Channel Blocking Activity Research Articles

Impaired Memory Following Repeated Pentylenetetrazol Treatments in Kindled Mice

Epilepsy is characterized by recurrent seizures, which are caused by excessive discharges from cerebral neurons. Currently, antiepileptic drugs that possess sodium channel blocking activities and also mediate GABA-ergic systems are primarily used to prevent epileptic seizure. However, approximately 40% of patients with epilepsy suffer from interictal psychiatric comorbidities in clinical practice. Furthermore, it is unclear whether epilepsy is associated with psychic function. The aim of the present study was to clarify the effects of kindling-induced epileptic seizures on psychic functioning using behavioral pharmacological tests. Pentylenetetrazol (PTZ)-kindled mice demonstrated no significant differences in locomotor activity and muscle relaxation compared with naïve mice. PTZ-kindled mice also demonstrated cognitive impairment in the objective location test, but no significant effects of PTZ-kindling were observed in the Y-maze test. These findings suggested that PTZ-kindling impairs reference memory, but not working memory. These results suggest that, with respect to their psychic functioning, PTZ-kindled mice have specific characteristics.

Synthesis and Toxicopharmacological Evaluation of m-Hydroxymexiletine, the First Metabolite of Mexiletine More Potent Than the Parent Compound on Voltage-Gated Sodium Channels

The first synthesis of m-hydroxymexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be ∼2-fold more potent than the parent mexiletine and to have more favorable toxicological properties than mexiletine. Thus, MHM and possible related prodrugs might be studied as agents for the treatment of arrhythmias, neuropathic pain, and myotonias in substitution of mexiletine (metabolite switch), which has turned out to be tainted with common toxicity.

Effect of non-steroidal anti-inflammatory drugs and new fenamate analogues on TRPC4 and TRPC5 channels

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used anti-inflammatory therapeutic agents, among which the fenamate analogues play important roles in regulating intracellular Ca2+ transient and ion channels. However, the effect of NSAIDs on TRPC4 and TRPC5 is still unknown. To understand the structure–activity of fenamate analogues on TRPC channels, we have synthesized a series of fenamate analogues and investigated their effects on TRPC4 and TRPC5 channels.Human TRPC4 and TRPC5 cDNAs in tetracycline-regulated vectors were transfected into HEK293 T-REx cells. The whole cell current and Ca2+ movement were recorded by patch clamp and calcium imaging, respectively.Flufenamic acid (FFA), mefenamic acid (MFA), niflumic acid (NFA) and diclofenac sodium (DFS) showed inhibition on TRPC4 and TRPC5 channels in a concentration-dependent manner. The potency was FFA>MFA>NFA>DFS. Modification of 2-phenylamino ring by substitution of the trifluoromethyl group in FFA with F, CH3, OCH3, OCH2CH3, COOH, and NO2 led to the changes in their channel blocking activity. However, 2-(2′-methoxy-5′-methylphenyl)aminobenzoic acid stimulated TRPC4 and TRPC5 channels. Selective COX1-3 inhibitors (aspirin, celecoxib, acetaminophen, and indomethacin) had no effect on the channels. Longer perfusion (>5min) with FFA (100μM) and MFA (100μM) caused a potentiation of TRPC4 and TRPC5 currents after their initial blocking effects that appeared to be partially mediated by the mitochondrial Ca2+ release.Our results suggest that fenamate analogues are direct modulators of TRPC4 and TRPC5 channels. The substitution pattern and conformation of the 2-phenylamino ring could alter their blocking activity, which is important for understanding fenamate pharmacology and new drug development targeting the TRPC channels.

