Isradipine prevents the development of spontaneously occurring cardiac necrosis in cardiomyopathic hamster

2003 ◽  
Vol 81 (2) ◽  
pp. 120-124 ◽  
Author(s):  
Danielle Jacques ◽  
Ghassan Bkaily ◽  
Gaétan Jasmin ◽  
Pedro D'Orléans-Juste ◽  
Mirna Chahine
Keyword(s):  
Channel Blocker ◽  
Hereditary Disease ◽  
Channel Blockers ◽  
Paraffin Sections ◽  
Hereditary Cardiomyopathy ◽  
Intracellular Ca ◽  
First Time ◽  
Hamster Cardiomyopathy ◽  
Cardiac Necrosis

Recent studies on the heart necrotizing process at the early stages of hamster polymyopathy have led us to believe that this hereditary disease derives from an anomalous transmembrane ion flux due to the presence of slow Na+ channels that contribute to intracellular Na+ accumulation which promote intracellular Ca2+ overload via the Ca2+ influx through the Na+–Ca2+ exchanger. In the present study, we investigated the potential beneficial effect of chronic treatment with a dual L-type Ca2+ and slow Na+ channel blockers isradipine, on the development of necrosis in myopathic hamster hearts. Young cardiomyopathic (CM) hamsters (CMH) were treated with isradipine (0.1 mg·kg–1·day–1) and nifedipine (1 mg·kg–1·day–1) for 4 consecutive weeks. Microscopic assessments were carried out in staged serial paraffin sections of heart ventricles from tissues freshly dissected at autopsy. In comparison with control nontreated hearts, which exhibited numerous necrotic calcific foci, myolytic lesions, and dilated right ventricle, isradipine treatment prevented, in a significant manner, all the above spontaneous pathological changes, while nifedipine had no effect. Our present observations provide evidence for the first time that in vivo treatment with a DHP Ca+ channel blocker, isradipine, is cardioprotective against the development of necrosis in hereditary cardiomyopathy in the hamster. It is possible that the protective effect of isradipine in CMH could be largely due to the indirect blockade of Ca2+ influx through the Na+–Ca2+ exchanger as well as to possible direct blockade of Ca2+ influx through the T-type Ca2+ channel.Key words: isradipine, cardioprotection, hamster cardiomyopathy, slow Na+ channel.

Evidence that signal transduction for osmoreception is mediated by stretch-activated ion channels in tilapia

2003 ◽  
Vol 284 (5) ◽  
pp. C1290-C1296 ◽  
Author(s):  
A. P. Seale ◽  
N. H. Richman ◽  
T. Hirano ◽  
I. Cooke ◽  
E. G. Grau
Keyword(s):  
Ion Channels ◽  
Channel Blocker ◽  
Oreochromis Mossambicus ◽  
Cell Swelling ◽  
Simultaneous Measurements ◽  
Perfusion Chamber ◽  
Intracellular Ca ◽  
Stretch Activated Ion Channels

Prolactin (PRL) plays a central role in the freshwater osmoregulation of teleost fish, including the tilapia ( Oreochromis mossambicus). Consistent with this action, PRL release from the tilapia pituitary increases as extracellular osmolality is reduced both in vitro and in vivo. Dispersed tilapia PRL cells were incubated in a perfusion chamber that allowed simultaneous measurements of cell volume and PRL release. Intracellular Ca2+ concentrations were measured from fura 2-loaded PRL cells treated in a similar way. Gadolinium (Gd3+), known to block stretch-activated cation channels, inhibited hyposmotically induced PRL release in a dose-related manner without preventing cell swelling. Nifedipine, an L-type Ca2+ channel blocker, did not prevent the increase in PRL release during hyposmotic stimulation. A high, depolarizing concentration of KCl induced a transient and marked increase of intracellular Ca2+ and release of PRL but did not prevent the rise in intracellular Ca2+ and PRL release evoked by exposure to hyposmotic medium. These findings suggest that a decrease in extracellular osmolality stimulates PRL release through the opening of stretch-activated ion channels, which allow extracellular Ca2+ to enter the cell when it swells.

