Li S J, Varga K, Archer P, Hruby V J, Sharma S D, Kesterson R A, Cone R D, Kunos G
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond 23298-0613, USA.
J Neurosci. 1996 Aug 15;16(16):5182-8. doi: 10.1523/JNEUROSCI.16-16-05182.1996.
Melanocortin peptides and at least two subtypes of melanocortin receptors (MC3-R and MC4-R) are present in brain regions involved in cardiovascular regulation. In urethane-anesthetized rats, unilateral microinjection of alpha-melanocyte-stimulating hormone (MSH) into the medullary dorsal-vagal complex (DVC) causes dose-dependent (125-250 pmol) hypotension and bradycardia, whereas gamma-MSH is less effective. The effects of alpha-MSH are inhibited by microinjection to the same site of the novel MG4-R/MC3-R antagonist SHU9119 (2-100 pmol) but not naloxone (270 pmol), whereas the similar effects of intra-DVC injection of beta-endorphin (1 pmol) are inhibited by naloxone and not by SHU9119. Hypotensive and bradycardic responses to electrical stimulation of the arcuate nucleus also are inhibited by ipsilateral intra-DVC microinjection of SHU9119. gamma-MSH and ACTH(4-10), but not alpha-MSH, elicit dose-dependent (0.1-12.5 nmol) pressor and tachycardic effects, which are much more pronounced after intracarotid than after intravenous administration. The effects of gamma-MSH (1.25 nmol) are not inhibited by the intracarotid injection of SHU9119 (1.25-12.5 nmol) or the novel MC3-R antagonist SHU9005 (1.25-12.5 nmol). We conclude that the hypotension and bradycardia elicited by the release of alpha-MSH from arcuate neurons is mediated by neural melanocortin receptors (MC4-R/MC3-R) located in the DVC, whereas the similar effects of beta-endorphin, a peptide derived from the same precursor, are mediated by opiate receptors at the same site. In contrast, neither MC3-R nor MC4-R is involved in the centrally mediated pressor and tachycardic actions of gamma-MSH, which, likely, are mediated by an as yet unidentified receptor.
促黑素肽和至少两种促黑素受体亚型（MC3-R和MC4-R）存在于参与心血管调节的脑区。在氨基甲酸乙酯麻醉的大鼠中，向延髓背迷走复合体（DVC）单侧微量注射α-黑素细胞刺激素（MSH）会引起剂量依赖性（125 - 250 pmol）的低血压和心动过缓，而γ-MSH的效果则较差。α-MSH的作用可被向同一部位微量注射新型MG4-R/MC3-R拮抗剂SHU9119（2 - 100 pmol）所抑制，但不能被纳洛酮（270 pmol）抑制，而向DVC内注射β-内啡肽（1 pmol）产生的类似作用可被纳洛酮抑制，而不能被SHU9119抑制。同侧DVC内微量注射SHU9119也可抑制对弓状核电刺激引起的低血压和心动过缓反应。γ-MSH和促肾上腺皮质激素（4 - 10），而非α-MSH，可引起剂量依赖性（0.1 - 12.5 nmol）的升压和心动过速作用，颈动脉内给药后比静脉给药后更为明显。γ-MSH（1.25 nmol）的作用不会被颈动脉内注射SHU9119（1.25 - 12.5 nmol）或新型MC3-R拮抗剂SHU9005（1.25 - 12.5 nmol）所抑制。我们得出结论，弓状神经元释放α-MSH所引起的低血压和心动过缓是由位于DVC的神经促黑素受体（MC4-R/MC3-R）介导的，而源自同一前体的肽β-内啡肽的类似作用则是由同一部位的阿片受体介导的。相比之下，MC3-R和MC4-R均不参与γ-MSH的中枢介导的升压和心动过速作用，这可能是由一种尚未确定的受体介导的。