Antifungal and antispasmodic activities of the extracts of Euphorbia granulata

The dichloromethane and methanolic extracts of the plant Euphorbia granulata were investigated for their antifungal, antibacterial, phytotoxic, brine-shrimp cytotoxic, antioxidant, spasmolytic (antispasmodic) and acetylcholinestrase inhibitory activities. The dichloromethane extract showed strong inhibition against Microsporum canis (90%) and against Aspergillus flavus (50%). Both the extracts inhibited the spontaneous contractions in rabbit jejunum preparations with EC50 value of 0.17 and 1.3 mg/ml, respectively and also relaxed the K+-induced contractions with EC50 0.2 and 2.8 mg/ml, respectively, suggesting a calcium channel blocking activity. However, the extracts did not show antibacterial, phytotoxic, brine-shrimp cytotoxic, antioxidant and acetylcholinestrase inhibitory activities. Key words: Euphorbia granulata, antispasmodic, antifungal.

Antihypertensive and Diuretic Effects of the Aqueous Extract of Colocasia esculenta Linn. Leaves in Experimental Paradigms.

Colocasia esculenta Linn (CE) is traditionally used for the treatment of various ailments such as high blood pressure, rheumatic pain, pulmonary congestion, etc. Hence in present study, the effect of aqueous extract of CE leaves (AECE) was evaluated for antihypertensive and acute diuretic activity in rats. Preliminary phytochemical evaluation revealed the presence of carbohydrate, saponins, tannins, and flavonoids in AECE. The animals did not show any sign of toxicity and mortality after the administration of AECE 2000 mg/Kg in acute oral toxicity study. The administration of AECE (100, 200, and 400 mg/Kg/day, p.o.) for six weeks and AECE (10, 20, and 40 mg/Kg, IV) on the day of experiment in renal artery-occluded hypertensive rats and AECE (20 and 40 mg/Kg, IV) in noradrenalin-induced hypertension in rats produced significant (p < 0.05) anti-hypertensive effects. AECE (400 mg/Kg, p.o.) showed positive diuretic activity at 5 h. AECE (200 and 400 mg/Kg, p.o.) significantly increased sodium and chloride content of urine in 5 h and 24 h and additionally potassium in 24 h urine. Hence, the results of the present study revealed the antihypertensive and weak diuretic activity of AECE. These effects may be attributed due to the ACE inhibitory, vasodilatory, β-blocking, and/ or Ca(2+) channel blocking activities, which were reported for the phytoconstitunts, specifically flavonoids such as vitexin, isovitexin, orientin, and isoorientin present in the leaves of CE.

Calcium antagonistic activity of Bacopa monniera in guinea-pig trachea

Objective:To demonstrate the calcium antagonistic property of ethanol extract of Bacopa monniera in guinea-pig trachea.Materials and Methods:The dose response curves of CaCl2 (1 × 10-5 to 1 × 10-1 M) were constructed in the absence and presence of ethanol extract of Bacopa monniera (100, 500 and 700 μg/ml) or nifedipine (1 × 10-6 M) in guinea-pig trachea in calcium free high K+-MOPS-PSS (3-(N-morpholino)-propanesulphonic acid physiological salt solution). The data was analyzed by ANOVA followed by least significant difference test or by Student's ‘t’ test for unequal variance when appropriate. A probability of at least P < 0.05 was considered statistically significant.Results:The plant extract (500 and 700 μg/ml) significantly (P < 0.05) depressed and shifted the calcium concentration-response curves (1 × 10-3- 1 × 10-1 M) to rightward similar to that of nifedipine.Conclusions:Bacopa monniera extract exhibited calcium channel blocking activity in guinea-pig tracheal smooth muscles that may rationalize its relaxant action on guinea-pig trachea and its traditional use in respiratory disorders.

