Use of Calcium Channel Antagonists for cardiovascular disease

Yedinak, Kimberly C.

doi:10.1016/s0160-3450(15)30720-0

Cited by 16 publications

(9 citation statements)

References 74 publications

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“…Because the expression of TXNIP is directly regulated by Ca 2+ influx (Yamanaka et al ., 2000), a recent study demonstrated that calcium channel blockers and verapamil in particular can effectively inhibit TXNIP expression in cardiomyocyte apoptosis in streptozotocin‐ and obesity‐induced diabetic mice (Chen et al ., 2009). Verapamil is an L‐type calcium channel blocker from the phenylalkylamine class that has been used routinely in the treatment of hypertension, angina pectoris and cardiac arrhythmia (Yedinak, 1993). Here, we have assessed the neuroprotective effects of verapamil by reducing the expression of TXNIP.…”

Section: Introductionmentioning

confidence: 99%

Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity

Al‐Gayyar

Abdelsaid

Matragoon

et al. 2011

British Journal of Pharmacology

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BACKGROUND AND PURPOSEUp-regulation of thioredoxin interacting protein (TXNIP), an endogenous inhibitor of thioredoxin (Trx), compromises cellular antioxidant and anti-apoptotic defences and stimulates pro-inflammatory cytokines expression, implying a role for TXNIP in apoptosis. Here we have examined the causal role of TXNIP expression in mediating retinal neurotoxicity and assessed the neuroprotective actions of verapamil, a calcium channel blocker and an inhibitor of TXNIP expression. EXPERIMENTAL APPROACHRetinal neurotoxicity was induced by intravitreal injection of NMDA in Sprague-Dawley rats, which received verapamil (10 mg·kg -1 , p.o.) or vehicle. Neurotoxicity was examined by terminal dUTP nick-end labelling assay and ganglion cell count. Expression of TXNIP, apoptosis signal-regulating kinase 1 (ASK-1), NF-kB, p38 MAPK, JNK, cleaved poly-ADP-ribose polymerase (PARP), caspase-3, nitrotyrosine and 4-hydroxy-nonenal were examined by Western and slot-blot analysis. Release of TNF-a and IL-1b was examined by ELISA. KEY RESULTSNMDA injection enhanced TXNIP expression, decreased Trx activity, causing increased oxidative stress, glial activation and release of TNF-a and IL-1b. Enhanced TXNIP expression disrupted Trx/ASK-1 inhibitory complex leading to release of ASK-1 and activation of the pro-apoptotic p38 MAPK/JNK pathway, as indicated by cleaved PARP and caspase-3 expression. Treatment with verapamil blocked these effects. CONCLUSION AND IMPLICATIONSElevated TXNIP expression contributed to retinal neurotoxicity by three different mechanisms, inducing release of inflammatory mediators such as TNF-a and IL-1b, altering antioxidant status and disrupting the Trx-ASK-1 inhibitory complex leading to activation of the p38 MAPK/JNK apoptotic pathway. Targeting TXNIP expression is a potential therapeutic target for retinal neurodegenerative disease. AbbreviationsASK-1, apoptosis signal-regulating kinase 1; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; NFL, nerve fiber layer; NMLA, N-methyl-L-aspartate; ONL, inner plexiform layer into the outer nuclear layer; PARP, poly-ADP-ribose polymerase; RGC, retinal ganglion cell; ROD, relative optical density; Trx, thioredoxin; TUNEL, terminal dUTP nick-end labelling; TXNIP, thioredoxin interacting protein BJP British Journal of Pharmacology

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Section: Introductionmentioning

confidence: 99%

Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity

Al‐Gayyar

Abdelsaid

Matragoon

et al. 2011

British Journal of Pharmacology

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“…There are three classes of calcium channel antagonists [5]. The phenylalkylamine and benzothiazepine derivatives such as verapamil and diltiazem, respectively, have direct cardiac as well as antihypertensive effects, and are often prescribed for adults when additional benefits outweigh potential adverse effects.…”

Section: Introductionmentioning

confidence: 99%

“…As with other calcium channel antagonists, amlodipine inhibits voltage-dependent calcium channels in vascular smooth muscle cells and cardiac muscle cells, which prevents the influx of calcium across cell membranes [5,7]. Although amlodipine has not been studied in children, it has been approved for use in adults with hypertension and angina [7].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of amlodipine in pediatric patients with hypertension

