[D-p-Cl-Phe6,Leu17]-VIP

Influence of [4Cl-D-Phe6,Leu17]VIP on VIP- and central TRH-induced gastric hyperemia.[Pubmed:9392832]

Peptides. 1997;18(9):1321-5.

The specific VIP receptor antagonist, [4Cl-D-Phe6,Leu17]VIP, infused i.v. blocked close-intra-arterial infusion of VIP-induced increase in gastric mucosal blood flow (GMBF, measured by the hydrogen gas clearance), and decrease in mean arterial blood pressure while not influencing basal levels in urethane-anesthetized rats. The thyrotropin-releasing hormone (TRH) stable analog, RX 77368, injected intracisternally (IC, 30 ng) increased GMBF and blood pressure. The VIP antagonist did not significantly reduce the GMBF response to IC RX 77368 while enhancing the rise in blood pressure. These findings indicate that [4Cl-D-Phe6,Leu17]VIP is an antagonist for exogenous VIP-induced gastric hyperemia and hypotension and that VIP modulates the systemic blood pressure response to IC RX 77368 at 30 ng while not playing a primary role in the increase of GMBF.

Effect of [4Cl-D-Phe6,Leu17]VIP on the inhibition of pulsatile LH release by VIP and related peptides in the ovariectomized rat.[Pubmed:1488097]

Neuroendocrinology. 1992 Nov;56(5):646-52.

Pulsatile LH secretion in the ovariectomized (OVX) rat is inhibited by intracerebroventricular (icv) infusion of vasoactive intestinal peptide (VIP). VIP, rat growth hormone-releasing hormone (rGRH) and secretin with and without an antagonist to VIP, [4Cl-D-Phe6,Leu17]VIP (VIPA), were infused icv into OVX rats. Both VIP and rGRH at an infusion rate of 3.5 nmol/h lowered mean LH concentrations and pulse frequency without affecting pulse amplitude, and these effects were blocked by concurrent infusion of VIPA (10.5 nmol/h). Secretin also inhibited pulsatile LH secretion, but was only fully effective at the higher infusion rate of 7 nmol/h. This effect of secretin was also blocked by concurrent infusion of 10.5 nmol/h of VIPA. These results suggest that all three of these peptide hormones inhibit pulsatile LH secretion by an interaction with VIP receptors.

[Inhalation of a precursor analogue of vasoactive intestinal polypeptide (Leu17 VIP-Gly-Lys) protects ascaris-induced bronchoconstriction in dog].[Pubmed:2634376]

Arerugi. 1989 Dec;38(12):1347-53.

We studied in vivo the effects of pre-inhalations of vasoactive intestinal polypeptide (VIP) and a precursor analogue of VIP (Leu17 VIP-Gly-Lys: preVIP) in mongrel dogs bronchoconstricted by ascaris. An inhalation of preVIP solution (2 mg/5 ml saline) gave significant protection for 120 min against increases in respiratory resistance (Rrs) and decreases in dynamic compliance (Cdyn) induced by ascaris challenges. An inhalation of VIP solution (2 mg/ml saline) also gave significant protection for 120 min against increases in Rrs induced by ascaris challenges. Protective effect of the inhalation of preVIP against ascaris-induced bronchoconstriction was more potent than that of VIP. The inhalations of preVIP and VIP solution did not change systemic blood pressure or heart rate. These results indicate that inhalations of preVIP or VIP solution would attenuate ascaris-induced bronchoconstriction in dogs without affecting cardiovascular dynamics.

Effects of intracoronary infusion of the vasoactive intestinal peptide antagonist [4Cl-D-Phe6-Leu17]VIP in the awake dog.[Pubmed:1800959]

Peptides. 1991 Sep-Oct;12(5):989-93.

Intracoronary infusion of [4Cl-D-Phe6-Leu17]VIP caused modest significant inhibition of the coronary vasodilation produced by intraarterial VIP, but did not significantly inhibit serotonin-induced coronary vasodilation. In addition, infusion of [4Cl-D-Phe6-Leu17]VIP did not result in significant changes in baseline coronary resistance, heart rate or left ventricular dP/dt. These findings demonstrate that [4Cl-D-Phe6-Leu17]VIP is a competitive antagonist of VIP-induced vasodilation in the canine coronary circulation, but fail to demonstrate a significant role for VIP in the regulation of resting coronary vasomotor tone, and do not support the hypothesis that VIP is a mediator of serotonin-induced coronary arteriolar dilation.

Vasoactive intestinal peptide transactivates the androgen receptor through a protein kinase A-dependent extracellular signal-regulated kinase pathway in prostate cancer LNCaP cells.[Pubmed:17430995]

Mol Pharmacol. 2007 Jul;72(1):73-85.