Perineural Local Anesthetic and Adjuvant Action

A bolus of long-acting local anesthetic can provide a sensory and motor block for more than 12 hours. However, it is often desirable to further prolong the duration of the sensory block. Achievement of this aim has been sought in 3 ways. The first approach is to increase the local anesthetic concentration and/or volume (thus dose), which is limited by increased risk of systemic toxicity and an increasedVand often undesirableVdensity of sensory and/or motor effects. A second approach has been to place a catheter that permits continued exposure of the perineural space to low-dose local anesthetic, with a theoretically lower risk of systemic toxicity. A third approach has been to use drug adjuvants that can change the physicochemical properties of the local anesthetic, augment inhibition of nerve impulse transmission through a direct effect on channel function, or augment the duration of local anesthetic action through an indirect mechanism. The latter has occasioned a variety of clinical reports (cited by Yilmaz-Rastoder et al in their accompanying article in this issue) in which agents, such as clonidine (>2-adrenergic agonist), buprenorphine (K-opioid partial agonist), midazolam (benzodiazepine), or dexamethasone (steroid), have been reported to increase the effective duration of the block. With the exception of midazolam, these agents alone do not usually produce a block, and are accordingly considered to be adjuvants to local anesthetics, which indeed block the sodium channel. These previously-reported findings are intriguing, as they raise questions as to the mechanism(s) of action of local anesthetic adjuvants. First, we might consider whether the adjuvant agent acts to reduce the clearance of the anesthetic from the perineural environment, as has been long appreciated with the codelivery of vasoconstrictive agents. Alternatively, we could query as to whether there is a direct interaction of the agents with the axonal membrane or channel that increases the effects of sodium channel blocker action. If it is the former, then augmentation should be absent when there is no blood flow, that is, in an ex vivo preparation, while the latter would be present in the ex vivo model. In this issue of Regional Anesthesia and Pain Medicine, Yilmaz-Rastoder et al report their examination in an ex vivo model of the effects of several agents on the compound action potential (CAP) of an isolated rat sciatic nerve and the agents’ interaction with ropivacaine or midazolam in blocking that CAP. Within the concentration ranges examined, the 3 agents alone had little effect on the CAP of either the rapidly conducting large myelinated A fibers or slowly conducting small unmyelinated C fibers. Nor did these adjuvants alter either the potency (concentration required to produce a criterion level of block) or efficacy (the maximum achievable block) of ropivacaine or midazolam. This study was thus aimed at addressing the very specific issue raised by clinical reports that indicate these agents in combination increase the duration of the local anesthetic effects. The model usedVthe isolated sciatic nerveVis common, and by assessing the area of the curve under the rapidand slow-conducting components, it can determine the effect of agents on large myelinated and small unmyelinated axons, respectively. Because the study occurs within a bath, local concentrations can be readily defined, and the clearance of drug can be determined by the simple expedient of changing the bathing solution. Therefore, the take-home message is that these agents do not interact with membrane channels to alter conduction in these fiber classes and that they do not alter the interaction of ropivacaine (or EDITORIAL

Synthesis, Evaluation of the Calcium Antagonistic Activity and Biotransformation of Hexahydroquinoline and Furoquinoline Derivatives

The objective of this study was to synthesise new condensed 1,4-dihydropyridine derivatives and investigate their calcium channel blocking activity. In addition, the in vitro hepatic microsomal bio-transformation of one hexahydroquinoline derivative was studied, 2,6,6-Trimethyl-3-carbmethoxy (carbethoxy)-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives were synthesised bymodified Hantzsch synthesis. 1,3,4,5,6,7,8,9-octahydro-7,7-dimethyl-9-arylfuro [3,4-b]quinoline-1,8-dione derivatives were synthesised the reaction of hexahydroquinoline derivatives with pyridinium bromide perbromide. The calcium antagonistic activities of the compounds were determined by tests performed on isolated rat ileum and lamb carotid artery. In vitro hepatic biotransformation of one compound was studied in rat microsomes. Although compounds 3, 18 and 28 showed promising relaxant activity, they were less active than nicardipine (CAS 55985-32-5) in isolated rat ileum. In all studied concentrations, compounds 5 and 20 were more active than nicardipine in lamb carotid artery. These compounds showed high tissue selectivity compared with nicardipine. In addition, in vitro hepatic microsomal biotransformation of compound 2 produced its lactone derivative (compound 34). This metabolite was verified by HPLC. In the hexahydroquinoline series, the compounds having ortho substituted phenyl substituent were more active than the meta isomers. Lactone derivatives were found less active than hexahydroquinoline derivatives in respect to calcium antagonistic activity.

