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 The endothelium is a highly active organ responsible for vasculatory tone and structure, angiogenesis, as well as hemodynamic, humoral, and inflammatory responses. The endothelium is constantly exposed to blood flow, sheer stress and tension. Endothelial cells are present as a vasculature in every tissue of the body and react to and control its microenvironment. A variety of ion channels are present in the plasma membranes of endothelial cells. These include potassium channels such as inwardly rectifying potassium (Kir) channels, voltage-dependent (Kv) channels, ATP-regulated potassium (KATP) channels and three types of calcium-activated potassium channels (KCa), the large (BKCa), intermediate (IKCa), and small (SKCa) -conductance potassium channels. Potassium current plays a critical role in action potentials in excitable cells, in setting the resting membrane potential, and in regulating neurotransmitter release. Mitochondrial isoforms of potassium channel contribute to the cytoprotection of endothelial cells. Prominent among potassium channels are families of calcium-activated potassium channels, and especially large-conductance calcium-activated potassium channels. The modulation of BKCa channels, which are voltage- and calcium-dependent, has been intensively studied. The BKCa channels show large expression dynamics in endothelial cells and tissue-specific expression of large numbers of alternatively spliced isoforms. In this review, a few examples of the modulatory mechanisms and physiological consequences of the expression of BKCa channels are discussed in relation to potential targets for pharmacological intervention.
It is widely accepted that Ca2+ is released from the sarcoplasmic reticulum by a specialized type of calcium channel, i.e., ryanodine receptor, by the process of Ca2+-induced Ca2+ release. This process is triggered mainly by dihydropyridine receptors, i.e., L-type (long lasting) calcium channels, directly or indirectly interacting with ryanodine receptor. In addition, multiple endogenous and exogenous compounds were found to modulate the activity of both types of calcium channels, ryanodine and dihydropyridine receptors. These compounds, by changing the Ca2+ transport activity of these channels, are able to influence intracellular Ca2+ homeostasis. As a result not only the overall Ca2+ concentration becomes affected but also spatial distribution of this ion in the cell. In cardiac and skeletal muscles the release of Ca2+ from internal stores is triggered by the same transport proteins, although by their specific isoforms. Concomitantly, heart and skeletal muscle specific regulatory mechanisms are different.
Neuropathic pain constitutes a serious therapeutic problem. In most cases polytherapy is necessary. Tramadol and antidepressants have common mechanisms of action and are frequently used together in clinical practice, thus interaction between them is very important. In the present study isobolographic analysis for equivalent doses of drugs was applied to examine the nature of interaction between tramadol and doxepin or venlafaxine in a neuropathic pain model in rats. Allodynia and hyperalgesia were assessed after intraperitoneal administration of each drug alone or in combination. Dose response curves were obtained and ED50 doses were calculated. All drugs were effective in reducing thermal hyperalgesia and mechanical allodynia, however doxepin was more effective than venlafaxine. Combined administration of tramadol and doxepin demonstrated synergistic action in reducing thermal hyperalgesia and additive action in reducing mechanical allodynia. Combined administration of tramadol and venlafaxine showed additive action in reducing hyperalgesia and allodynia. Moreover, combined administration of tramadol and doxepin was more effective than combined administration of tramadol and venlafaxine. The experiments demonstrated that the nature of interaction between tramadol and doxepin is synergistic, which is not the case for tramadol and venlafaxine, what provides a valuable information referring to clinical practice, rationalizing administration of such drug combination.
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