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Abstract
Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide implicated in a wide range of functions, such as nociception and in primary headaches. Regarding its localization, PACAP has been observed in the sensory trigeminal ganglion (TG), in the parasympathetic sphenopalatine (SPG) and otic ganglia (OTG), and in the brainstem trigeminocervical complex. Immunohistochemistry has shown PACAP-38 in numerous cell bodies of SPG/OTG, co-stored with vasoactive intestinal peptide (VIP), nitric oxide synthase (NOS) and, to a minor degree, with choline acetyltransferase. PACAP has in addition been found in a subpopulation of calcitonin gene-related peptide (CGRP)-immunoreactive cells in the trigeminal system. The PACAP/VIP receptors (PAC1, VPAC1, and VPAC2) are present in sensory neurons and in vascular smooth muscle related to the trigeminovascular system. It is postulated that PACAP is involved in nociception. In support, abolishment of PACAP synthesis or reception leads to diminished pain responses, whereas systemic PACAP-38 infusion triggers pain behavior in animals and delayed migraine-like attacks in migraine patients without marked vasodilatory effects. In addition, increased plasma levels have been documented in acute migraine attacks and in cluster headache, in accordance with findings in experimental models of trigeminal activation. This suggest that the activation of the trigeminal system may result in elevated venous levels of PACAP, a change that can be reduced when headache is treated. The data presented in this review indicate that PACAP and its receptors may be promising targets for migraine therapeutics.
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Ivic I, Solymar M, Fulop BD, Hashimoto H, Toth G, Tamas A, Juhasz T, Koller A, Reglodi D. Aging-Induced Modulation of Pituitary Adenylate Cyclase-Activating Peptide- and Vasoactive Intestinal Peptide-Induced Vasomotor Responses in the Arteries of Mice. J Vasc Res 2017; 54:359-366. [PMID: 29131060 DOI: 10.1159/000481781] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 09/23/2017] [Indexed: 12/17/2022] Open
Abstract
Pituitary adenylate cyclase-activating peptide (PACAP; 1-38 and 1-27) and vasoactive intestinal peptide (VIP) are related neuropeptides of the secretin/glucagon family. Overlapping signaling through G-protein-coupled receptors mediates their vasomotor activity. We previously showed that PACAP deficiency (PACAP-KO) shifts the mechanisms of vascular response and maintains arterial relaxation through the VIP backup mechanism and (mainly) its VPAC1R, but their age-dependent modulation is still unknown. We hypothesized that backup mechanisms exist, which maintain the vasomotor activity of these peptides also in older age. Thus, we investigated the effects of exogenous VIP and PACAP peptides in isolated carotid arteries of 2- and 15-month-old wild-type (WT) and PACAP-KO mice. All peptides induced relaxation in the arteries of young WT mice, whereas in young PACAP-KO mice PACAP1-27 and VIP, but not PACAP1-38, induced relaxation. Unlike VIP, PACAP-induced vasomotor responses were reduced in aging WT mice. However, in the arteries of aging PACAP-KO mice, PACAP1-27- and VIP-induced responses were reduced, but PACAP1-38 showed a greater vasomotor response compared to that of young PACAP-KO animals. There were no significant differences between the vasomotor responses of aging WT and PACAP-KO mice. Our data suggest that, in the absence of PACAP both in young and old ages, the vascular response is mediated through backup mechanisms, most likely VIP, maintaining proper vascular relaxation in aging-induced PACAP insufficiency.
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Affiliation(s)
- Ivan Ivic
- Department of Anatomy, MTA-PTE PACAP Research Group, Medical School, University of Pecs, Pecs, Hungary
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3
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Vamos Z, Ivic I, Cseplo P, Toth G, Tamas A, Reglodi D, Koller A. Pituitary adenylate cyclase-activating polypeptide (PACAP) induces relaxations of peripheral and cerebral arteries, which are differentially impaired by aging. J Mol Neurosci 2014; 54:535-42. [PMID: 24939249 DOI: 10.1007/s12031-014-0349-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 06/04/2014] [Indexed: 01/15/2023]
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-known neuropeptide, which also has vasomotor effects. However, little is known regarding its age-related and organ-specific vasomotor effects. We hypothesized that the vasomotor effects of PACAP depend on the tissue origin of the vessels and aging substantially modulates its actions. Thus, carotid (CA) and basilar arteries (BA) were isolated from young (2 months old), middle age (12 months old), and old (30 months old) rats. Their vasomotor responses were measured with an isometric myograph (DMT610M) in response to cumulative concentrations of PACAP1-38 (10(-9)-10(-6) M). PACAP1-38 induced (1) significantly greater concentration-dependent relaxations in CA compared to that of BA of young, middle age, and old rats; (2) relaxations of CA significantly decreased, whereas they did not change substantially in BA, as a function of age; (3) sodium nitroprusside (SNP)-induced relaxation did not change after PACAP1-38 administration in any conditions; and (4) inhibition of PAC1 receptors by selective PAC1 receptor blocker (PACAP6-38) completely diminished the responses to PACAP in all age groups of BA and CA. In conclusion, these findings suggest that PACAP1-38 has greater vasomotor effect in CA than that in BA, whereas aging has less effect on PACAP-induced relaxation of cerebral arteries and BA than that in peripheral arteries and CA suggesting that the relaxation to PACAP is maintained in cerebral arteries even in old age.
