血圧降下薬の耐性に関する薬理学的研究
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概要
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In order to know the mechanisms of tolerance to the depressor actions of hypotensive agents, Hexamethonium chloride (C_6), Regitine hydrochloride (Rg.) and Apresoline hydrochloride (Ap.), the present author has investigated changes in the response of blood pressure to various drugs by means of both direct and indirect measurements of blood pressure and moreover changes in the diameter of the central artery of the ear, pupil and blood histamine content in addition to histopathological changes in rabbits which were made tolerant to the depressor actions by the repeated administration of the agents. The results thus obtained were as follows: 1. The hypotensive effects of C_6, Rg. or Ap. decreased and finally became pressor following the daily intravenous injection of constant doses respectively for a long time to normal rabbits. Thus, tolerance was demonstrated for their depressor effects in the normotensive animals. 2. C_6-, Rg.- or Ap.-tolerant rabbits showed cross-tolerance to several different hypotensive drugs. In the animals, these drugs exerted, on the contrary, pressor effects. 3. Blood pressure in C_6-, Rg.- or Ap.-tolerant rabbits was raised much more sensitively with Adt enaline; Noradrenaline, Privina, Atropine, Acetylcholine, Nicotine, Strychnine, Atonine, Barium chloride, various kinds of antihistaminic drugs, 2987 R. P. and Chlorpromazine than that in normal rabbits. Such blood pressure rises were strikingly inhibited with Phenobarbital but were not affected with Urethane. 4. In the rabbits that had become tolerant to the depressor action of C_6, Rg. or Ap., the peripheral vasodilating action of the agents decreased and the relaxing effect of Sodium nitrite on the smooth muscles in vascular wall diminished. 5. In the rabbits that had received C_6 or Rg. repeatedly, tolerance to their mydriatic action developed. When Ap. was given repeatedly, tolerance to its miotic action developed.6. In the rabbits that had been given C_6 repeatedly, no tolerance was demonstrated for the action of C_6, which was of interference with pupillary light reaction. 7. There was no great difference in the blood histamine content between C_6-, Rg.- or Ap.-tolerant and nontolerant rabbits. 8. Histopathological researches on the C_6-, Rg.- or Ap.-tolerant rabbits revealed distinct changes in the places which seemed to be the sites of action of the agents; in sympathetic ganglia for the C_6-tolerant rabbits, in the medullary cells of the adrenal glands for the Rg.-tolerant rabbits and in vascular wall for the Ap.-tolerant rabbits. And moreover the researches revealed findings from which an increased function in nerve cells in the hypothalamus, especially in the corpus subthalamicum Luysi was supposed. 9. The development of tolerance to the hypotensive actions of C_6, Rg. or Ap. is due to compensatory hypersensitivities in the adrenergic effector cells, vasomotor centrum and smooth muscles in vascular wall, which cause easily rise in blood pressure. Moreover, the diencephalon plays an important role in the phenomenon.
- 千葉大学の論文