Na+-K+-ATPase inhibitors and renin release: relationship to calcium

1984 ◽  
Vol 247 (4) ◽  
pp. F650-F655 ◽  
Author(s):  
M. Cruz-Soto ◽  
J. E. Benabe ◽  
J. M. Lopez-Novoa ◽  
M. Martinez-Maldonado
Keyword(s):  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Cardiac Glycosides ◽  
Channel Blocker ◽  
Renin Secretion ◽  
Sodium Reabsorption ◽  
Channel Blockers ◽  
Atpase Inhibitor ◽  
Renal Vasoconstriction

The inhibition of renin secretion and the vasoconstrictive action of cardiac glycosides may be attributed to increases in cytosolic calcium as a result of inhibition of Na+-K+-ATPase. These studies examined in the dog in vivo the role of calcium on the renal actions of ouabain as assessed from the modifying effects of calcium channel blockers. Since vanadate, another Na+-K+-ATPase, inhibitor, enhances in vitro the binding of ouabain to Na+-K+-ATPase, we examined the capacity of vanadate to modify the renal effects of ouabain in vivo. Infusion of ouabain (1 microgram X kg-1 X min-1) into the renal artery decreased RBF, GFR, and renin secretion, and produced diuresis and natriuresis. When ouabain was infused in dogs receiving the calcium channel blocker verapamil (100 microgram/min), it failed to suppress renin secretion or cause renal vasoconstriction. In addition, verapamil produced diuresis and natriuresis, which were greatly enhanced by ouabain (e.g., verapamil FENa 12.0 +/- 1.1----34.2 +/- 5.1%). The data strongly suggest that calcium entry into cells is a major mediator of the renin inhibitory effect and of the renal vasoconstriction induced by cardiac glycosides. The natriuresis observed during the calcium channel blocker infusion suggests that this drug may have a direct tubular effect on sodium reabsorption. Superimposition of vanadate (0.5 mumol/min) on ouabain infusion led to massive natriuresis (FENa, 5 +/- 1----35 +/- 4%), renal vasodilation (RBF 90 +/- 12----170 +/- 15 ml/min), and an increase in renin secretion (delta, 100%).(ABSTRACT TRUNCATED AT 250 WORDS)

Isoflurane-induced Dilation of Porcine Coronary Microvessels Is Endothelium Dependent and Inhibited by Glibenclamide

2002 ◽  
Vol 96 (6) ◽  
pp. 1465-1471 ◽  
Author(s):  
A. Kurt Gamperl ◽  
Travis W. Hein ◽  
Lih Kuo ◽  
Brian A. Cason
Keyword(s):  
Potassium Channel ◽  
Sodium Nitroprusside ◽  
Adenosine Triphosphate ◽  
Channel Blocker ◽  
Minimum Alveolar Concentration ◽  
Channel Blockers ◽  
Dependent Manner ◽  
Presence And Absence ◽  
Dose Dependent

Background Isoflurane has been reported to cause dose-dependent constriction in isolated coronary microvessels. However, these results are inconsistent with data from in situ and in vivo heart preparations which show that isoflurane dilates the coronary vasculature. To clarify the direct effects of isoflurane on coronary tone, we measured the response of isolated porcine resistance arterioles (ID, 75 +/- 4.0 microm; range, 41-108 microm) to isoflurane in the presence and absence of adenosine triphosphate-sensitive and Ca2+-activated potassium channel blockers and also after endothelial removal. Methods Subepicardial arterioles were isolated, cannulated, and pressurized to 45 mmHg without flow in a 37 degrees C vessel chamber filled with MOPS buffer (pH = 7.4). After all vessels developed spontaneous (intrinsic) tone, dose-dependent (0.17-0.84 mm; approximately 0.5-2.5 minimum alveolar concentration) isoflurane-mediated effects on vessel ID were studied in the presence and absence of extraluminal glibenclamide (1 microm; an adenosine triphosphate-sensitive channel blocker) or iberiotoxin (100 nm; a Ca2+-activated potassium channel blocker) or before and after endothelial denudation using the nonionic detergent CHAPS (0.4%). Vessel ID was measured using an inverted microscope and videomicrometer, and vasomotor responses were analyzed by normalizing changes in arteriole ID to the dilation observed after exposure to 10-4 m sodium nitroprusside, which causes maximal dilation. Results Isoflurane caused dose-dependent dilation of all coronary arterioles. This vasodilation was 6.0 +/- 0.7 microm at an isoflurane concentration of 0.16 mm (approximately 0.5 minimum alveolar concentration) and 25.3 +/- 2.1 microm at 0.75 mm (approximately 2.5 minimum alveolar concentration). These values represent 18.1 +/- 1.7% and 74.1 +/- 3.3%, respectively, of that observed with 10-4 sodium nitroprusside (34 +/- 3 microm). Glibenclamide, but not iberiotoxin, exposure affected arteriolar dilation in response to isoflurane. Glibenclamide caused a downward displacement of the isoflurane dose-response curve, reducing isoflurane-mediated dilation by an average of 36%. Denuded arterioles showed a marked (approximately 70%) reduction in their ability to dilate in response to isoflurane. Conclusions The authors conclude that isoflurane dilates coronary resistance arterioles in a dose-dependent manner, and that this dilation is partially mediated by adenosine triphosphate-sensitive channels and is highly dependent on the presence of a functioning endothelium.

