Caffrey J L, Hathorne L F, Carter G C, Sinclair R J
Department of Physiology, Texas College of Osteopathic Medicine, Fort Worth 76107.
Circ Shock. 1990 Jul;31(3):317-32.
The beneficial pressor effects of naloxone in shock have been associated with existing adrenergic systems and in particular with circulating epinephrine. Vascular interactions among alpha adrenergic receptor agents, naloxone, and selected opioids were investigated. The addition of pharmacologic concentrations of the opiate antagonist naloxone enhanced contractile responses to lower doses of epinephrine by more than 100% in isolated renal interlobar arteries. Naloxone lowered the EC50 for both epinephrine and norepinephrine but the magnitude of enhanced responses were much greater for epinephrine. Responses in the presence of naloxone to more selective alpha agonists, phenylephrine and clonidine, were also much less. The enhanced contraction cannot be demonstrated in the absence of added catecholamine and is eliminated by alpha but not by beta adrenergic blockade. Dose responses for naloxone provided an EC50 (micromolar) above those reported for known opiate receptors. Representative mu (morphiceptin), delta (DADL), and kappa (dynorphin 1-9) receptor agonists were ineffective in altering the EC50 for naloxone. Responses opposite to naloxone could be generated with pharmacological additions of another kappa opioid, dynorphin 1-8. This effect was also accomplished without shifting the EC50 for naloxone to the right, suggesting dynorphin and naloxone operate via separate mechanisms. The (+) stereoisomer of naloxone was as or more effective than (-) naloxone, adding support for a nontraditional or nonopiate receptor mechanism. Corticosterone produced responses indistinguishable from naloxone. These pharmacological steroid-like responses to naloxone are used to suggest a hypothesis based upon modulation of extra-neuronal uptake and/or adrenergic receptor desensitization mechanisms.
纳洛酮在休克中的有益升压作用与现有的肾上腺素能系统有关，尤其是与循环中的肾上腺素有关。研究了α肾上腺素能受体激动剂、纳洛酮和特定阿片类药物之间的血管相互作用。在离体肾叶间动脉中，添加药理浓度的阿片拮抗剂纳洛酮可使对较低剂量肾上腺素的收缩反应增强100%以上。纳洛酮降低了肾上腺素和去甲肾上腺素的半数有效浓度（EC50），但对肾上腺素增强反应的幅度要大得多。在纳洛酮存在下，对更具选择性的α激动剂去氧肾上腺素和可乐定的反应也小得多。在没有添加儿茶酚胺的情况下，无法证明增强的收缩作用，并且α肾上腺素能阻滞剂可消除这种作用，而β肾上腺素能阻滞剂则不能。纳洛酮的剂量反应提供的半数有效浓度（微摩尔）高于已知阿片受体报道的浓度。代表性的μ（吗啡肽）、δ（DADL）和κ（强啡肽1-9）受体激动剂在改变纳洛酮的半数有效浓度方面无效。通过药理添加另一种κ阿片类药物强啡肽1-8，可以产生与纳洛酮相反的反应。这种作用也在不将纳洛酮的半数有效浓度向右移动的情况下实现，表明强啡肽和纳洛酮通过不同的机制起作用。纳洛酮的（+）立体异构体与（-）纳洛酮一样有效或更有效，这为非传统或非阿片受体机制提供了支持。皮质酮产生的反应与纳洛酮无法区分。这些对纳洛酮的药理类固醇样反应被用来提出一个基于对神经外摄取和/或肾上腺素能受体脱敏机制调节的假设。
