Brain interior

The number of active LDL receptors is also affected by a condition called familial hypercholesterolemia, in which there is a defective gene coding for the receptor. In either case, the reduction of active receptors means that the LDL carrying cholesterol is unable to enter the cell interior instead, it is deposited in the arteries leading to the heart or brain. These deposits build up over time and may block blood supply to the heart muscle or brain, resulting in a heart attack or stroke. In contrast, HDL transports cholesterol from other parts of the body to the liver, where it is degraded to bile acids. 

More than a decade ago, it became clear that the human body makes NO. It is made in the brain, in the muscle cells which exist in the interior of the blood vessels, by macrophages (white cells that form an important part of the immune system), by the corpus cavemosum of the penis, and perhaps elsewhere. NO plays an important role in each of these tissues. The source of the atoms for the synthesis of NO is the common amino acid arginine (chapter 9). Under the influence of an enzyme termed NO synthase, arginine is converted to NO (and other products). The lifetime of NO in the tissues is quite short, a few seconds, but it lasts long enough to be effective. 

An ability to penetrate lipid bilayers is a prerequisite for the absorption of drugs, their entry into cells or cellular organelles, and passage across the blood-brain barrier. Due to their amphiphilic nature, phospholipids form bilayers possessing a hydrophilic surface and a hydrophobic interior (p. 20). Substances may traverse this membrane in three different ways. 

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

The blood-brain barrier is a biochemical as well as a physical barrier. Brain endothelial cells create an enzymatic barrier composed of secreted proteases and nucleotidases, as well as intracellular metabolizing enzymes such as cytochrome P-450. Furthermore, y-glutamyl transpeptidase, alkaline phosphatase, and aromatic acid decarboxylase are more prevalent in cerebral microvessels than in nonneuronal capillaries. The efflux transporter P-glycoprotein and other extrusion pumps are present on the membrane surface of endothelial cells, juxtaposed toward the interior of the capillary. Furthermore, CNS endothelial cells display a net negative charge at the interior of the capillaries and at the basement membrane. This provides an additional selective mechanism by impeding passage of anionic molecules across the membrane. 

The motor unit has four components a motor neuron in the brain or spinal cord, its axon and related axons that comprise the peripheral nerve, the neuromuscular junction, and all the muscle fibers activated by the neuron. Like other cells, nerve and muscle cells have an external membrane that separates the inner fluids from those on the outside. The fluid on the inside is rich in potassium (K), magnesium (Mg), and phosphorus (P), whereas the fluid on the outside contains sodium (Na), calcium (Ca), and chloride (Cl). When all is quiet, the internal chemical composition of both nerve and muscle cells is remarkably constant and is called resting membrane potential. A primary reason for this constancy lies in the cells ability to regulate the flow of sodium— thanks to an enzyme in the membrane called Na+/K+ ATP-ase. Because the inside of the cell has less sodium than the outside, there is a negative potential (like a microscopic battery) of 70-90 mV. Under ordinary circumstances, the interior of the cell is 30 times richer in potassium than the extracellular fluid and the sodium concentration is 10-12 times greater on the outside of the cell. At rest, sodium tends to flow into cells and potassium oozes out. 

The second barrier separating the central nervous system from blood circulation is the choroid plexus or plexus choroideus. It is formed by a vascular sponge, which is surrounded by epithelial cells (ECs) and which is located within the ventricles ofthe brain. The actual barrier is formed by the epithelial cells and not by the interior capillary. One of the major functions of the choroid plexus is the production of cerebrospinal fluid (liquor). In addition, the epithelial cells secrete ions, peptides, nutrients, and vitamins [105]. 

Nicotinic acetylcholine (ACh) receptors are responsible for transmission of nerve impulses from motor nerves to muscle fibers (muscle types) and for synaptic transmission in autonomic ganglia (neuronal types). They are also present in the brain, where they are presumed to be responsible for nicotine addiction, although little is known about their normal physiological function there. Nicotinic receptors form cation-selective ion channels. When a pulse of ACh is released at the nerve-muscle synapse, the channels in the postsynaptic membrane of the muscle cell open, and the initial electrochemical driving force is mainly for sodium ions to pass from the extracellular space into the interior of the cell. However, as the membrane depolarizes, the driving force increases for potassium ions to go in the opposite direction. Nicotinic channels (particularly some of the neuronal type) are also permeable to divalent cations, such as calcium. 

The difference in polarity between epinephrine and amphetamine has an important physiological consequence. The cell membranes that separate the blood stream from the inside of brain cells have a nonpolar interior and a polar exterior that tend to slow down the movement of polar substances in the blood into the brain tissue. Epinephrine is too polar to move quickly from the blood stream into the brain, but amphetamine is not. The rapid stimulant effects of amphetamine are in part due to its ability to pass more quickly through the blood brain barrier. 

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