Tissues peripheral

Three tachykinin GPCRs, NK, NK, and NK, have been identified and cloned. AH are coupled to phosphatidjhnositol hydrolysis. The NK receptor is selective for substance P (SP) and is relatively abundant in the brain, spinal cord, and peripheral tissues. The NK receptor is selective for NKA and is present in the gastrointestinal tract, urinary bladder, and adrenal gland but is low or absent in the CNS. The NIC receptor is selective for NKB and is present in low amounts in the gastrointestinal tract and urinary bladder, but is abundant in some areas of the CNS, ie, the spinal dorsal bom, soUtary nucleus, and laminae IV and V of the cortex with moderate amounts in the interpeduncular nucleus. Mismatches in the distribution of the tachykinins and tachykinin receptors suggest the possibility of additional tachykinin receptor subtypes. 

In addition to the weU-defined opioid systems in the central nervous system, the three opioid peptides and their precursor mRNA have also been identified in peripheral tissues. ( -Endorphin is most abundant in the pituitary, where it exists in corticotroph cells with ACTH in the anterior lobe and in melanotroph cells with MSH in the intermediate lobe (59). Enkephalin and pre-pro-enkephalin mRNA have been identified in the adrenal medulla (60) and this has been the source of material for many studies of pro-enkephalin synthesis and regulation. Pre-pro-enkephalin mRNA has also been identified in the anterior and posterior lobes of the pituitary (61). mRNA for all three opioid precursors has been identified in the reproductive system (62—64). POMC... 

The chromaffin cells of the adrenal medulla may be considered to be modified sympathetic neurons that are able to synthesize E from NE by /V-methylation. In this case the amine is Hberated into the circulation, where it exerts effects similar to those of NE in addition, E exhibits effects different from those of NE, such as relaxation of lung muscle (hence its use in asthma). Small amounts of E are also found in the central nervous system, particularly in the brain stem where it may be involved in blood pressure regulation. DA, the precursor of NE, has biological activity in peripheral tissues such as the kidney, and serves as a neurotransmitter in several important pathways in the brain (1,2). 

NSAIDs inhibit cyclooxygenases (COX), the enzymes that catalyze the transformation of arachidonic acid (a ubiquitous cell component generated from phospholipids) to prostaglandins and thromboxanes. Two isoforms, COX-1 and COX-2, are constitutively expressed in peripheral tissues and in the central nervous... 

Second generation COMT inhibitors were developed by three laboratories in the late 1980s. Apart from CGP 28014, nitrocatechol is the key structure of the majority of these molecules (Fig. 3). The current COMT inhibitors can be classified as follows (i) mainly peripherally acting nitrocatechol-type compounds (entacapone, nitecapone, BIA 3-202), (ii) broad-spectrum nitrocatechols having activity both in peripheral tissues and the brain (tolcapone, Ro 41-0960, dinitrocatechol, vinylphenylk-etone), and (iii) atypical compounds, pyridine derivatives (CGP 28014,3-hydroxy-4-pyridone and its derivatives), some of which are not COMT inhibitors in vitro but inhibit catechol O-methylation by some other mechanism. The common features of the most new compounds are excellent potency, low toxicity and activity through oral administration. Their biochemical properties have been fairly well characterized. Most of these compounds have an excellent selectivity in that they do not affect any other enzymes studied [2,3]. 

COMT inhibitors rescue l-dopa and improve the brain entry of L-dopa by decreasing 3-OMD formation in peripheral tissues. The dose of L-dopa could be decreased, compared with the present combination therapy. Dose interval of L-dopa could also be prolonged. Further, COMT inhibitors should decrease fluctuations of dopamine formation in the brain. 

Lipoprotein metabolism is the process by which hydrophobic lipids, namely triglycerides and cholesterol, are transported within the interstitial fluid and plasma. It includes the transport of energy in the form of triglycerides from intestine and liver to muscles and adipose, as well as the transport of cholesterol both from intestine and liver to peripheral tissues, as well as from peripheral tissues back to the liver. 

Y2 receptors were originally cloned from human SMS-KAN cells. Later cloning studies in rats demonstrated that the cloned Y2 receptor is also the molecular correlate of a previously proposed PYY-preferring receptor in the gastrointestinal tract. Messenger RNA for the Y2 receptor has been detected in various parts of the CNS, whereas only low levels of Y2 mRNA were found in human peripheral tissues. 

Highest concentrations of MOPs are found in the thalamus, caudate, neocortex in the brain, but the receptors are also present in gastrointestinal tract, immune cells, and other peripheral tissues. 

A high concentration of DOPs is found in the olfactory bulb, the neocortex, caudate putamen, and in the spinal cord, but they are also present in the gastrointestinal tract and other peripheral tissues. The functional roles of DOP are less clearly established than for MOP they may have a role in analgesia, gastrointestinal motility, mood and behaviour as well as in cardiovascular regulation [2]. 

High concentrations of KOP have been found in the cerebral cortex and hypothalamus KOP is also present in the gastrointestinal tract, in immune cells as well as in other peripheral tissues. KOPs have been implicated in the regulation of nociception, diuresis, feeding, neuroendocrine and immune system functions [2]. 

The exact mechanism by which PPARy ligands affect insulin resistance (improved glucose uptake by peripheral tissues, most notably skeletal muscle) remains unclear. 

PPARa Liver, heart, skeletal muscle, atherosclerotic lesions TG- and LDL-C-lowering and HDL-C-raising re-directs excess cholesterol from the peripheral tissues to the liver for excretion into the bile via HDL-C slowed progression of atherosclerosis Fatty acids, eico-sanoids (fatty acids derived from FAS ) Fibrates fenofibrate (Tricor ), genfibrozil (Lopid ) Dyslipidemia... 

Similar Ca2+ release mechanism operates also in smooth muscles, neurons and some peripheral tissues. 

TK NKxr displays a broad distribution in both peripheral tissues and in the central nervous system (CNS). In both CNS and enteric neurons, NKxr stimulation increase their excitability, whereas in trigeminal ganglion neurons SP has no intrinsic electrophysio-logical effects but is capable to enhance the amplitude of the inward current induced by the stimulation of serotonin 5-HT3 recqrtors. This enhancement dqjends on the activation of PKC via the stimulation of NKX recqrtors. This is an interesting case of receptor cross talk. Other functions of NKxr have been also highlighted. 

Thyroxine (3, 5, 3,5-L-teraiodothyronine, T4) is a thyroid hormone, which is transformed in peripheral tissues by the enzyme 5 -monodeiodinase to triiodothyronine. T4 is 3-8 times less active than triiodothyronine. T4 circulates in plasma bound to plasma proteins (T4-binding globulin, T4-binding prealbumin and albumin). It is effective in its free non-protein-bound form, which accounts for less than 1%. Its half-life is about 190 h. 

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