Administration of synthetic ovine corticotropin-releasing factor led to rapid, parallel increases in adrenocorticotropin and alpha-melanocyte-stimulating hormone concentrations in rat plasma. Prior treatment with dexamethasone almost completely blocked the adrenocorticotropin response but not the increase in melanocyte-stimulating hormone. These data demonstrate that corticotropin-releasing factor is a potent stimulator not only of adrenocorticotropin secretion from the corticotrophs of the anterior pituitary gland but also of peptide secretion from the intermediate lobe. Such data suggest that melanocyte-stimulating hormone and beta-endorphin play a role in the physiological response to stress.
Intracarotid infusion of des-His-2-des-Gly-10-LH-RH-ethylamide (pGlu-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-NH-CH2-CH3), an analog of LH-RH, into estrogen-progesterone pretreated rats effectively blocked responses to subsequent intravenous injections of LH-RH. The octapeptide antagonist itself possessed only minimal LH-releasing activity.
Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates protein and/or amylase secretion from isolated rat pancreatic acini. The effect of PACAP on pancreatic secretion in vivo and its mechanism of action were studied.Rats were prepared with pancreatic duct cannulation, pyloric ligation, and bile diversion into duodenum, and 2.5, 5, and 10 nmol/kg PACAP-27 was administered intravenously while pancreatic juice was collected for 30 minutes. In other groups of rats, the effect of 10 nmol/kg PACAP-27 was studied under the influence of either atropine; loxiglumide, an antisecretin serum; a combination of both loxiglumide and the antiserum; or a PACAP antagonist (PACAP 6-38). Plasma secretin and cholecystokinin concentrations were measured by radioimmunoassay.(1) PACAP dose-dependently increased pancreatic secretion of fluid, bicarbonate, and protein; (2) the increase in pancreatic secretion paralleled that of plasma secretin and cholecystokinin; (3) a combination of loxiglumide and antisecretin serum eliminated the PACAP-stimulated pancreatic secretion, whereas loxiglumide or antisecretin serum alone partially but significantly blocked pancreatic secretion; (4) atropine failed to influence PACAP-induced pancreatic secretion; and (5) PACAP antagonist profoundly suppressed the PACAP action.PACAP-27 dose-dependently stimulates pancreatic secretion of fluid, bicarbonate, and protein in rats. This effect is mediated by release of both secretin and cholecystokinin and is independent of cholinergic tone.
Combretastatin A-4 (CA-4) and its analogs are potent inhibitors of tubulin polymerization and display strong inhibitory activity on both solid tumor and tumor cell growth. Since natural CA-4 is difficult to synthesize and also isomerizes to an inactive form quite readily, a recently reported new 3,4-diarylfuran-2-one-based series of CA-4 analogs was investigated, in the hope of bypassing some of these difficulties. These analogs appear to offer a valuable tool for CA-4 research because of their extremely facile synthesis from readily available starting materials.The CA-4 analogs were evaluated by MTT assay, cell cycle analysis, tubulin polymerization and tumor-inhibiting experiments.Various benzene ring substitutions on the furan-2-one skeleton (analogs to the two aromatic rings on the CA-4 styrene skeleton) quickly demonstrated that the structure-activity relationships are quite similar to previously synthesized CA-4 analogs. The most interesting analog appears to be an anilino compound (NV-5-9) which was also quite soluble. Analog NV-5-9 was remarkably potent in all tested tumor cell lines and could strongly inhibit tubulin polymerization at doses as low as 1 mM. Further experiments with tumor-bearing mice indicated that NV-5-9 and other potent analogs (NV-4-82 and NV-4-86) were effective in treating human prostate PC-3 and SCLC NCI-H69 tumors at well below an oral MTD dose of around 200 mg/kg body weight. This suggests some bioavailability by this route.These data strongly support that NV-5-9 is extremely potent, readily synthesizable and apparently suitable for in vivo studies employing transplanted tumors.
We characterized highly selective receptors for PACAP, the pituitary adenylate cyclase activating peptide, in the tumoral acinar cell line AR 4‐2J derived from the rat pancreas. PACAP, a novel hypothalamic peptide related to vasoactive intestinal peptide (VIP), was tested as the full natural 38‐residue peptide (PACAP‐38) and as an N‐terminal amidated 27‐residue derivative (PACAP‐27). The binding sites showed considerable affinity for [ 125 I]PACAP‐27 ( K d =0.4 nM) and PACAP‐38, while their affiity for VIP and the parent peptide helodemin was 1000‐fold lower. These receptors were coupled to adenylate cyclase, the potency of PACAP‐38 and PACAP‐27 ( K act = 0.2 nM) being much higher than that of VIP ( K act = 100 nM) and helodemin ( K act = 30 nM). Chemical cross‐linking of [ 125 I]PACAP‐27 followed by SDS‐PAGE and autoradiography revealed a specifically cross‐linked peptide with an M r , of 68000 (including 3000 for one PACAP‐27 molecule).