Tallian

Nahata

Turman³

et al. 1999

Pediatric Nephrology

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We designed a study to determine the efficacy and safety of amlodipine given once daily in the pediatric population. Twenty-one patients (mean age 13.1 years) with either essential (n=160) or renal (n=5) hypertension, and newly diagnosed (n=15) or poorly controlled or intolerant on existing antihypertensive therapy (n=6), were included. Patients received amlodipine once daily at a starting mean dose of 0.07+/-0.04 mg/kg per day. The total daily dose of amlodipine was increased 25%-50% every 5-7 days if the mean home blood pressure measurements (HBPM) were above the 95th percentile for age and gender. A baseline followed by a repeat 24-h ambulatory blood pressure monitor study (ABPM) was performed in 20 patients when the mean HBPM was below the 95th percentile goal. The mean titrated dose required to control BP was 0.29+/-0.11 mg/kg per day for those < 13 years, 0.16+/-0.11 mg/kg per day for those > or = 13 years, 0.23+/-0.14 mg/kg per day for essential, hypertension and 0.24+/-0.13 mg/kg per day for renal hypertension. The ABPM demonstrated that amlodipine provided effective BP control as primary therapy in 14 essential patients. Adverse effects included fatigue (n=6), headache (n=5), facial flushing (n=4), dizziness (n=3), edema (n=3), abdominal pain (n=3), chest pain (n=2), nausea (n=1), and vomiting (n=1). Quality of life appeared to improve during therapy. Amlodipine was an effective once daily antihypertensive agent with an acceptable safety profile. Higher doses of amlodipine were required for younger patients, and monotherapy was effective in patients with essential hypertension.

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“…V erapamil (VER) is a calcium channel blocker used clinically for hypertension, atrial fibrillation or atrial flutter, cluster headache, and angina (1,2). Recently, there has been a growing interest in repurposing verapamil and other efflux pump inhibitors for the treatment of tuberculosis (TB).…”

mentioning

confidence: 99%

New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells

Abate

Ruminiski

Kumar

et al. 2016

Antimicrob Agents Chemother

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eThere is a growing interest in repurposing mycobacterial efflux pump inhibitors, such as verapamil, for tuberculosis (TB) treatment. To aid in the design of better analogs, we studied the effects of verapamil on macrophages and Mycobacterium tuberculosis-specific T cells. Macrophage activation was evaluated by measuring levels of nitric oxide, tumor necrosis factor alpha (TNF-␣), interleukin-1 beta (IL-1␤), and gamma interferon (IFN-␥). Since verapamil is a known autophagy inducer, the roles of autophagy induction in the antimycobacterial activities of verapamil and norverapamil were studied using bone marrow-derived macrophages from ATG5 flox/flox (control) and ATG5 flox/flox Lyz-Cre mice. Our results showed that despite the well-recognized effects of verapamil on calcium channels and autophagy, its action on intracellular M. tuberculosis does not involve macrophage activation or autophagy induction. Next, the effects of verapamil and norverapamil on M. tuberculosis-specific T cells were assessed using flow cytometry following the stimulation of peripheral blood mononuclear cells from TB-skin-test-positive donors with M. tuberculosis whole-cell lysate for 7 days in the presence or absence of drugs. We found that verapamil and norverapamil inhibit the expansion of M. tuberculosis-specific T cells. Additionally, three new verapamil analogs were found to inhibit intracellular Mycobacterium bovis BCG, and one of the three analogs (KSV21) inhibited intracellular M. tuberculosis replication at concentrations that did not inhibit M. tuberculosis-specific T cell expansion. KSV21 also inhibited mycobacterial efflux pumps to the same degree as verapamil. More interestingly, the new analog enhances the inhibitory activities of isoniazid and rifampin on intracellular M. tuberculosis. In conclusion, KSV21 is a promising verapamil analog on which to base structureactivity relationship studies aimed at identifying more effective analogs.

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Use of Calcium Channel Antagonists for cardiovascular disease

Cited by 16 publications

References 74 publications

Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity

Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity

Efficacy of amlodipine in pediatric patients with hypertension

New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells

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