Annual review of pharmacology最新文献

In the striated muscle of the upper esophageal sphincter, tonic maintenance of closure is probably mediated via tonic central excitation of the extrinsic motor innervation; relaxation represents central inhibition of this mechanism. The motor nerves are probably cholinergic and act through nicotinic receptors like those of somatic striated muscle. In the striated muscle of the esophageal body, swallowing-induced contraction is also probably a cholinergic and nicotinic response. In the smooth muscle of the esophageal body, the control of contractions is cholinergic and muscarinic in part, but there is evidence for a nonadrenergic and noncholinergic component as well. The muscarinic component may arise from the cholinergic innervation of the longitudinal muscle layer. The other component may lie in the cryptic innervation of the circular muscular layer. In the smooth-muscled lower esophageal sphincter, resting closure tension appears to reflect a variety of possible control mechanisms. No single control system predominates. The evidence for muscarinic excitation is equivocal. An excitatory adrenergic alpha mechanism and inhibitory adrenergic beta receptors may contribute. A role for the polypeptide hormones from the gastrointestinal tract seems unlikely. Relaxation of the lower sphincter with swallowing seems not to involve any of these mechanisms, but is apparently accomplished by nonadrenergic noncholinergic inhibitory nerves like those present elsewhere in the gut (87). The possibility that the transmitter of these nerves is an adenine nucleotide has been raised from studies of other parts of the gut, but that hypothesis has not yet been examined critically in the lower esophageal sphincter.

The role of Se in biology appears from the evidence now at hand to be as a catalyst par excellence. As unique prosthetic group of a variety of enzymes, presumably as Se(2-), Se functions with tocopherol to protect cell and organelle membranes from oxidative damage, to facilitate the union between oxygen and hydrogen at the end of the metabolic chain, and to transfer ions across cell membranes, in protein synthesis in erythrocytes and in liver organelles, in immunoglobulin synthesis, and in ubiquinone syntheses. As perhaps the most versatile and rapid nucleophile, Se is thought to amplify and orient SH in equilibrium -S-S-interactions involving glutathione and proteins. Its toxicity appears to be due to overaccumulation of selenite ions, which act as oxidants to inhibit SH interactions. Such toxicity is readily avoided or reversed in many ways. Although not yet recognized as essential for man, Se is clearly essential for many animal species and some microorganisms. As the active selenide, Se emerged as the target for many heavy metal toxicities; contrariwise, as a specific antidote against heavy metal toxicities. Despite all this, its unusual toxicity and the many preconceived notions about Se continue to confuse attitudes toward the safe uses of selenicals. From a suspected cause of cancer, Se metamorphosed, via evidence over many years, into something of possible anticancer value. Interrelations between Se, Vitamin E, the ubiquinones, and various chronic diseases appear as beckoning research areas. The reported veterinary values of Se-tocopherol combinations in animals, together with clinical evidence, plus human and animal evidence for safety, offer promise for intensive medical investigation. The historical confusion and misunderstandings regarding Se must be corrected, however, before advantage can be taken of its potential for human welfare. The many misjudgments about Se, ever since 1900 and more obviously since the 1930s, have involved other trace elements. Unrealistic regulations stemming from these misunderstandings prevail worldwide. Evidence suggests that, once the nutrition biochemistry and toxicology of Se is sufficiently understood and appreciated, major breakthroughs in agriculture, medicine, and public health can result. Much has been accomplished along these lines in New Zealand in animal agriculture, in the US and other countries in veterinary medicine, and in Mexico in human medicine.