PubMed · 8854663
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C P Tountas. 1996. Digital blocks.. https://pubmed.ncbi.nlm.nih.gov/8854663/
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1. Effects of tetracaine on membrane currents and cell shortening were measured with high resistance electrodes, single-electrode voltage clamp (switch clamp) and a video edge detector at 37 C in cardiac ventricular myocytes. 2. Sequential voltage steps from -65 mV to -40 and 0 mV were used to activate two mechanisms of excitation-contraction (EC) coupling separately. The step to -40 mV activated the voltage-sensitive release mechanism (VSRM); the step to 0 mV1 activated Ca2+-induced Ca2+ release (CICR) coupled to inward Ca2+ current (IL). 3. Exposure to 100-300 microM tetracaine inhibited VSRM contractions but not CICR contractions. Inhibition of VSRM contractions was independent of INa blockade. In contrast, 100 microM Cd2+ blocked IL and CICR contractions, but not VSRM contractions. Simultaneous application of both agents blocked both mechanisms of EC coupling. 4. Contraction-voltage relationships were sigmoidal when the VSRM was available. However, when the VSRM was inhibited with 100-300 microM tetracaine, contraction-voltage relationships became bell-shaped. The tetracaine-insensitive contractions were abolished by 0.1 microM ryanodine, indicating that they were dependent on release of SR Ca2+. 5. At a higher concentration (1 mM) tetracaine also inhibited IL and contractions triggered by IL; however, the time course of effects on IL and associated contractions were different than for VSRM contractions. 6. With continuous application of tetracaine, the VSRM remained inhibited although SR Ca2+ stores increased 4-fold as assessed with caffeine. CICR contractions were not inhibited and maximum amplitude of contraction was not reduced. 7. Rapid application of tetracaine just before and during test steps also inhibited VSRM contractions, but without significantly affecting sarcoplasmic reticulum (SR) Ca2+ stores or CICR contractions. Maximum amplitude of contraction was reduced. 8. Rapid application of tetracaine (100-300 microM) allows preferential inhibition of the VSRM and provides a pharmacological method to assess the contribution of the VSRM to EC coupling.
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The mechanism of the release of encapsulated lidocaine from spherical nanoparticles based on poly(D,L-lactic acid) polymer carrier (PLA) was studied through mathematical modelling. The drug was incorporated in the PLA matrix with particle sizes from approximately 250 to 820 nm and corresponding loadings varying from about 7 to 32% (w/w). The rate of release correlated with the particle drug loading and was fastest at small particles with a low drug content. It was about four times slower at large particles with a high loading when the process of release took up to 100 h. Two simple models, diffusion and dissolution, were applied for the description of the experimental data of lidocaine release and for the identification of the release mechanisms for the nanoparticles of different drug loading. The modelling results showed that in the case of high drug loadings (about 30% w/w), where the whole drug or a large part of it was in the crystallised form, the crystal dissolution could be the step determining the release rate. On the other hand, the drug release was diffusion-controlled at low loadings (less than 10% w/w) where the solid drug was randomly dispersed in the matrix. The estimated values of the diffusion coefficient of lidocaine in these particles were in the range of 5-7x10(-20) m(2)/s. A significant influence of both crystal dissolution and drug diffusion on the overall rate of release was assumed at PLA nanoparticles with medium lidocaine loadings.