1.
Effect of late sodium current inhibition on MRI measured diastolic dysfunction in aortic stenosis: a pilot study.
Singh, A, Steadman, CD, Khan, JN, Reggiardo, G, McCann, GP
BMC research notes. 2016;:64
Abstract
BACKGROUND Ranolazine is a new anti-anginal drug that acts via late sodium current inhibition, and has been shown to improve diastolic dysfunction in isolated myocytes. Diastolic dysfuntion is common in patients with aortic stenosis (AS), and precedes symptom development and systolic dysfunction. The purpose of this study was to assess the effects of ranolazine on peak early diastolic strain rate (PEDSR) and exercise capacity in patients with AS. METHODS Patients with asymptomatic moderate to severe AS and diastolic dysfunction underwent trans-thoracic echocardiography, exercise testing and cardiac magnetic resonance (CMR) imaging at baseline, 6 weeks after commencing ranolazine and at 10 weeks (4 weeks after discontinuation). Diastolic function was assessed using PEDSR measured on tagged CMR images. RESULTS Fifteen patients (peak pressure gradient 48.8 ± 12.4 mmHg, mean pressure gradient 27.1 ± 7.5 mmHg, aortic valve area 1.26 ± 0.31 cm(2)) completed the week-6 visit and 13 completed the final visit. Global PEDSR did not significantly increase from baseline (0.79 ± 0.15) to week-6 (0.86 ± 0.18, p = 0.198). There was a borderline significant increase in total exercise duration from 10.47 ± 3.68 min to 11.60 ± 3.25 min (p = 0.06). CONCLUSION This small pilot study did not show a significant improvement in diastolic function with the use of ranolazine in asymptomatic patients with moderate-severe AS. Further studies with a larger population may be indicated. EduraCT number 2011-000111-26.
2.
Dose effects of oxaliplatin on persistent and transient Na+ conductances and the development of neurotoxicity.
Park, SB, Lin, CS, Krishnan, AV, Goldstein, D, Friedlander, ML, Kiernan, MC
PloS one. 2011;(4):e18469
Abstract
BACKGROUND Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction. METHODOLOGY/PRINCIPAL FINDINGS Specifically the function of transient and persistent Na(+) currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na(+) channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na(+) conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = -.65; P<.05; Sensory correlation coefficient = .67; P<.05). CONCLUSIONS/SIGNIFICANCE It is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na(+) conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies.
3.
Effect of spironolactone on K(+) homeostasis and ENaC expression in lymphocytes from chronic hemodialysis patients.
Michea, L, Vukusich, A, González, M, Zehnder, C, Marusic, ET
Kidney international. 2004;(4):1647-53
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Abstract
BACKGROUND Cardiac disease is the major cause of death in hemodialysis patients (HD). It is now clear that aldosterone has deleterious effects in the cardiovascular system. In the present study, we evaluated the effects of an aldosterone-antagonist, spironolactone, on the extrarenal regulation of potassium in HD patients. Furthermore, to validate the effectiveness of the spironolactone dose-design, we measured the expression of Na(+)-channel (ENaC alpha subunit) in peripheral blood mononuclear cells (PBMC), before and after a two-week course of spironolactone. METHODS The study design included a two-week baseline period, followed by spironolactone treatment (50 mg three times weekly for 15 days), and by a two-week washout period and then a two-week placebo period. An oral K(+) load (0.3 mEq/K(+) kg body weight plus carbohydrates) was administered at the end of each period, and time-course of plasma potassium was evaluated. ENaC expression in PBMC was assessed before and after spironolactone. RESULTS The maximal increase in plasma potassium after the K(+) carbohydrate load was: control 5.33 +/- 0.88 mEq K(+)/L; spironolactone 5.23 +/- 0.68 mEq K(+)/L; placebo 5.38 +/- 0.61 mEq K(+)/L (N= 9). No patients developed hyperkalemia during the spironolactone treatment period. ENaC expression was significantly higher in all six HD patients studied, compared to control subjects (P < 0.05). Treatment with spironolactone in HD patients reduced alpha subunit mRNA expression to values similar to those of normal subjects. CONCLUSION Spironolactone may be considered for the treatment of selected chronic HD patients. The effect of the drug on a known target of aldosterone, the ENaC, demonstrates the effectiveness of the drug to block aldosterone effects in nonepithelial tissues.