Tseng A, Inglis A, Selbie L A, Moriarty M, Potter E K
Garvan Institute for Medical Research, Darlinghurst, Sydney, Australia.
Eur J Pharmacol. 1994 Dec 27;271(2-3):265-71. doi: 10.1016/0014-2999(94)90783-8.
Neuropeptide, a 36 amino acid peptide, is one of the most ubiquitous neuropeptides in the nervous system. It is released during stimulation of sympathetic nerves and is implicated as an important neurotransmitter regulating cardiovascular activity. Administration of neuropeptide Y results in vasoconstriction and inhibition of neurotransmitter release. However, the absence of any effective inhibitors of neuropeptide Y action have precluded the examination of its possible role in hypertension. Here we describe a synthetic hexapeptide (BRC 672), corresponding to residues 22-27 of neuropeptide Y. Following the administration of BRC 672 (6.7 mumol/kg), neuropeptide Y-induced pressor responses were reduced by 32-48% in a dose-dependent fashion. The inhibition was specific for neuropeptide Y, as the pressor response to phenylephrine, an alpha-adrenoceptor agonist, was unchanged. It was selective for the postsynaptic (neuropeptide Y Y1 receptor-mediated) vasoconstrictor activity, because the presynaptic (neuropeptide Y Y2 receptor-mediated) cardiac vagal inhibition evoked by injection of neuropeptide Y to rats was not affected. The hexapeptide inhibited the neuropeptide Y-induced increase in cytosolic free Ca2+ in mammalian cells expressing the cloned human neuropeptide Y Y1 receptor. Injections of BRC 672 significantly reduced blood pressure in anaesthetised rats and in conscious spontaneously hypertensive rats. Resting arterial blood pressure decreased from 136 +/- 4 mm Hg to 122 +/- 3 mm Hg and remained depressed 2 h after the administration of the hexapeptide in anaesthetised rats. In spontaneously hypertensive rats blood pressure was decreased for up to 4 h.
神经肽Y是一种由36个氨基酸组成的肽，是神经系统中分布最广泛的神经肽之一。它在交感神经受到刺激时释放，被认为是调节心血管活动的重要神经递质。给予神经肽Y会导致血管收缩并抑制神经递质释放。然而，由于缺乏任何有效的神经肽Y作用抑制剂，阻碍了对其在高血压中可能作用的研究。在此，我们描述了一种合成六肽（BRC 672），它对应于神经肽Y的第22 - 27位氨基酸残基。给予BRC 672（6.7 μmol/kg）后，神经肽Y诱导的升压反应以剂量依赖性方式降低了32% - 48%。这种抑制作用对神经肽Y具有特异性，因为对α - 肾上腺素能受体激动剂去氧肾上腺素的升压反应没有改变。它对突触后（神经肽Y Y1受体介导）的血管收缩活性具有选择性，因为向大鼠注射神经肽Y所诱发的突触前（神经肽Y Y2受体介导）的心脏迷走神经抑制不受影响。该六肽抑制了在表达克隆的人类神经肽Y Y1受体的哺乳动物细胞中神经肽Y诱导的胞质游离Ca2+增加。注射BRC 672可显著降低麻醉大鼠和清醒自发性高血压大鼠的血压。在麻醉大鼠中，静息动脉血压从136±4 mmHg降至122±3 mmHg，并在给予六肽后2小时仍保持降低。在自发性高血压大鼠中，血压降低可持续长达4小时。