Acquisition of androgen independence by prostate cancer is the key problem of prostate cancer progression. Vasoactive intestinal peptide (VIP), a neuropeptide, may act as a survival factor for prostate cancer cells under androgen deprivation. However, the molecular mechanisms by which VIP promotes the androgen-independent growth of androgen-sensitive prostate cancer cells have not been addressed. We therefore investigated the biological effect and signal pathway of VIP in LNCaP cells, a prostate cancer cell line that requires androgens for growth. We showed that low nanomolar concentrations of VIP, acting through G(s)-protein-coupled VIP receptors, can induce LNCaP cell growth in the absence of androgen. Blockade of androgen-receptor (AR) in these cells by AR antagonist bicalutamide or by anti-AR small interfering RNA, inhibited the proliferative effect of VIP. In addition, VIP stimulated androgen-independent activation of AR with an EC(50) of 3.0 +/- 0.8 nM. We then investigated VIP-stimulated signaling events that may interact with the AR pathway in prostate cancer cells. VIP regulation of AR activation, mediated by VIP receptors, was protein kinase A (PKA)-dependent, and extracellular signal-regulated kinase 1/2 (ERK1/2) activation contributes to VIP-mediated AR activation. Furthermore, PKA-dependent Rap1 activation is required for both ERK1/2 activation and androgen-independent AR activation in LNCaP cells upon VIP stimulation. Finally, we showed that VIP-induced AR activation was also present in prostate cancer CWR22Rv1 and PC3 cells transfected with the wild-type AR. Altogether, we demonstrate that VIP acting through its G(s)-protein-coupled receptors can cause androgen-independent transactivation of AR through a PKA/Rap1/ERK1/2 pathway, thus promoting androgen-independent proliferation of androgen-sensitive prostate cancer cells.

Characterization of VIP receptor-effector system antagonists in rat and mouse peritoneal macrophages.[Pubmed:9085051]

Eur J Pharmacol. 1997 Mar 5;321(3):379-86.

In the present study we show that the synthetic peptides [4-Cl-D-Phe6,Leu17]VIP and the growth hormone releasing factor (GRF) analog [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 inhibit in a competitive manner the specific [125I]VIP binding to both rat and mouse peritoneal macrophages. In rat peritoneal macrophages, the order of potency of the different peptides, as expressed by the IC50 values was: VIP (IC50 = 1.90 +/- 0.16 nM) > [4-Cl-D-Phe6,Leu17]VIP (IC50 = 125.8 +/- 13.2 nM) > [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 (IC50 = 354.8 +/- 21.2 nM). In mouse peritoneal macrophages a similar pattern of potency was observed: VIP (IC50 = 1.58 +/- 0.12 nM) > [4-Cl-D-Phe6,Leu17]VIP (IC50 = 110.8 +/- 10.7 nM) > [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 (IC50 = 251 +/- 19.2 nM). The behavior as VIP receptor antagonists of both [4-Cl-D-Phe6,Leu17]VIP and [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 in rat and mouse peritoneal macrophages was confirmed by: (a) the shift to the right of VIP dose-stimulated cyclic AMP production curves in the presence of the two antagonists; (b) the agreement between the order of efficacy of the two peptides in competition experiments with the corresponding inhibition of cyclic AMP production; (c) the inefficiency of the two antagonists on the stimulation of cyclic AMP production by the beta-adrenoceptor agonist isoproterenol, which indicates the specificity of the interaction; (d) the synergic effect of VIP on isoproterenol-stimulated cyclic AMP production was completely abolished by [4-Cl-D-Phe6,Leu17]VIP or [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2, suggesting that both antagonists acted via specific VIP receptors. Moreover, propranolol, a beta-adrenoceptor antagonist, did not affect the VIP-stimulated cyclic AMP production and the antagonist role of [4-Cl-D-Phe6,Leu17]VIP or [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2; (e) in cross-linking experiments, the intensity of the labeling of the [125I]VIP/receptor complexes was significantly lower with the antagonists than in the control experimental situation in both mouse and rat peritoneal macrophage membranes.

Vasoactive intestinal peptide receptor antagonist [4Cl-D-Phe6, Leu17] VIP.[Pubmed:2421587]

Am J Physiol. 1986 Apr;250(4 Pt 1):G553-7.

From structure-activity relationship studies of rat growth hormone-releasing factor (rGFR) on the vasoactive intestinal peptide (VIP) receptor in an in vitro preparation of exocrine pancreas, we predicted that [4Cl-D-Phe6, Leu17]VIP would be a competitive antagonist for the action of VIP. Micromolar concentrations of synthetic [4Cl-D-Phe6, Leu17]VIP competitively antagonized VIP-stimulated amylase release in the pancreatic preparation and VIP-stimulated short-circuit current changes in a colonic tumor cell line. In addition, [4Cl-D-Phe6, Leu17]VIP inhibited amylase release stimulated by rGRF, high concentrations of secretin (agents that act through the VIP receptor), and peptide contaminants in a preparation of natural glucagon. Finally, [4Cl-D-Phe6, Leu17]VIP did not inhibit the action of agonists for the secretin, GRF, or glucagon receptors.