Inhibition of growth of PC-82 human prostate cancer line xenografts in nude mice by bombesin antagonist RC-3095 or combination of agonist [D-Trp6]-luteinizing hormone-releasing hormone and somatostatin analog RC-160.

The effects of treatment with a bombesin receptor antagonist [D-Tpi6, Leu13 psi (CH2NH) Leu14]BN(6-14)(RC-3095) and the combination of an agonist of luteinizing hormone-releasing hormone [D-Trp6]-LH-RH and somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val- Cys-Trp-NH2 (RC-160) were studied in nude mice bearing xenografts of the hormone-dependent human prostate tumor PC-82. During the 5 weeks of treatment, tumor growth was decreased in all treated groups compared with controls. Bombesin antagonist RC-3095 and the combination of [D-Trp6]-LH-RH and RC-160 caused a greater inhibition of tumor growth than [D-Trp6]-LH-RH or RC-160 alone as based on measurement of tumor volume and percentage change in tumor volume. The largest decrease in tumor weight was also seen in the groups treated with the bombesin antagonist and with the combination of RC-160 and [D-Trp6]-LH-RH. Serum prostatic-specific antigen levels were greatly decreased, and insulin-like growth factor I (IGF-I) as well as growth hormone levels were reduced in all treated groups. Specific binding sites for [D-Trp6]-LH-RH, epidermal growth factor (EGF), IGF-I, and somatostatin (SS-14) were found in the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with the bombesin antagonist or RC-160. Combination of LH-RH agonists with somatostatin analog RC-160 might be considered for improvement of hormonal therapy for prostate cancer. The finding that bombesin antagonist RC-3095 inhibits the growth of PC-82 prostate cancer suggests the merit of further studies to evaluate the possible usefulness of antagonists of bombesin in the management of prostatic carcinoma.     

Triflavin, an Arg-Gly-Asp containing snake venom peptide, inhibits aggregation of human platelets induced by human hepatoma cell line

Triflavin, an Arg-Gly-Asp (RGD)-containing peptide, purified from snake venom of Trimeresurus flavoviridis, inhibits human platelet aggregation through the blockade of fibrinogen binding to fibrinogen receptors associated with glycoprotein IIb/IIIa complex. In this report, we examined the effect of triflavin on tumor cells (human hepatoma J-5)-induced platelet aggregation (TCIPA) of heparinized platelet-rich plasma (PRP). ADP-scavenger agents, apyrase (10 U/ml) and creatine phosphate (5 mM)/creatine phosphokinase (5 U/ml) did not inhibit TCIPA while hirudin (5u/ml) completely inhibited it. J-5 cells initially induced platelet aggregation, then blood coagulation occurred. J-5 cells concentration-dependently shortened the recalcification time of normal as well as Factor VIII, IX-deficient human plasmas, while it was inactive at shortening the recalcification time of Factor VII-deficient plasma, suggesting J-5 cells induced platelet aggregation through activation of extrinsic pathway, leading to thrombin formation as evidenced by the amidolytic activity on S-2238 by expressing tissue factor-like activity. Triflavin inhibited TCIPA in a dose-dependent manner (IC₅₀, 0.02 μM). When compared on molar ratio, triflavin was approximately 30,000 times more potent than GRGDS (IC₅₀,0.58 mM). On the other hand, GRGES showed no significant effect on TCIPA, even its concentration was raised to 4 mM. Additionally, the monoclonal antibodies, raised against glycoprotein IIb/IIIa complex (i.e., 7E₃ and 10 E₅) inhibited J-5 TCIPA. In conclusion, we suggest the inhibitory effect of triflavin on J-5 TCIPA may be chiefly mediated by the binding of triflavin to the fibrinogen receptor associated with glycoprotein IIb/IIIa complex on platelet surface membrane.     

Increase of prolactin mRNA in the rat hypothalamus after intracerebroventricular injection of VIP or PACAP

Vasoactive intestinal peptide (VIP), the structurally homologous pituitary adenylate cyclase-activating peptide (PACAP) and the pituitary hormone, prolactin (PRL) enhance rapid eye movement sleep (REMS). VIP and PACAP are both inducers of PRL gene expression and release in the pituitary gland. Little is known about PRL regulation in the brain although it is hypothesized that the REMS-promoting activity of i.c.v. administered VIP may be mediated via the activation of cerebral PRL. To test whether VIP or PACAP in fact increase intracerebral mRNA, the peptides (VIP: 30 or 300 pmol; PACAP: 220 pmol) were injected i.c.v. into rats at dark onset. 1 h later, cDNA was synthesized from purified hypothalamic mRNA. Standardized amounts were analysed for PRL using the polymerase chain reaction followed by Southern blotting and hybridization. Compared with β-actin mRNA levels, both VIP and PACAP increased PRL mRNA levels in a dose-dependent fashion though VIP was more effective on a molar basis. The previously reported alternatively spliced PRL mRNA (lacking exon 4) was not detected. The data support the hypothesis that the REMS-promoting activity of central VIP and PACAP might be mediated by cerebral PRL.     