Vanilloid Receptor Agonists Potentiate the In Vivo Local Anesthetic Activity of Percutaneously Injected Site 1 Sodium Channel Blockers 

1999 ◽  
Vol 90 (2) ◽  
pp. 524-534 ◽  
Author(s):  
Daniel S. Kohane ◽  
Yu Kuang ◽  
Nu T. Lu ◽  
Robert Langer ◽  
Gary R. Strichartz ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Channel Blocker ◽  
Synergistic Effects ◽  
Small Diameter ◽  
Channel Blockers ◽  
Sodium Channel Blocker ◽  
Sodium Channel Blockers ◽  
Nerve Blockade ◽  
Motor Strength

Background Capsaicin, the pungent ingredient in chili peppers, is a vanilloid with noxious and analgesic effects that inhibits tetrodotoxin-resistant sodium currents. Because tetrodotoxin-resistant currents are found primarily in small-diameter nociceptor afferents of the peripheral nerves, their inhibition may lead to selective analgesia. Therefore, the authors evaluated the interactions between tetrodotoxin, a site 1 sodium channel blocker, and capsaicin on nerve blockade in vivo. Methods Percutaneous sciatic nerve injections with 0 to 9.9 mM capsaicin, 0 to 120 microM tetrodotoxin, or both were administered to male Sprague-Dawley rats. Thermal nociceptive and motor blockade were measured. Data were expressed as medians with 25th and 75th percentiles. Results Capsaicin produced a transient increase in thermal latency with no effect on motor strength. Tetrodotoxin reduced motor strength for a longer duration than nociception. The interaction between tetrodotoxin and capsaicin was synergistic, as evidenced by (1) supraadditive prolongation of both nociceptive and motor block, with the effect of capsaicin reversed by the vanilloid antagonist capsazepine, and (2) synergism in the frequency that rats achieved maximal block shown by isobolographic analysis. The combination of tetrodotoxin and capsaicin showed less motor predominance than tetrodotoxin did alone. Similar interactions were found between tetrodotoxin and resiniferatoxin (another vanilloid), and between capsaicin and saxitoxin (another site 1 sodium channel blocker), but much less so between bupivacaine and capsaicin. Conclusions Site 1 sodium channel blockers and vanilloids have synergistic effects on nerve blockade in vivo. These interactions may be useful in developing prolonged local anesthetics and elucidating mechanisms of functionally selective nerve blockade.

scholarly journals Examination of the contribution of Nav1.7 to axonal propagation in nociceptors

2021 ◽  
Author(s):  
George Goodwin ◽  
Sheridan McMurray ◽  
Edward B Stevens ◽  
Franziska Denk ◽  
Stephen B McMahon
Keyword(s):  
Sciatic Nerve ◽  
Sodium Channel ◽  
Channel Blocker ◽  
Lower Proportion ◽  
Neurological Deficits ◽  
Channel Blockers ◽  
Loss Of Function ◽  
Nociceptive Neurons ◽  
C Fibre

