Medical brain Notes 3

  Some aspects of calcium pharmacology   Calcium has a dual role in the regulation of cell function: It carries charge and thus contributes to the changes of membrane potential in excitable cells, and it acts as a biochem-ical messenger by directly binding to proteins and modify-ing their functional state. Proteins directly or indirectly af-fected by calcium are very diverse and include enzymes, cy-toskeletal proteins, ion channels, and transcription factors.   The level of free calcium in the cytosol is affected by mul-tiple mechanisms of active and passive transport. These are summarized in Figure 6.1. While the level of calcium in the cytosol varies in time, it is always much lower than in the extracellular space, or than in the mitochondria and ER. These two organelles function as intracellular buffers or reservoirs of calcium. Accordingly, calcium transport systems operating in both directions exist not only at the cytoplasmic membrane but also at the mitochondrial (...

  Calcium in muscle cell function   Calcium has a pivotal role in the control of muscle cell action. Muscle cells occur in different types:   •       Smooth muscle cells. They occur in hollow organs, including blood vessels,   •       Heart muscle cells,   •       Skeletal muscle cells.   Heart and skeletal muscle together are classified as striated muscle yet do have some important functional differences (see below). The muscle cells in vessel walls control the blood pressure, which makes them important drug targets; that heart muscle cells are important targets, too should go without saying.   We will first look at the role of calcium in the contraction of striated muscle. Figure 6.2a shows a light-microscopic picture of heart muscle. The striations are oriented perpen-dicularly to the longitudinal axis of the cells. The borders between the individual heart muscle cells are br...

  Calcium channel blockers Examples of such calcium channel blockers are shown in Figure 6.7. While nifedipine contains the dihydropyridine moiety (in red) after which the receptor has been named, verapamil does not, indicating that the receptor's name does not reflect any fundamental requirement of drug molecular structure. We have seen before that calcium channels are not only im-portant in the contraction of the heart muscle but also in the generation of cardiac rhythm. The DHPR is present in both the pacemaker and the muscle cells of the heart mus-cle. This means that calcium channel blockers will not only reduce the contractility of the heart muscle cells but also slow down the rhythm. Slowing down the rhythm means increased duration of the interval between two contrac-tions (the diastole). The diastole is the only period during which the pressure within the heart tissue does not exceed the arterial blood pressure; therefore, only during the dias-tole the heart tissue itself i...

  Digitalis (foxglove) glycosides In other (mainly elderly) patients, the main problem may consist not so much in under-perfusion of the heart muscle but in a weak contractility. The heart becomes distended, further reducing the effectiveness of contraction 5 . Here, we clearly want to increase the contractility of the heart mus-cle. The most effective way to do this is to raise the avail-ability of calcium in the cytosol. This is done with digitalis (foxglove) glycosides. The mechanism of action of these is outlined in Figure 6.8a. Digitalis glycosides bind to and block the Na + /K + -ATP'ase in the cytoplasmic membrane. The backup of sodium in the cell reduces the active export of Ca ++  from the cytoplasm. Although the transfer of cal-cium across the cytoplasmic membrane is small relative to the fluxes occurring across the ER membrane, the ER stores will eventually fill up, and the cytosolic Ca  ++  level will be raised. This treatment is quite effective and was r...

  Calcium-dependent signaling by adrenergic receptors Calcium is also involved in the cellular effects of media-tors such as epinephrine and norepinephrine. In the heart, the predominant adrenergic receptors are of the type  β 1 , and both agonists and antagonists of  β  receptors are being used in cardiac therapy.  β -Adrenoceptors always activate adenylate cyclase and, through cAMP, protein kinase A (PKA). However, the downstream effectors may differ de-pending on the cell type. In the heart, PKA changes the ac-tivity of several target proteins including RyR, DHPR, and the regulatory ER membrane protein phospholamban (Fig-ure 6.10a). While the effect of phospholamban phosphory-lation is a disinhibition of SERCA (SR/ER calcium trans-porter, an ATP-dependent uniporter) that will tend to reduce cytosolic Ca ++ , the first two will increase the availability of Ca ++ , which seems to be the net effect. In smooth muscle, contraction is slower and longer lasting than...