The Calcium Channel Blocking and Phosphodiesterase Inhibitory Activities of the Extract of Andropogon muricatus Explains its Medicinal Use in Airways Disorders

The present work was carried out to provide a pharmacological base for the medicinal use of Andropogon muricatus in airways disorders, such as asthma. In isolated guinea-pig tracheal strips, the crude extract of Andropogon muricatus exhibited a non-specific relaxant effect against carbachol (1 µM) and high K⁺ precontractions, with EC₅₀ values of 0.10 (0.07-0.11) and 0.15 mg/mL (0.11-0.18), respectively, similar to papaverine, while verapamil was more potent against high K⁺. This suggests the involvement of a non-specific relaxant effect, mediated possibly through Ca⁺⁺ channel blockade and phosphodiesterase inhibition. The functional nature of the relaxant effect was further confirmed through indirect evidence when pretreatment of the tissues with the plant extract caused potentiation of the isoprenaline inhibitory response curves, similar to papaverine, while the effect of verapamil remained unchanged. These data indicate that the crude extract of Andropogon muricatus contains constituent(s) that mediate the tracheal relaxant effect, possibly through dual inhibition of Ca⁺⁺ channels and phosphodiesterase and provide pharmacological evidence for its medicinal use in airways disorders, particularly asthma.

Synthesis, cytotoxicity and calcium antagonist activity of novel imidazolyl derivatives of 1,8-acridinediones

A series of novel imidazolyl derivatives of fully and partially hydrogenated 1,8-acridinediones were synthesized and assessed for their cytotoxic activity on four different human cancer cell lines (HeLa, MCF-7, LS-180, and Raji cells). Although being inactive on LS-180 and Raji cell lines, the compounds showed weak to moderate anti-tumor activities on other cell lines and their IC50 ranged from 31.7 to more than 100 μM. Among the synthesized compounds 12b, 13b, 12c and 13c, bearing an electronattracting substituent on the imidazole ring, and 12f and 13f, with a benzyl substituent, showed higher activities. Furthermore, the calcium channel antagonist activity of the derivatives, an undesired effect when these compounds are used as anti-tumor agents, was much lower than that of Nifedipine, a reference antagonist. Imidazolyl derivatives of 1,8-acridinedione represent an interesting template, showing promising biological properties. Further investigation on this chemical scaffold could potentially lead to the discovery of cytotoxic agents with low calcium channel blocking activity.

Pharmacological effects of extract of Carthamus tinctorius on volume and acidity of stimulated gastric secretion

Over production of gastric acid in response to various stimuli is responsible for peptic ulceration in majority of patients. Calcium plays an important role in the release of various stimulant mediators. The aerial part of Carthamus tinctorius L. are reported to have calcium channel blocking activity. This study was designed to find out the effects of extract on the volume and acidity, free and total, of Carbachol induced gastric secretion and to compare the results with that of Cimetidine and Verapamil on the same parameters. The animals were kept on fasting for 48 h after which the pylorus of each animal was ligated. The extract was administered 200 and 400 mg/kg of body weight, Cimetidine 2.5 mg/kg and Carbachol 600 μg/kg and Verapamil 10 mg/kg body weight, intraperitoneally, in pylorus ligated rats. It was found that the extract reduced the volume, free and total acidity of gastric secretion, which were statistically highly significant when compared with Carbachol (P < 0.001). Cimetidine also had the same effects. When the difference of mean values, brought about by extract, was compared with those of Cimetidine, it was found that these differences in the volume and free acidity were significant indicating that Cimetidine is more effective than the extract. The extract can, however, be used effectively in the treatment of peptic ulcer. Although, the extract reduced gastric acidity significantly, but is less effective than Cimetidine

