animals↗

PubMed1995

Effect of platelet-derived growth factor on voltage-operated calcium channels in rabbit isolated ear artery cells.

1. Platelet derived growth factor (PDGF), AB and BB isoforms (100 pM) increased calcium channel currents measured by whole cell voltage clamp technique in single vascular smooth muscle cells isolated from rabbit ear arteries. 2. Tyrphostin-23 (100 microM) a selective inhibitor of protein tyrosine kinases, reduced calcium channel currents. Pre-incubation with tyrphostin-23 prevented PDGF-AB induced increase in calcium channel currents. However, in these same cells 10 nM (+)-202791, a dihydropyridine calcium channel agonist, did increase calcium channel currents. 3. Bistyrphostin (10 microM), a selective inhibitor of epidermal growth factor (EGF)-kinase also reduced calcium channel currents and inhibited PDGF-AB-induced increases in calcium channel currents. 4. Genistein (100 microM) a selective inhibitor of tyrosine kinases, structurally unrelated to the tryphostins, also inhibited calcium channel currents and pre-incubation with genistein prevented the PDGF-AB-induced rise in calcium channel currents. 5. These results indicate that PDGF increases calcium channel currents in vascular smooth muscle. This action of PDGF probably involves a tyrosine kinase.

Analysis of Variance↗

PubMed2001

Contraction of human colonic circular smooth muscle cells is inhibited by the calcium channel blocker pinaverium bromide.

UNLABELLED: The effects of L-type calcium channel blockers (CCBs) selective for the gastrointestinal tract (pinaverium) or non-selective (nicardipine and diltiazem), were investigated on CCK-, CCh- or KCl-induced contraction of smooth muscle cells (SMC) isolated from the circular muscle layer of normal or of inflamed human colons. In the normal tissue colon, whatever the contractile agent used, CCK-8 (1nM), CCh (1nM) or KCl (20mM), a micromolar concentration of pinaverium significantly inhibited contraction (88.36%, 93.10%, 93.92% inhibition respectively); this effect was concentration-dependent for CCh (IC50 = 0.73 +/- 0.08nM) and for CCK (IC50 = 0.92 +/- 0.12nM). In parallel, both nicardipine and diltiazem inhibit significantly contraction of isolated SMC. In inflamed colons, pinaverium (1 microM) display a significant higher efficacy than diltiazem or nicardipine to reduce cell contraction induced by CCK-8 or by KCl. In addition, RT-PCR experiments were performed to evidence tissue specificity of the L-type calcium channel. They revealed the expression of the messenger of the a-1 subunit L-type calcium channel (binding site of such CCBs), consistent with the expression of the rbC-2 splice variant of the alpha1-C gene. IN CONCLUSION: (i) the inhibition by calcium channel blockers of agonist-induced contractile activity suggest a modulation of SMC contraction upon extracellular calcium via 'L-type' voltage-dependent calcium channel; (ii) this study provides a rationale for the clinical use of pinaverium in colonic motor disoders affecting the contractility of SMC, since it appeared to decrease the contraction even in pathological situation; and (iii) RT-PCR experiments confirms the presence in human colon SMC of the alpha-1 subunit mRNA of calcium channel.

Adult↗