Steiner A A, Branco L G
Departamento de Morfologia, Estomatologia e Fisiologia, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, 14040-904 Ribeirão Preto, São Paulo, Brazil.
Am J Physiol Regul Integr Comp Physiol. 2001 Feb;280(2):R448-57. doi: 10.1152/ajpregu.2001.280.2.R448.
We have recently reported that the central heme oxygenase (HO) pathway has an important role in the genesis of lipopolysaccharide fever. However, the HO product involved, i.e., biliverdine, free iron, or carbon monoxide (CO), has not yet been identified with certainty. Therefore, in the present study, we tested the thermoregulatory effects of all HO products. Body core temperature (T(c)) and gross activity of awake, freely moving rats was measured by biotelemetry. Intracerebroventricular administration of heme-lysinate (152 nmol), which induces the HO pathway, evoked a marked increase in T(c), a response that was attenuated by intracerebroventricular pretreatment with the HO inhibitor zinc deuteroporphyrin 2,4-bis glycol (200 nmol), indicating that an HO product has a pyretic action in the central nervous system (CNS) of rats. Besides, heme-lysinate also increased gross activity, but no correlation was found between this effect and the increase in T(c). Moreover, intracerebroventricular biliverdine or iron salts at 152 nmol, a dose at which heme-lysinate was effective in increasing T(c), produced no change in T(c). Accordingly, intracerebroventricular treatment with the iron chelator deferoxamine elicited no change in basal T(c) and did not affect heme-induced pyresis. However, heme-induced pyresis was completely prevented by the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxaline-1-one. Because biliverdine and iron had no thermoregulatory effects and CO produces most of its actions via sGC, these data strongly imply that CO is the only HO product with a pyretic action in the CNS.
我们最近报道，中枢血红素加氧酶（HO）途径在脂多糖发热的发生中起重要作用。然而，所涉及的HO产物，即胆绿素、游离铁或一氧化碳（CO），尚未得到确切鉴定。因此，在本研究中，我们测试了所有HO产物的体温调节作用。通过生物遥测技术测量清醒、自由活动大鼠的体核温度（T(c)）和总体活动。脑室内注射诱导HO途径的血红素赖氨酸盐（152 nmol）可引起T(c)显著升高，脑室内预先用HO抑制剂锌原卟啉2,4-双二醇（200 nmol）处理可减弱该反应，表明HO产物在大鼠中枢神经系统（CNS）中具有致热作用。此外，血红素赖氨酸盐还增加了总体活动，但未发现这种作用与T(c)升高之间存在相关性。而且，脑室内注射152 nmol的胆绿素或铁盐（血红素赖氨酸盐在此剂量下可有效升高T(c)）对T(c)无影响。因此，脑室内用铁螯合剂去铁胺处理对基础T(c)无影响，也不影响血红素诱导的发热。然而，可溶性鸟苷酸环化酶（sGC）抑制剂1H-[1,2,4]恶二唑并[4,3,-a]喹喔啉-1-酮可完全阻止血红素诱导的发热。由于胆绿素和铁没有体温调节作用，且CO大多通过sGC发挥作用，这些数据强烈表明CO是CNS中唯一具有致热作用的HO产物。