SdPI, The First Functionally Characterized Kunitz-Type Trypsin Inhibitor from Scorpion Venom

BackgroundKunitz-type venom peptides have been isolated from a wide variety of venomous animals. They usually have protease inhibitory activity or potassium channel blocking activity, which by virtue of the effects on predator animals are essential for the survival of venomous animals. However, no Kunitz-type peptides from scorpion venom have been functionally characterized.Principal FindingsA new Kunitz-type venom peptide gene precursor, SdPI, was cloned and characterized from a venom gland cDNA library of the scorpion Lychas mucronatus. It codes for a signal peptide of 21 residues and a mature peptide of 59 residues. The mature SdPI peptide possesses a unique cysteine framework reticulated by three disulfide bridges, different from all reported Kunitz-type proteins. The recombinant SdPI peptide was functionally expressed. It showed trypsin inhibitory activity with high potency (Ki = 1.6×10−7 M) and thermostability.ConclusionsThe results illustrated that SdPI is a potent and stable serine protease inhibitor. Further mutagenesis and molecular dynamics simulation revealed that SdPI possesses a serine protease inhibitory active site similar to other Kunitz-type venom peptides. To our knowledge, SdPI is the first functionally characterized Kunitz-type trypsin inhibitor derived from scorpion venom, and it represents a new class of Kunitz-type venom peptides.

Cymatherelactone and cymatherols A− C, polycyclic oxylipins from the marine brown alga Cymathere triplicata

An investigation of the oxylipin chemistry of the temperate brown alga Cymathere triplicata led to the isolation of several secondary metabolites, cymatherelactone ( 1) and cymatherols A− C ( 2– 4), the latter as their methyl ester derivatives ( 5– 7), which contained cyclopentyl, cyclopropyl, epoxide and lactone rings. Their structures were elucidated using a combination of spectroscopic techniques and synthetic chemistry. Cymatherelactone ( 1), as well as R- and S-Mosher’s esters of its seco acid, exhibited moderate sodium channel blocking activity.

Structural Nucleotide Analogs Are Potent Activators/Inhibitors of Pancreatic β Cell KATP Channels: An Emerging Mechanism Supporting Their Use as Antidiabetic Drugs

The 2H-1,4-benzoxazine derivatives are novel drugs structurally similar to nucleotides; however, their actions on the pancreatic β cell ATP-sensitive K+ (KATP) channel and on glucose disposal are unknown. Therefore, the effects of the linear/branched alkyl substituents and the aliphatic/aromatic rings at position 2 of the 2H-1,4-benzoxazine nucleus on the activity of these molecules against the pancreatic β cell KATP channel and the Kir6.2ΔC36 subunit were investigated using a patch-clamp technique. The effects of these compounds on glucose disposal that followed glucose loading by intraperitoneal glucose tolerance test and on fasting glycemia were investigated in normal mice. The 2-n-hexyl analog blocked the KATP (IC₅₀ = 10.1 × 10⁻⁹ M) and Kir6.2ΔC36 (IC₅₀ = 9.6 × 10⁻⁹ M) channels, which induced depolarization. In contrast, the 2-phenyl analog was a potent opener (drug concentration needed to enhance the current by 50% = 0.04 × 10⁻⁹ M), which induced hyperpolarization. The ranked order of the potency/efficacy of the analog openers was 2-phenyl > 2-benzyl > 2-cyclohexylmethyl. The 2-phenylethyl and 2-isopropyl analogs were not effective as blockers/openers. The 2-n-hexyl (2-10 mg/kg) and 2-phenyl analogs (2-30 mg/kg) reduced and enhanced the glucose areas under the curves, respectively, after glucose loading in mice. These compounds did not affect the fasting glycemia as is observed with glibenclamide. The linear alkyl chain and the aromatic ring at position 2 of the 1,4-benzoxazine nucleus are the determinants, which confer the KATP channel blocking action with glucose-lowering effects and the opening action with increased glucose levels, respectively. The opening/blocking actions of these compounds mimic those that were observed with ATP and ADP. The results support the use of these compounds as novel antidiabetic drugs.

