Outcomes of Hypertensive Patients with Renal Fibromuscular Dysplasia Compared with Patients with Concomitant Atherosclerotic Renal Artery Stenosis following Endovascular Therapy.

PURPOSE: To examine if the outcomes after endovascular treatment in hypertensive patients with renal artery fibromuscular dysplasia (FMD) and incidental atherosclerotic renal artery stenosis (ARAS) differ from the outcomes in patients with FMD alone. MATERIALS AND METHODS: All cases of patients with renal artery FMD undergoing percutaneous transluminal angioplasty during the period 2002-2012 were reviewed. The patients with complete data before and after the procedure were identified (N = 84). Based on the procedural reports, these patients were separated into two cohorts: patients with isolated FMD (n = 59) and patients with concomitant atherosclerotic renal artery stenosis and FMD (ARAS-FMD) (n = 25). The medical record of each patient was reviewed for baseline blood pressure, antihypertensive medication use, and renal function data and the same data after the procedure. Procedural details including the angiographic findings, the number of stents placed, the average number of revascularization procedures, and the number of patients requiring more than one revascularization procedure were noted. RESULTS: The study population included 68 patients (FMD, n = 46; ARAS-FMD, n = 22). Patients in the FMD and ARAS-FMD cohorts experienced comparable significant decreases in systolic and mean arterial pressures after endovascular intervention. There was no change in the number of antihypertensive medications after the procedure within or between groups. Patients in the ARAS-FMD cohort had lower baseline estimated glomerular filtration rates (P = .007); however, renal function stabilized in both groups after endovascular therapy. CONCLUSIONS: Patients with ARAS-FMD respond to endovascular therapy with outcomes similar to patients with isolated renal artery FMD.

Synthesis and biological evaluation of a fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain and imaging agent.

Here we report on a novel fluorescent analog of phenytoin as a potential inhibitor of neuropathic pain with potential use as an imaging agent. Compound 2 incorporated a heptyl side chain and dansyl moiety onto the parent compound phenytoin and produced greater displacement of BTX from sodium channels and greater functional blockade with greatly reduced toxicity. Compound 2 reduced mechano-allodynia in a rat model of neuropathic pain and was visualized ex vivo in sensory neuron axons with two-photon microscopy. These results suggest a promising strategy for developing novel sodium channel inhibitors with imaging capabilities.

Temporal lobe epilepsy induces intrinsic alterations in Na channel gating in layer II medial entorhinal cortex neurons.

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy involving the limbic structures of the temporal lobe. Layer II neurons of the entorhinal cortex (EC) form the major excitatory input into the hippocampus via the perforant path and consist of non-stellate and stellate neurons. These neurons are spared and hyper-excitable in TLE. The basis for the hyper-excitability is likely multifactorial and may include alterations in intrinsic properties. In a rat model of TLE, medial EC (mEC) non-stellate and stellate neurons had significantly higher action potential (AP) firing frequencies than in control. The increase remained in the presence of synaptic blockers, suggesting intrinsic mechanisms. Since sodium (Na) channels play a critical role in AP generation and conduction we sought to determine if Na channel gating parameters and expression levels were altered in TLE. Na channel currents recorded from isolated mEC TLE neurons revealed increased Na channel conductances, depolarizing shifts in inactivation parameters and larger persistent (I(NaP)) and resurgent (I(NaR)) Na currents. Immunofluorescence experiments revealed increased staining of Na(v)1.6 within the axon initial segment and Na(v)1.2 within the cell bodies of mEC TLE neurons. These studies provide support for additional intrinsic alterations within mEC layer II neurons in TLE and implicate alterations in Na channel activity and expression, in part, for establishing the profound increase in intrinsic membrane excitability of mEC layer II neurons in TLE. These intrinsic changes, together with changes in the synaptic network, could support seizure activity in TLE.

2,4(5)-diarylimidazoles as inhibitors of hNaV1.2 sodium channels: pharmacological evaluation and structure-property relationships.

Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal Na(V)1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D(7.4)) and basicity (pK(a)) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC(50) values that were considerably lower than our lead compound. In particular, the m-CF(3) disubstituted 22 was the most active compound, inhibiting hNa(V)1.2 currents within the nanomolar concentration range (IC(50)=200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC(50)'s values that were greater than 100 microM.

2,4(5)-Diarylimidazoles: synthesis and biological evaluation of a new class of sodium channel blockers against hNa(v)1.2.

A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synthesis and evaluated as potential inhibitors of hNa(v)1.2 sodium channel currents. One member of this series (4) exhibited profound inhibition of Na(v)1.2 currents, emerging as a promising lead compound for further structure-activity relationship studies for the development of novel sodium channel blockers.