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Affiliation(s)
- Zoltan Vamos
- Department of Pathophysiology and Gerontology, Szentagothai Research Centre, University of Pecs, Medical School, Szigeti út 12, Pecs, 7624, Hungary
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4
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Guo S, Barringer F, Zois NE, Goetze JP, Ashina M. Natriuretic peptides and cerebral hemodynamics. ACTA ACUST UNITED AC 2014; 192-193:15-23. [DOI: 10.1016/j.regpep.2014.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 07/08/2014] [Accepted: 07/23/2014] [Indexed: 12/26/2022]
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Szanto Z, Sarszegi Z, Reglodi D, Nemeth J, Szabadfi K, Kiss P, Varga A, Banki E, Csanaky K, Gaszner B, Pinter O, Szalai Z, Tamas A. PACAP immunoreactivity in human malignant tumor samples and cardiac diseases. J Mol Neurosci 2012; 48:667-73. [PMID: 22648511 DOI: 10.1007/s12031-012-9815-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Accepted: 05/15/2012] [Indexed: 01/21/2023]
Abstract
Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic and multifunctional neuropeptide having important roles in various physiological processes. Recent trends in PACAP research point to the clinical introduction of PACAP or its analogs/fragments possibly in the near future. Recently, we have shown the presence of PACAP in human plasma, milk, placenta, and follicular fluid samples. However, relatively few data are available on PACAP in human tissues from patients with different disorders. The aim of the present study was to determine, by radioimmunoassay, the tissue level of PACAP38-like immunoreactivity (LI) and PACAP27-LI in different primary non-small cell lung cancer, colon tumor samples, and in cardiac muscle samples from patients suffering from ischemic heart disease and valvular disorders. We also labeled the PAC1 receptors in human cardiac cells. All samples showed significantly higher PACAP38-LI compared with PACAP27-LI. We found significantly lower levels of PACAP38-LI and PACAP27-LI in tumoral and peripheral samples compared with normal healthy tissue in both lung and colon cancers. Further investigations are necessary to describe the exact function of PACAP in oncogenesis. We showed that PACAP38-LI and PACAP27-LI are significantly higher in ischemic heart diseases compared with valvular abnormalities, suggesting that PACAP might play a role in ischemic heart disorders.
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Affiliation(s)
- Z Szanto
- Surgery Clinic, University of Pecs, Pecs, Hungary
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6
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Wei MX, Hu P, Wang P, Naruse S, Nokihara K, Wray V, Ozaki T. Possible key residues that determine left gastric artery blood flow response to PACAP in dogs. World J Gastroenterol 2010; 16:4865-70. [PMID: 20939117 PMCID: PMC2955258 DOI: 10.3748/wjg.v16.i38.4865] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on left gastric artery (LGA) flow and to unveil the structural or functional important sites that may be critical for discrimination of different receptor subtypes.
METHODS: Peptides, including PACAP-27, PACAP-38, amino acid substituted PACAP-27 and C-terminus truncated analogues PACAP (27-38), were synthesized by a simultaneous multiple solid-phase peptide synthesizer. Flow probes of an ultrasound transit-time blood flowmeter were placed around the LGA of beagle dogs. When peptides were infused intravenously, the blood flow was measured.
RESULTS: [Ala4, Val5]-PACAP-27 caused a concentration-dependent vasodepressor action which was similar to that caused by PACAP-27. The LGA blood flow response to [Ala4, Val5]-PACAP-27 was significantly higher than that to PACAP-27, which was similar to that to vasoactive intestinal polypeptide (VIP) at the same dose. [Ala6]-PACAP-27 did not increase the peak LGA flow. [Gly8]-PACAP-27 showed a similar activity to VIP. [Asn24, Ser25, Ile26]-PACAP-27 did not change the activity of peptides at all doses.
CONCLUSION: NH2 terminus is more important to biological activity of peptides and specific receptor recognition than COOH-terminus.