降钙素基因相关肽对犬冠脉流量及冠状动脉的作用

本研究通过整体及离体灌流实验观察到重庆冠脉狭窄时，犬冠脉流量（ＣＢＦ），平均动脉压（ＭＡＰ）明显减小，而心率（ＨＲ）则增加。狭窄３０ｍｉｎ后由冠状动脉注射降钙素基因相关肽（ＣＧＲＰ）０．３μｇ／ｋｇ后，ＣＢＦ、ＭＡＰ和ＨＲ可恢复正常水平。同时，缺血犬的离体冠状动脉对ＣＧＲＰ的反应也出现改变。大冠脉舒张反应明显降低，而小冠脉的舒张反应与正常相比，无明显改变，这可能与缺血后大冠脉的内皮细胞容易损伤有关。同时也提示:急性心肌缺血时，冠脉流量的减少，主要由于小冠状动脉收缩所致。     

A VIP antagonist distinguishes VIP receptors on spinal cord cells and lymphocytes

Vasoactive intestinal peptide (VIP) is a neuropeptide which also interacts with cells of the immune system. The paucity of specific VIP receptor antagonists has hampered studies of possible receptor heterogeneity and of VIP function. To aid in achieving these goals, a new VIP antagonist, a hybrid between neurotensin and VIP, has been synthesized. This peptide interacted with VIP receptors on spinal cord cells with an affinity 10-fold greater than VIP itself. In contrast, 1000-fold higher concentrations of the antagonist were required to displace labeled VIP from its receptor on lymphoid cells as compared to VIP itself, suggesting VIP receptor heterogeneity between immune and spinal cord cells.     

急性等容性血液稀释对血浆ET和CGRP水平的影响

目的　探讨急性等容性血液稀释 (ANH)对血浆内皮素 (ET)和降钙基因相关肽(CGRP)水平的影响。方法　选择非心脏手术ASAⅠ～Ⅱ级患者 2 0例 ,麻醉前快速输入复方乳酸钠1 0～ 1 5ml/kg。麻醉后从桡动脉放血 1 0ml/kg ,同时经静脉输入等量的 4 %琥珀酰明胶。观察ANH麻醉前 (T0 )、血液稀释完成后 1 0min(T1 )、2 0min(T2 )、30min(T3 )的血液动力学、血浆ET和CGRP浓度的变化。结果　ANH前后MAP、HR、SpO2 和ECG均较稳定。ANH后 1 0min、2 0min血浆ET水平分别为 (1 4 4 4 7± 1 9 1 7) pg/ml和 (1 5 7 1 7± 1 2 4 5 ) pg/ml,但明显高于ANH前的 (1 2 7 6 8±2 0 92 ) pg/ml(P <0 0 5 )。ANH后 1 0min、2 0min血浆CGRP水平分别为 (5 4 72± 2 5 6 5 )pg/ml和(5 5 32± 1 7 94 )pg/ml,也明显高于ANH前的 (4 4 6 2± 1 6 90 ) pg/ml(P <0 0 5 )。而ET/CGRP比值无明显变化。结论　ANH近期血浆ET和CGRP水平均有一定的增加 ,但ET/CGRP比值的变化无统计学意义 ,同时心血管反应不明显 ,表明血浆ET和CGRP的动态平衡对ANH时的循环稳定起着重要的作用     

CGRP免疫反应神经纤维在大鼠胆总管与十二指肠连接处的分布

用免疫组织化学ＡＢＣ法，研究了降钙素基因相关肽（ＣＧＲＰ）免疫反应神经纤维在大鼠胆总管末端与十二指肠连接处的分布。大鼠的胆总管末端有较丰富的ＣＧＲＰ免疫反应神经纤维，它们多呈串珠（膨体）状，少数为无膨体的细长纤维。ＣＧＲＰ－ＩＲ纤维主要分布肌层及血管周围，在神经纤维的附近可见到含ＣＧＲＰ－ＩＲ阳性颗粒的肥大细胞。本实验为神经免疫调节机制的研究提供了形态学依据。     

ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS AND KININ METABOLISM: EVIDENCE THAT ACE INHIBITORS MAY INHIBIT A KININASE OTHER THAN ACE

1. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, and also metabolizes bradykinin-(1–9) to bradykinin-(1–7) and bradykinin-(1–7) to bradykinin-(1–5). Increases in endogenous kinin levels may contribute to the therapeutic effects of ACE inhibitors. 2. ACE inhibitors increase vascular levels of both bradykinin-(1–9) and its ACE cleavage product bradykinin-(1–7), at doses below the threshold for ACE inhibition, leading to the proposal that ACE inhibitors may also inhibit a non-ACE kininase which cleaves both kinin peptides; this non-ACE kininase may be the major pathway of kinin metabolism in the vasculature and some other tissues. 3. In support of this proposal, ACE inhibitors potentiate bradykinin-(1–9) effects at doses which have little or no effect on ACE activity, as indicated by angiotensin I conversion to angiotensin II. ACE inhibitors also potentiate the actions of ACE-resistant kinin analogues, which may be susceptible to metabolism by a non-ACE kininase. 4. Identification and characterization of the putative non-ACE kininase which is inhibited by ACE inhibitors may reveal novel approaches to the tissue-specific modulation of kinin levels.     

SD大鼠肺中降钙素基因相关肽的分布及缺氧对其含量的影响

本研究用免疫细胞化学方法(ABC法)观察了降钙素基因相关肽(CGRP)在SD大鼠肺中的分布,缺氧对肺中神经内分泌细胞内CGRP含餐的影响。结果表明:含CGRP的神经纤维分布在肺血管平滑肌层中及其周围、气管-支气管树的粘膜下层;含CGRP的神经内分泌细胞位于气管一支气管树的上皮层、粘液腺中和肺实质内。缺氧不引起火鼠肺的神经内分泌细胞数目改变,但可使这些细胞内的CGRP含量增加。