Previous studies have shown that solutions of mainstream and sidestream cigarette smoke decrease both ciliary beat frequency and oocyte cumulus complex pick-up rate of hamster oviducts in vitro. The purpose of this study was to identify the component(s) in smoke that produces these effects. Chemicals reported to be ciliotoxic in other systems were tested on hamster infundibula at various concentrations to determine whether a dose-response inhibition of ciliary beat frequency occurred. In addition, the concentration of each test component was measured in mainstream and sidestream smoke solutions (whole, particulate, and gas phase). All test components (acrolein, formaldehyde, phenol, acetaldehyde, and potassium cyanide [KCN]) inhibited ciliary beat frequency in a dose-dependent manner. Inhibition of ciliary beat frequency was at least partially reversible for all test compounds except acrolein. The concentrations of acrolein, formaldehyde, and phenol that were required to inhibit beat frequency were at least 3-50 times higher than their corresponding concentrations in smoke solutions. In contrast, cyanide was present in all smoke solutions at concentrations sufficient to inhibit ciliary beat frequency. Cilia on the outer surface of the infundibulum function in picking up the oocyte cumulus complex. Oocyte cumulus complex pick-up rate was measured in vitro at KCN concentrations shown to inhibit ciliary beat frequency. Pick-up rate was likewise inhibited by KCN and remained significantly depressed after washout of KCN. These data show that cyanide is a potent inhibitor of both ciliary beat frequency and oocyte cumulus complex pick-up rate and that its concentration in smoke solutions is sufficiently high to explain the previously reported inhibition of these oviductal processes.

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Cholesterol is known to modulate membrane's biophysical properties plus influence in the function and trafficking of membrane proteins. We have shown that point mutations in the nicotinic acetylcholine receptor (nAChR) can evoke increased macroscopic responses upon cholesterol depletion and at the same time, some can result in a Slow Channel Congenital Myasthenic Syndrome (SCCMS) characterized by muscle weakness and fatigue. Our main goal is to characterize a cholesterol reduction treatment in a model in which both the SCCMS and the cholesterol sensitivity phenotype coexist, αC418W mutation. Using various approaches, we uncovered a fraction of αC418W located in caveolin‐1 rich domains, suggesting a non‐functional state and possibly susceptible to cholesterol levels. Cholesterol depletion by Lipitor® resulted in the rearrangement of these receptors to a now functional pool. After treatment, the model presented calcium overload, high caspase activity, lower motor activity and significant differentiation in relation to the neuromuscular junction and its volume under confocal microscopy. Better molecular understanding of the statins' role on membrane proteins and cholesterol's participation is crucial for novel approaches to old physiological phenomena's that haven't been solved. Ultimately addressing the biggest problem, are statins safe?

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Cholesterol is known to modulate membrane's biophysical properties and influence function and trafficking of membrane proteins. Cholesterol levels may regulate the movement of membrane proteins from functional to nonfunctional pools. To study this, the nicotinic acetylcholine receptor (nAChR) is used as a model due to its location on a functional pool and also, recent findings indicate that a nAChR mutation (αC418W) displayed an increase in macroscopic response upon cholesterol depletion. The αC418W is the first nAChR mutation identified as cause for a congenital myasthenic syndrome. Using various approaches, we uncovered a fraction of αC418W nAChRs located in caveolin‐positive domains, captive in a non‐functional state and susceptible to cholesterol levels. Cholesterol depletion resulted in the relocation of these receptors to a functional pool. Using a transgenic mouse model bearing the αC418W nAChR, we studied the effects of Lipitor®. After 18 days of statin treatment, the number of nAChRs and the total number of endplates in the diaphragm of the mutant were reduced. As a result, a generalized weakness of the αC418W mutant is present and in some animals an average of 60% loss of spontaneous activity. Understanding the molecular basis for the side‐effects of statins is critical to prevent the collateral contraindications and also to improve therapeutic intervention in hypercholesterolemic patients.