Pharmacological basis for the medicinal use of Psidium guajava leave in hyperactive gut disorders

Psidium guajava L. is reputed for its medicinal use in hyperactive gut disorders. This study was aimed to investigate mechanism responsible for its medicinal use in diarrhea and gut spasm. In castor oil-induced diarrheal model, the crude extract of P. guajava (100-1,000 mg/kg), provided 20.52-81.05% protection, similar to loperamide. In isolated rabbit jejunum preparations, crude extract was found more potent against high K + than spontaneous pre-contractions, similar to verapamil, with EC 50 values of 0.66 (0.44-0.97; n=8) and 2.28 mg/mL (1.43-3.62; n=8), respectively, suggests calcium channel blocking activity, as a possible mode of action. The Ca ++ channel blocking activity was further confirmed when pre-treatment of tissue with crude extract (0.3-1 mg/mL) caused a rightward shift in the Ca ++ concentration-response curves, similar to verapamil. Loperamide also inhibited spontaneous and high K + -induced contractions and shifted the Ca ++ curves to the right. These data indicate that crude extract of P. guajava possesses Ca ++ antagonist-like constituent(s), which explain its inhibitory effect on gut motility.

Blood Pressure Lowering Effect of the Extract of Aerial Parts of Capparis aphylla is Mediated Through Endothelium-Dependent and Independent Mechanisms

This investigation was aimed to provide pharmacological evidences for the medicinal use of Capparis aphylla in hypertension. In normotensive anesthetized rats, intravenous administration of the crude extract of Capparis aphylla (Ca.Cr; 3–100 mg/kg) caused a fall in mean arterial pressure (MAP), which was partially blocked in the presence of atropine (2 mg/kg). In isolated rabbit aortic rings, Ca.Cr inhibited phenylephrine (1 μM) and high K+ (80 mM) precontractions with respective EC50 values of 0.10 (0.07–0.15) and 1.22 mg/mL (1.00–1.50), suggesting calcium channel blocking (CCB) activity with a predominant inhibitory effect on receptor operated Ca2+ channels. Pretreatment of the arotic rings with Ca.Cr (0.1–1 mg/mL) caused a rightward shift in the Ca2+ concentration response curves, similar to verapamil. In isolated rat aorta preparations, Ca.Cr caused a partial endothelium-dependent L-NAME/atropine-sensitive vasodilator effect. In guinea-pig atria, Ca.Cr suppressed both rate and force of spontaneous atrial contractions with respective EC50 values of 1.35 (1.01–1.79) and 1.60 mg/mL (1.18–2.17), which remained unchanged in the presence of atropine (1 μM). These data indicate that the blood pressure (BP) lowering effect of the crude extract of Capparis aphylla is mediated through a vasodilator and cardiac depressant effect. The vasodilator effect is partly mediated by an endothelium-dependent, atropine-sensitive NO pathway, while the CCB effect is partly responsible for endothelium-independent vasodilatation and also for the cardiac depressant effect; thus, this study provides pharmacologic evidence with respect to the medicinal use of the plant in hypertension.

