Physiological mediators

Balia, G., Jacobs, H.S., Eaton, J.W., Belcher, J.D. and Vercel-totti, G.M. (1991). Hemin a physiological mediator of low-density lipxjprotein oxidation and endothelial injury. Arteriosclerosis 11, 1700-1711. 

In contrast to the posterior pituitary lobe, the anterior pituitary lobe is under the control of several releasing and inhibiting hormones secreted from the hypothalamus via a portal vein system. The anterior pituitary lobe, in turn, synthesizes and secretes six major hormones. Figure 43-1 summarizes the physiologic mediators and effects of each of these hormones. 

From 1987 until now only a few years have passed, but in that time a new physiological mediator has been found, NO. In this short time the three enzymes that individually mediate this reaction in mammals have been characterized and the occurrence of similar enzymes in invertebrates have been determined. It is not only new, but surprising, that this physiological agent is a gas that is formed in one cell and spreads its function to nearby cells, but that its function is limited by oxidation. In the case of brain, Verma and coworkers151 have recently suggested that carbon monoxide may be a similar activator of cGMP. The period of surprises is not yet over. 

A signaling rheostat has been proposed where the relative level of SIP and ceramide determines cellular fate. This was based on the observation that ceramide, Fas and TNFa-mediated programmed cell death is suppressed by the addition of SIP (Cuvillier et al, 1996). The model assumes that ceramide is a physiological mediator of apoptosis although this is subject to controversy (Hofmann and Dixit, 1998 Kolesnick and Hannun, 1999). Indeed, sphingosine is also implicated as an apoptotic agent (see above). 

Even though nitric oxide is the physiological mediator of a variety of responses, excess nitric oxide is toxic to many cells as a result of its role in the production of per-oxynitrite and resultant lipid oxidation. Inhibitors of the NOS enzyme are in clinical trials for the treatment of hypotension associated with septic shock. Administration of low concentrations of nitric oxide through respiratory ventilators has been implemented to treat persistent pulmonary hypertension of the newborn. 

Both exocytotic and nonexocytotic mechanisms can contribute to adverse drug reactions that involve histamine release. Histamine is only one of several potent physiological mediators that are released from mast cells the other substances can also contribute to the overall immediate hypersensitivity reaction. 

M. C. Venuti (1985). Platelet-activating factor multifaceted biochemical and physiological mediator. Anna. Rep. Med. Chem. 20 193-202. 

IV. UNIQUE CHEMICAL PROPERTIES FOR A UBIQUITOUS AND GENERAL PHYSIOLOGICAL MEDIATOR... 

Abe H, Engler D, Molitch ME, Bollinguer-Gruber J, Reinchlin S. Vasoactive intestinal peptide is a physiological mediator of prolactin release in the rat. Endocrinology 1985 1116 1383-1390. 

Macica CM, von Hehn CA, Wang LY et al (2003) Modulation of the kv3.1b potassium channel isoform adjusts the fidelity of the firing pattern of auditory neurons. J Neurosci 23 1133 11 Majewski H, Iannazzo L (1998) Protein kinase C a physiological mediator of enhanced transmitter output. Prog Neurobiol 55 463-75... 

Gershengorn et al. [9] found in thyrotropic tumor cells in culture that cAMP analogues, phosphodiesterase inhibitors and cholera toxin caused an increase in TSH release that was additive to that of TRH, that there was no correlation between TSH release and cAMP levels and that there was no change in binding of cAMP to protein kinase, suggesting that cAMP is not the physiological mediator of TRH-in-duced TSH release. 

So far, we have encountered two reasons for designing drug molecules that are structurally different from physiological mediators ... 

All three catecholamines are rather polar, due to both the hydroxyl groups and the amino group, which will be mostly protonated at physiological pH. They will thus not cross the blood brain barrier easily, so that in effect the catecholamine pools in the brain and in the periphery will not interfere with each other. Exclusion by the blood brain barrier also applies to many synthetic agonists and antagonists that act on catecholamine receptors, as these compounds often are structurally similar to the physiological mediators. These drugs are useful to influence the peripheral... 

Saralasin illustrates that the stmcture of the physiological mediator or substrate is a logical starting point for the s m-thesis of inhibitors. However, it is not a completely satisfactory dmg, because it cannot be orally applied - can you see why The more recently developed dmg valsartan (Figure... 

Nagata E, Luo HR, Saiardi A, Bae BI, Suzuki N, Snyder SH. Inositol hexakisphosphate kinase-2, a physiologic mediator of cell death. J. Biol. Chem. 2005 280 1634-1640. 

Thus, whereas there is no doubt that acyl-CoAs will interact unspecifically with the membrane if added at very high concentrations ((6) on Fig. 10.13), the possibility remains that acyl-CoAs may interact in a more specific way at low concentrations with thermogenin, and thus be the physiological mediators of thermogenesis. 

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