Propranolol Blocks Cardiac and Neuronal Voltage-Gated Sodium Channels

Wang, Dao Wen; Mistry, Akshitkumar M.; Kahlig, Kristopher M.; Kearney, Jennifer A.; Xiang, Jizhou; George, Alfred L.

doi:10.3389/fphar.2010.00144

Cited by 88 publications

(81 citation statements)

References 36 publications

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“…29 The decrease in beat rate is expected since B-adrenergic receptor blocker prevents the ligands to bind and, in effect, the G-protein complex associated with the receptor cannot activate the production of cyclic adenosine monophosphate responsible for turning on the calcium inflow channels. 30,31 Adding this to Na + blocking channel effect, ¹86% change ratio at 30 µM of propranolol which is more potent than quinidine as a negative chronotropic agent should be projected (Fig.…”

Section: Drug Screening Applicability Of the Combined Methodsmentioning

confidence: 99%

Non-invasive Video Image-based Analysis Method Coupled to Field Potential Recording for Evaluation of the Drug-induced Effect in Cardiac Tissue

et al. 2016

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Reports on the use multi electrode arrays (MEA) systems for screening the electrophysiological effects of drug candidates on cardiac tissues as a response to the need of the pharmaceutical industry for a high-throughput screening method have increased in the past decades. Though the field potential (FP) measured in MEA have been reported coherent to the progression of the well-established progression of action potential (AP), certain pharmacological effects do not accurately reflect in the observed FP waveform alteration. Here, we revisit the imaging analysis algorithm developed in our lab based on the pixel intensity variation that can be utilized to improve the FP measurement and interpretation. Imaging analysis was done on videos recorded with a microscope camera at 30 Hz frame rate and 680 × 510 pixel resolution resulting to a relative lower system requirement compared to other methods. It is expected that combining our method with MEA systems can greatly aid in developing a screening platform for cardiovascular effect profiling of candidate drugs.

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Section: Drug Screening Applicability Of the Combined Methodsmentioning

confidence: 99%

Non-invasive Video Image-based Analysis Method Coupled to Field Potential Recording for Evaluation of the Drug-induced Effect in Cardiac Tissue

et al. 2016

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“…Human embryonic kidney (HEK) cells stably expressing the human brain (h) Na V 1.2 channel were described previously (Wang et al, 2010). The cell line was created by simultaneous stable integration of piggyBac transposons encoding the cDNA for either SCN2A (G418 selection) or SCN1B-IRES2-SCN2B (puromycin selection), as described previously (Kahlig et al, 2010b).…”

Section: Methodsmentioning

confidence: 99%

Ranolazine Reduces Neuronal Excitability by Interacting with Inactivated States of Brain Sodium Channels

Kahlig¹,

Hirakawa

Liu

et al. 2013

Mol Pharmacol

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Ranolazine is an approved drug for chronic stable angina that acts by suppressing a noninactivating current conducted by the cardiac sodium channel [persistent sodium ion current (I Na )]. Ranolazine has also been shown to inhibit the increased persistent I Na carried by Na V 1.1 channels encoding epilepsy-and migraine-associated mutations. Here, we investigate the antiepileptic properties of ranolazine exhibited through the reduction of hippocampal neuronal excitability. At therapeutically relevant concentrations, ranolazine reduced action potential firing frequency of hippocampal neurons in response to repetitive depolarizing current injections. Similarly, using a single current injection paradigm, ranolazine required a long depolarization (4 seconds) to produce significant inhibition of excitability, which was similar to that observed for the anticonvulsants phenytoin (slowly binds to the fast-inactivated state) and lacosamide (binds to the slow-inactivated state). Ranolazine enhanced the development of fast and slow inactivation assessed with conditioning prepulses of 100, 1000, or 10,000 milliseconds. Recovery of channels from inactivated states was also slowed in the presence of ranolazine. Interestingly, the use-dependent inhibition of hippocampal neurons was dependent on the duration of the voltage step, suggesting ranolazine does not selectively affect the open state and may also interact with inactivated states. NEURON (Yale University, New Haven, CT) computational simulations predict equal inhibition of action potential generation for binding to either fast-inactivated or slow-inactivated states. Binding of ranolazine to either preopen or open states did not affect the excitability of the simulation. Ranolazine was able to significantly reduce the epileptiform activity of the neuronal cultures, suggesting possible antiepileptic activity.

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“…Protocol (1): During the MP recordings of the bulbospinal RVLM neurons, the preparations were superfused with metoprolol (20 mmol l À1 , 23 Sigma) and/or butoxamine (20 mmol l À1 , 24 Sigma) dissolved in artificial cerebrospinal fluid. To confirm the effects opposite to those of metoprolol and butoxamine, the preparations were superfused with dobutamine (5 mmol l À1 , 25 Sigma) and salbutamol (5 mmol l À1 , 25 Sigma).…”

Section: Experimental Protocolsmentioning

confidence: 99%

Expression and functions of β1- and β2-adrenergic receptors on the bulbospinal neurons in the rostral ventrolateral medulla

et al. 2014

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The expression and effects of b-adrenergic receptors (b-ARs) on the neurons of the bulbospinal rostral ventrolateral medulla (RVLM) have been limitedly examined to date. The objective of this study was to examine the expression of b 1 -and b 2 -ARs on the bulbospinal RVLM neurons electrophysiologically and histologically. To directly investigate whether RVLM neurons display sensitivity to metoprolol (a b 1 -AR antagonist), dobutamine (a b 1 -AR agonist), butoxamine (a b 2 -AR antagonist), and salbutamol (a b 2 -AR agonist), we examined changes in the membrane potentials of the bulbospinal RVLM neurons using the whole-cell patch-clamp technique during superfusion of these drugs. During metoprolol superfusion, 16 of the 20 RVLM neurons were hyperpolarized, and 5 of the 6 RVLM neurons were depolarized during dobutamine superfusion. During butoxamine superfusion, 11 of the 16 RVLM neurons were depolarized, and all of the 8 RVLM neurons were hyperpolarized during salbutamol superfusion. These results suggest the expression of b 1 -and b 2 -ARs on the RVLM neurons. To determine the presence of b 1 -and b 2 -ARs histologically, immunofluorescence examination was performed. Five metoprolol-hyperpolarized neurons were examined for b 1 -AR and tyrosine hydroxylase (TH) immunoreactivity. All of the neurons displayed b 1 -AR immunoreactivity, whereas three of the neurons displayed TH immunoreactivity. All of the five RVLM neurons that became depolarized during metoprolol superfusion and hyperpolarized during butoxamine superfusion displayed b 1 -and b 2 -AR immunoreactivity. Our findings suggest that b 1 -AR antagonists or b 2 -AR agonists may decrease blood pressure through decreasing the activity of the bulbospinal RVLM neurons.

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Propranolol Blocks Cardiac and Neuronal Voltage-Gated Sodium Channels

Cited by 88 publications

References 36 publications

Non-invasive Video Image-based Analysis Method Coupled to Field Potential Recording for Evaluation of the Drug-induced Effect in Cardiac Tissue

Non-invasive Video Image-based Analysis Method Coupled to Field Potential Recording for Evaluation of the Drug-induced Effect in Cardiac Tissue

Ranolazine Reduces Neuronal Excitability by Interacting with Inactivated States of Brain Sodium Channels

Expression and functions of β1- and β2-adrenergic receptors on the bulbospinal neurons in the rostral ventrolateral medulla

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