Characterization of a unique dihydropyrimidinone, ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate, as an effective antithrombotic agent in a rat experimental model

To evaluate the potential of a novel dihydropyrimidinone, ethyl 4-(4'-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (H-DHPM), as a calcium channel blocker, endowed with the ability to inhibit platelet aggregation effectively. In-vitro and in-vivo studies were conducted for the determination of antiplatelet activity using adenosine diphosphate (ADP), collagen or thrombin as inducers. Calcium channel blocking activity and nitric oxide synthase (NOS) activity were monitored. Lipopolysaccharide (LPS)-mediated prothrombotic conditions were developed in rats to study the efficacy of H-DHPM to suitably modulate the inflammatory mediators such as inducible NOS (iNOS) and tissue factor. The cGMP level and endothelial NOS (eNOS) expression were checked in aortic homogenate of LPS-challenged rats pretreated with H-DHPM. The effect of H-DHPM on FeCl(3) -induced thrombus formation in rats was examined. The concentrations of H-DHPM required to give 50% inhibition (IC50) of in-vitro platelet aggregation induced by ADP, collagen or thrombin were 98.2±2.1, 74.5±2.3 and 180.7±3.4µm, respectively. H-DHPM at a dose of 52.0±0.02mg/kg (133µmol/kg) was found to optimally inhibit ADP-induced platelet aggregation in-vivo. The level of nitric oxide was found to be up to 9±0.08-fold in H-DHPM-treated platelets in-vitro and 8.2±0.05-fold in H-DHPM-pretreated rat platelets in-vivo compared with control. OH-DHPM, the parent compound was found to be ineffective both in-vitro and in-vivo. H-DHPM-pretreated rats were able to resist significantly the prothrombotic changes caused by LPS by blunting the expression of iNOS, tissue factor and diminishing the increased level of cGMP to normal. H-DHPM enhanced the eNOS expression in aorta of rats treated with LPS. H-DHPM displayed synergy with antiplatelet activity of aspirin even at lower doses. H-DHPM was found to inhibit the LPS-induced platelet aggregation in younger as well as older rats. H-DHPM exhibited the ability to markedly decrease FeCl(3) -induced thrombus formation in rats. H-DHPM has the attributes of a promising potent antiplatelet candidate molecule that should attract further study. H-DHPM displayed antiplatelet activity both in vivo and in vitro, which was due partially by lowering the intraplatelet calcium concentration.

Arrhythmogenic Ion-Channel Remodeling in Heart Failure and Upstream Approach

Class I antiarrhythmic drugs with Na+ channel blocking action cannot be readily used for the treatment of various arrhythmias associated with heart failure because the antiarrhthmic drugs may worsen cardiac function. In failing hearts ion-channel remodeling, such as downregulation of K channels and connexin 43, upregulation of Na-Ca exchanger and HCN channels, and instability of Ca release channels in sarcoplasmic reticulum, can be observed. These electrophysiological abnormalities can produce severe ventricular tachyarrhythmias through reentrant and automatic mechanisms. Neurohumoral factors such as renin-angiotensin system, endothelin system and sympathetic nervous system play an important role in the establishment of the ion-channel remodeling. Upstream approach with blockade of the neurohumoral factors may prevent lethal ventricular arrhythmias. In congestive heart failure atrial tissues are expanded and susceptibility to atrial fibrillation is increased. Control of neurohumoral factors may be also beneficial for the prevention of atrial fibrillation. Recently it has been suggested that inflammatory mechanisms may be also involved in not only the deterioration of heart failure but also induction of atrial fibrillation and ventricular tachyarrhythmias. Drugs with anti-inflammatory action, including the antiarrhythmic drug amiodarone, may be effective for the treatment of arrhythmias associated with heart failure. Current perspective of upstream approach to preventing atrial and ventricular arrhythmias associated with heart failure will be discussed.

Emerging roles for gasotransmitters

Emerging roles for gasotransmitters

Synthesis and Biological Evaluation of 1-Heteroarylmethyl 1,4-Diazepanes Derivatives as Potential T-type Calcium Channel Blockers

The synthesis and biological evaluation of 1-heteroarylmethyl 1,4-diazepane derivatives as potential T-type calcium channel blockers is described. In this study, we have identified the compound 211 exhibiting the most potent T-type calcium channel blocking activity with IC(50) value of 0.20 mu M, which is superior to that of mibefradil.