Rigamonti A E, Cella S G, Marazzi N, Müller E E
Department of Medical Pharmacology, University of Milan, Italy.
Metabolism. 1999 Feb;48(2):176-82. doi: 10.1016/s0026-0495(99)90030-6.
The growth hormone (GH)-releasing activity of Hexarelin, a potent GH-releasing peptide (GHRP) analog, was evaluated in eight young (aged 1 to 6 years) and five old (10 to 16 years) beagle dogs pretreated with erythrityl tetranitrate, a liposoluble nitric oxide (NO) donor, and/or indomethacin, an inhibitor of cyclooxygenase enzymes, and N-nitro-L- or N-nitro-D-arginine methylester (L-NAME and D-NAME), active and inactive NO synthase (NOS) inhibitors, respectively. Erythrityl tetranitrate (0.3 mg x kg(-1) oral [p.o.]) strikingly potentiated Hexarelin-stimulated GH secretion (31.25 microg x kg(-1) intravenous [i.v.]) in both young (area under the time-concentration curve at 0 to 90 minutes AUC(0-90)] 878.50 +/- 267.02 v 1,994.04 +/- 434.20 ng x mL(-1) x h, P < .01) and aged animals (314.82 +/- 117.11 v 1,314.12 +/- 484.75 ng x mL(-1) x h, P < .01). The NO donor alone did not modify baseline GH levels in either young dogs (188.68 +/- 85.24 ng x mL(-1) x h) or old dogs (120.49 +/- 22.03 ng x mL(-1) x h). L-NAME (5 mg x kg(-1) x 2 i.v.) suppressed GH release induced by the peptide in young dogs (1,367.68 +/- 251.87 v 411.12 +/- 68.49 ng x mL(-1) x h, P < .01), but potentiated it in old dogs (314.73 +/- 117.10 v 1,103.97 +/- 374.11 ng x mL(-1) x h, P < .01). D-NAME (5 mg x kg(-1) x 2 i.v.) did not affect the GH response to Hexarelin in either young (1,328.68 +/- 433.54 ng x mL(-1) x h) or aged (342.32 +/- 84.82 ng x mL(-1) x h) dogs. Indomethacin (1.5 mg x kg(-1) i.m.) abolished the NO-donor potentiation of the GH response induced by Hexarelin in both young dogs (1,627.25 +/- 260.90 v 1,163.37 +/- 334.84 ng x mL(-1) x h, P < .05) and old dogs (1,061.47 +/- 210.38 v 365.69 +/- 79.27 ng x mL(-1) x h, P < .01) without affecting the plasma GH peak evoked by the peptide alone (young dogs, 786.04 +/- 153.44 v 960.04 +/- 444.44 ng x mL(-1) x h, P = NS; old dogs, 474.55 +/- 47.30 v 490.82 +/- 144.86 ng x mL(-1) x h, P = NS). In conclusion, (1) NO donors are capable to further increase the strong GH-releasing activity of Hexarelin in both young and old dogs, although the site(s) and mechanism(s) of action of NO is still obscure; (2) the different GH response to the peptide after NOS inhibition in young and old dogs signifies in the latter an alteration of the somatotrope function; and (3) prostaglandins are the downstream effectors of the chain of events triggered by activation of the NO-ergic system.
在八只年轻（1至6岁）和五只老年（10至16岁）的比格犬中评估了一种强效生长激素释放肽（GHRP）类似物六肽素的生长激素（GH）释放活性，这些犬预先用四硝酸赤藓醇（一种脂溶性一氧化氮（NO）供体）和/或吲哚美辛（一种环氧化酶抑制剂）以及N-硝基-L-或N-硝基-D-精氨酸甲酯（L-NAME和D-NAME）（分别为活性和非活性一氧化氮合酶（NOS）抑制剂）进行预处理。四硝酸赤藓醇（0.3mg·kg⁻¹口服[p.o.]）显著增强了六肽素刺激的GH分泌（31.25μg·kg⁻¹静脉注射[i.v.]），在年轻犬（0至90分钟时间 - 浓度曲线下面积AUC(0 - 90)]878.50±267.02对1,994.04±434.20ng·mL⁻¹·h，P <.01）和老年动物（314.82±117.11对1,314.12±484.75ng·mL⁻¹·h，P <.01）中均如此。单独的NO供体未改变年轻犬（188.68±85.24ng·mL⁻¹·h）或老年犬（120.49±22.03ng·mL⁻¹·h）的基础GH水平。L-NAME（5mg·kg⁻¹×2静脉注射）抑制了年轻犬中该肽诱导的GH释放（1,367.68±251.87对411.12±68.49ng·mL⁻¹·h，P <.01），但在老年犬中增强了它（314.73±117.10对1,103.97±374.11ng·mL⁻¹·h，P <.01）。D-NAME（5mg·kg⁻¹×2静脉注射）在年轻（1,328.68±433.54ng·mL⁻¹·h）或老年（342.32±84.82ng·mL⁻¹·h）犬中均未影响GH对六肽素的反应。吲哚美辛（1.5mg·kg⁻¹肌肉注射）消除了年轻犬（1,627.25±260.90对1,163.37±334.84ng·mL⁻¹·h，P <.05）和老年犬（1,061.47±210.38对365.69±79.27ng·mL⁻¹·h，P <.01）中六肽素诱导的GH反应的NO供体增强作用，而不影响单独肽引起的血浆GH峰值（年轻犬，786.04±153.44对960.04±444.44ng·mL⁻¹·h，P =无显著性差异；老年犬，474.55±47.30对490.82±144.86ng·mL⁻¹·h，P =无显著性差异）。总之，（1）NO供体能够进一步增加六肽素在年轻和老年犬中的强大GH释放活性，尽管NO的作用位点和机制仍不清楚；（2）年轻和老年犬中NOS抑制后对该肽的不同GH反应表明老年犬中生长激素细胞功能发生改变；（3）前列腺素是由NO能系统激活引发的一系列事件的下游效应器。