AbstractNav1.7 is a promising drug target for the treatment of pain because individuals with Nav1.7 loss-of-function mutations are insensitive to pain and do not have other serious neurological deficits. However, current peripherally restricted Nav1.7 inhibitors have not performed well in clinical pain trials, which may reflect a lack of understanding of the function of Nav1.7 in the transmission of nociceptive information. Although numerous studies have reported that Nav1.7 has a moderate role in peripheral transduction, the precise contribution of Nav1.7 to axonal propagation in nociceptors is not clearly defined, particularly for afferents innervating deep structures.In this study, we examined the contribution of Nav1.7 to axonal propagation in nociceptors utilising sodium channel blockers in in vivo electrophysiological and calcium imaging recordings from L4 in the mouse. Using the sodium channel blocker TTX (1-10μM) to inhibit Nav1.7 and other TTX-S sodium channels along the sciatic nerve, we first showed that around 2/3rds of nociceptive neurons innervating the skin, but a lower proportion innervating the muscle (45%), are blocked by TTX. In contrast, nearly all large-sized A-fibre cutaneous afferents (95-100%) were blocked by axonal TTX. Characterisation of TTX resistant cutaneous nociceptors revealed that many were polymodal (57%) and capsaicin sensitive (57%).Next, we examined the role of Nav1.7 in axonal propagation in nociceptive neurons by applying the selective channel blocker PF-05198007 (300nM-1μM) to the sciatic nerve between stimulating and recording sites. 100-300nM PF-05198007 blocked propagation in 63% of C-fibre sensory neurons, whereas similar concentrations did not affect propagation in rapidly conducting A-fibre neurons. We conclude that Nav1.7 has an essential contribution to axonal propagation in only around 2/3rds of nociceptive C-fibre neurons, and a lower proportion (≤45%) of nociceptive neurons innervating muscle.

Comparative effects of adenosine and nifedipine in rabbit vascular smooth muscle

1983 ◽  
Vol 61 (9) ◽  
pp. 1057-1062 ◽  
Author(s):  
M. A. Young ◽  
G. F. Merrill
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Calcium Channel ◽  
Channel Blocker ◽  
Reactive Hyperemia ◽  
Channel Blockers ◽  
Vascular Relaxation ◽  
Negative Interaction

The calcium channel blocker nifedipine attenuates the coronary response to adenosine infusion and reactive hyperemia in dogs. Other evidence indicates adenosine may dilate vascular smooth muscle with a mechanism similar to the calcium channel blockers. In isolated rabbit femoral arterial rings, we studied the interaction of adenosine and nifedipine in mediating vascular relaxation. We also compared the actions of adenosine and nifedipine in relaxing norepinephrine- and K+-stimulated tension, and Ca2+-free contractions in an effort to elucidate differences in the specificity of the two agents. Nifedipine (10–25 μg/L) was without effect on adenosine-mediated relaxation of femoral arteries. Adenosine exhibited a greater ability to relax NE-induced contractions and contractions in Ca2+-free medium than did nifedipine. Conversely, nifedipine attenuated K+-induced contractions more effectively than adenosine. These results suggest that adenosine and nifedipine have different cellular actions and that part of adenosine-mediated relaxation may operate intracellularly. Furthermore, the negative interaction of nifedipine and adenosine in vivo suggests that these agents might act differently in an in vitro setting.

scholarly journals Systemic administration of Ivabradine, an HCN channel inhibitor, blocks spontaneous absence seizures

2021 ◽  
Author(s):  
Yasmine Iacone ◽  
Tatiana P. Morais ◽  
François David ◽  
Francis Delicata ◽  
Joanna Sandle ◽  
...  
Keyword(s):  
Oral Administration ◽  
Channel Blocker ◽  
Brain Slices ◽  
Cortical Layer ◽  
Model Systems ◽  
Hcn Channels ◽  
Channel Blockers ◽  
Hcn Channel ◽  
Absence Seizures

SummaryObjectiveHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a pro-absence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, that is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection in the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices.MethodsWe used EEG recordings in freely moving Genetic Absence Epilepsy from Strasbourg Rats (GAERS) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected in the CIN and VB of GAERS in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical layer 5/6 and thalamocortical neurons, respectively.ResultsOral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection in CIN abolished ASs and elicited small-amplitude 4-7 Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN-channel-dependent properties of cortical layer 5/6 pyramidal and thalamocortical neurons, respectively.SignificanceThese results provide the first demonstration of the anti-absence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.

