Mioni Chiara, Giuliani Daniela, Cainazzo Maria Michela, Leone Sheila, Bazzani Carla, Grieco Paolo, Novellino Ettore, Tomasi Aldo, Bertolini Alfio, Guarini Salvatore
Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, via G. Campi 287, 41100, Modena, Italy.
Eur J Pharmacol. 2003 Sep 23;477(3):227-34. doi: 10.1016/s0014-2999(03)02184-8.
In rats subjected to myocardial ischemia/reperfusion, melanocortin peptides, including gamma(1)-melanocyte-stimulating hormone (gamma(1)-MSH), are able to exert a protective effect by stimulating brain melanocortin MC(3) receptors. A non-melanocortin receptor belonging to a group of receptors for Phe-Met-Arg-Phe-NH(2) (FMRFamide)-like peptides may be involved in some of the cardiovascular effects of the gamma-MSHs. FMRFamide-like peptides and gamma(1)-/gamma(2)-MSH share, among other things, the C-terminal Arg-Phe sequence, which seems to be essential for cardiovascular effects in normal animals. So we aimed to further investigate which receptor and which structure are involved in the protective effects of melanocortins in anesthetized rats subjected to myocardial ischemia by ligature of the left anterior descending coronary artery (5 min), followed by reperfusion. In saline-treated rats, reperfusion induced, within a few seconds, a high incidence of ventricular tachycardia and ventricular fibrillation, and a high percentage of death within the 5 min of observation period. Reperfusion was associated with a massive increase in free radical blood levels and with an abrupt and marked fall in systemic arterial pressure. The i.v. treatment (162 nmol/kg) during the ischemic period with the adrenocorticotropin fragment 1-24 [ACTH-(1-24): the reference protective melanocortin which binds all melanocortin receptors], as well as with both the melanocortin MC(3) receptor agonists gamma(2)-MSH and [D-Trp(8)]gamma(2)-MSH, reduced the incidence of ventricular tachycardia, ventricular fibrillation and death, the increase in free radical blood levels and the fall in arterial pressure. On the contrary, gamma(2)-MSH-(6-12) (a fragment unable to bind melanocortin receptors) was ineffective. Such protective effect was prevented by the melanocortin MC(3)/MC(4) receptor antagonist SHU 9119. In normal (i.e., not subjected to myocardial ischemia/reperfusion) rats, the same i.v. dose (162 nmol/kg) of gamma(2)-MSH, [D-Trp(8)]gamma(2)-MSH and gamma(2)-MSH-(6-12) provoked a prompt and transient increase in arterial pressure; on the other hand, ACTH-(1-24), which lacks the C-terminal Arg-Phe sequence, decreased arterial pressure, but only at higher doses. Heart rate of normal rats was not affected by any of the assayed peptides. The present data confirm and extend our previous findings that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC(3) receptors. Moreover, they further support the notion that, in normal rats, cardiovascular effects of gamma-MSHs are mediated by receptors for FMRFamide-like peptides, for whose activation, but not for that of melanocortin MC(3) receptors, the C-terminal Arg-Phe structure being relevant.
在经受心肌缺血/再灌注的大鼠中，包括γ(1)-促黑素细胞激素（γ(1)-MSH）在内的黑皮质素肽，能够通过刺激脑黑皮质素MC(3)受体发挥保护作用。一种属于苯丙氨酸-甲硫氨酸-精氨酸-苯丙氨酸-酰胺（FMRF酰胺）样肽受体组的非黑皮质素受体，可能参与了γ-MSHs的某些心血管效应。FMRF酰胺样肽与γ(1)/γ(2)-MSH除其他外，共享C末端的精氨酸-苯丙氨酸序列，这似乎对正常动物的心血管效应至关重要。因此，我们旨在进一步研究在通过结扎左冠状动脉前降支（5分钟）然后再灌注而经受心肌缺血的麻醉大鼠中，哪种受体和哪种结构参与了黑皮质素的保护作用。在生理盐水处理的大鼠中，再灌注在几秒钟内诱发了高发生率的室性心动过速和心室颤动，以及在观察期5分钟内的高死亡率。再灌注与自由基血水平的大量增加以及全身动脉压的突然且显著下降有关。在缺血期静脉注射治疗（162 nmol/kg）促肾上腺皮质激素片段1-24 [ACTH-(1-24)：结合所有黑皮质素受体的参考保护性黑皮质素]，以及黑皮质素MC(3)受体激动剂γ(2)-MSH和[D-色氨酸(8)]γ(2)-MSH，降低了室性心动过速、心室颤动和死亡的发生率、自由基血水平的增加以及动脉压的下降。相反，γ(2)-MSH-(6-12)（一个无法结合黑皮质素受体的片段）无效。这种保护作用被黑皮质素MC(3)/MC(4)受体拮抗剂SHU 9119阻断。在正常（即未经受心肌缺血/再灌注）大鼠中，相同静脉注射剂量（162 nmol/kg）的γ(2)-MSH、[D-色氨酸(8)]γ(2)-MSH和γ(2)-MSH-(6-12)引起动脉压迅速且短暂的升高；另一方面，缺乏C末端精氨酸-苯丙氨酸序列的ACTH-(1-24)仅在较高剂量时降低动脉压。正常大鼠的心率不受任何所检测肽的影响。目前的数据证实并扩展了我们先前的发现，即黑皮质素通过激活黑皮质素MC(3)受体预防心肌再灌注损伤。此外，它们进一步支持了这样一种观点，即在正常大鼠中，γ-MSHs的心血管效应由FMRF酰胺样肽的受体介导，对于其激活而言，C末端精氨酸-苯丙氨酸结构是相关的，但对于黑皮质素MC(3)受体的激活则不然。