Extracellular Ca2+ and Mg2+ modulate aminoglycoside blockade of mechanotransducer channel-mediated Ca2+ entry in zebrafish hair cells: an in vivo study with the SIET

2013 ◽  
Vol 305 (10) ◽  
pp. C1060-C1068 ◽  
Author(s):  
Li-Yih Lin ◽  
Wei Pang ◽  
Wei-Min Chuang ◽  
Giun-Yi Hung ◽  
Yuan-Hsiang Lin ◽  
...  
Keyword(s):  
Hair Cell ◽  
Lateral Line ◽  
Hair Cells ◽  
In Vivo Model ◽  
Zebrafish Embryos ◽  
Channel Blockers ◽  
Electrophysiological Method ◽  
First Time ◽  
Electrode Technique

Zebrafish lateral-line hair cells are an in vivo model for studying hair cell development, function, and ototoxicity. However, the molecular identification and properties of the mechanotransducer (MET) channel in hair cells are still controversial. In this study, a noninvasive electrophysiological method, the scanning ion-electrode technique (SIET), was applied for the first time to investigate properties of MET channels in intact zebrafish embryos. With the use of a Ca2+-selective microelectrode to deflect hair bundles and simultaneously record the Ca2+ flux, the inward Ca2+ flux was detected at stereocilia of hair cells in 2- to ∼4-day postfertilization embryos. Ca2+ influx was blocked by MET channel blockers (BAPTA, La3+, Gd3+, and curare). In addition, 10 μM aminoglycoside antibiotics (neomycin and gentamicin) were found to effectively block Ca2+ influx within 10 min. Elevating the external Ca2+ level (0.2–2 mM) neutralized the effects of neomycin and gentamicin. However, elevating the Mg2+ level up to 5 mM neutralized blockade by gentamicin but not by neomycin. This study demonstrated MET channel-mediated Ca2+ entry at hair cells and showed that the SIET to be a sensitive approach for functionally assaying MET channels in zebrafish.

Chronic treatment by the calcium channel blocker ± PN 200-110 in the rat counteracts the stimulations of pituitary weight, prolactin release and pituitary C-kinase activity induced by a chronic estradiol treatment, in vivo

1990 ◽  
Vol 122 (3) ◽  
pp. 403-408
Author(s):  
Ph. Touraine ◽  
P. Birman ◽  
F. Bai-Grenier ◽  
C. Dubray ◽  
F. Peillon ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Channel Blocker ◽  
Plasma Prolactin ◽  
Estradiol Treatment ◽  
Kinase C ◽  
Protein Kinase C Activity

Abstract In order to investigate whether a calcium channel blocker could modulate the protein kinase C activity in normal and estradiol pretreated rat pituitary, female Wistar rats were treated or not (controls) with ± PN 200-110 (3 mg · kg−1 · day−1, sc) for 8 days or with estradiol cervical implants for 8 or 15 days, alone or in combination with PN 200-110 the last 8 days. Estradiol treatment induced a significant increase in plasma prolactin levels and pituitary weight. PN 200-110 administered to normal rats did not modify these parameters, whereas it reduced the effects of the 15 days estradiol treatment on prolactin levels (53.1 ± 4.9 vs 95.0 ±9.1 μg/l, p<0.0001) and pituitary weight (19.9 ± 0.4 vs 23.0 ± 0.6 mg, p <0.001), to values statistically comparable to those measured after 8 days of estradiol treatment. PN 200-110 alone did not induce any change in protein kinase C activity as compared with controls. In contrast, PN 200-110 treatment significantly counteracted the large increase in soluble activity and the decrease in the particulate one induced by estradiol between day 8 and day 15. We conclude that PN 200-110 opposed the stimulatory effects of chronic in vivo estradiol treatment on plasma prolactin levels and pituitary weight and that this regulation was related to a concomitant modulation of the protein kinase C activity.

An Anthrone-Based Kv7.2/7.3 Channel Blocker with Improved Properties for the Investigation of Psychiatric and Neurodegenerative Disorders

2019 ◽  
Author(s):  
Jacob Porter ◽  
Oscar Vivas-Rodriguez ◽  
C. David Weaver ◽  
Eamonn Dickson ◽  
Abdulmohsen Alsafran ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Neurodegenerative Disorders ◽  
Channel Blocker ◽  
Optimal Combination ◽  
Channel Blockers ◽  
Enolate Alkylation ◽  
Cyp Inhibition ◽  
Alkylation Reactions ◽  
Metabolic Instability

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (JDP-107) with an optimal combination of potency (IC<sub>50</sub>= 0.16 𝜇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

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