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7
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Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BKC, Hashimoto H, Galas L, Vaudry H. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 2009; 61:283-357. [PMID: 19805477 DOI: 10.1124/pr.109.001370] [Citation(s) in RCA: 848] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid C-terminally alpha-amidated peptide that was first isolated 20 years ago from an ovine hypothalamic extract on the basis of its ability to stimulate cAMP formation in anterior pituitary cells (Miyata et al., 1989. PACAP belongs to the vasoactive intestinal polypeptide (VIP)-secretin-growth hormone-releasing hormone-glucagon superfamily. The sequence of PACAP has been remarkably well conserved during evolution from protochordates to mammals, suggesting that PACAP is involved in the regulation of important biological functions. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, respiratory and urogenital tracts. Characterization of the PACAP precursor has revealed the existence of a PACAP-related peptide, the activity of which remains unknown. Two types of PACAP binding sites have been characterized: type I binding sites exhibit a high affinity for PACAP and a much lower affinity for VIP, whereas type II binding sites have similar affinity for PACAP and VIP. Molecular cloning of PACAP receptors has shown the existence of three distinct receptor subtypes: the PACAP-specific PAC1-R, which is coupled to several transduction systems, and the PACAP/VIP-indifferent VPAC1-R and VPAC2-R, which are primarily coupled to adenylyl cyclase. PAC1-Rs are particularly abundant in the brain, the pituitary and the adrenal gland, whereas VPAC receptors are expressed mainly in lung, liver, and testis. The development of transgenic animal models and specific PACAP receptor ligands has strongly contributed to deciphering the various actions of PACAP. Consistent with the wide distribution of PACAP and its receptors, the peptide has now been shown to exert a large array of pharmacological effects and biological functions. The present report reviews the current knowledge concerning the pleiotropic actions of PACAP and discusses its possible use for future therapeutic applications.
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Affiliation(s)
- David Vaudry
- Institut National de la Santé et de la Recherche Médicale U413, European Institute for Peptide Research (Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23), Mont-Saint-Aignan, France.
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Boni LJ, Ploug KB, Olesen I, Jansen-Olesen I, Gupta S. The in vivo Effect of VIP, PACAP-38 and PACAP-27 and mRNA Expression of Their Receptors in Rat Middle Meningeal Artery. Cephalalgia 2009; 29:837-47. [DOI: 10.1111/j.1468-2982.2008.01807.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The parasympathetic nervous system is probably involved in migraine pathogenesis. Its activation releases a mixture of signalling molecules including vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), which subsequently stimulate VPAC1, VPAC2 and PAC1 receptors. The objective of the present study was to investigate the in vivo effect of VIP, PACAP-27, PACAP-38, the selective VPAC1 agonist ([Lys15, Arg16, Leu27]-VIP(1–7)-GRF(8–27)) and a PAC1 agonist, maxadilan on rat middle meningeal artery (MMA) diameter using the closed cranial window model. Selective antagonists were used for further characterization of the responses. Reverse transcriptase-polymerase chain reaction experiments were also conducted to determine expression of mRNA of PACAP receptors in the MMA. The results showed that VIP, PACAP-38, PACAP-27 and the VPAC1 specific agonist evoked significant dilations with the rank order of potency; VIP = PACAP-38 > PACAP-27 = [Lys15, Arg16, Leu27]-VIP(1–7)-GRF(8–27). Significant inhibition of dilation was only observed for the VPAC1 antagonist PG97–269 on PACAP-38-induced dilation of MMA. The VPAC2 antagonist PG99–465 and PAC1 antagonist PACAP(6–38) did not significantly block VIP- or PACAP-induced dilation. Expression of mRNA of all three receptors was detected in the MMA. In conclusion, the VPAC1 receptor seems to be predominant in mediating MMA dilation. A selective VPAC1 antagonist may be a candidate molecule in the treatment of migraine headache.
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Affiliation(s)
- LJ Boni
- Department of Neurology, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark
| | - KB Ploug
- Department of Neurology, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark
| | - I Olesen
- Department of Neurology, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark
| | - I Jansen-Olesen
- Department of Neurology, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark
| | - S Gupta
- Department of Neurology, Glostrup Research Institute, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark
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Differences in Action of PACAP-27 and PACAP-38 on Guinea Pig Gallbladder Smooth Muscle Using Synthetic C-terminally Modified PACAP Peptides. Int J Pept Res Ther 2009. [DOI: 10.1007/s10989-009-9183-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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10
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Matsuno R, Ohtaki H, Nakamachi T, Watanabe J, Yofu S, Hayashi D, Takeda T, Nonaka N, Seki M, Nakamura M, Itabashi K, Shioda S. Distribution and localization of pituitary adenylate cyclase-activating polypeptide-specific receptor (PAC1R) in the rostral migratory stream of the infant mouse brain. ACTA ACUST UNITED AC 2008; 145:80-7. [PMID: 17900711 DOI: 10.1016/j.regpep.2007.08.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to participate in the regulation of neuronal proliferation and differentiation. While these processes are considered to be mediated via PACAP's actions on the PACAP-specific receptor, PAC1R, the precise distribution of PAC1R during neurodevelopment has not yet to be elucidated in detail. The purpose of this study is to examine the distribution of PAC1R in the neurogenic region of the rostral migratory stream (RMS) from the apical subventricular zone (SVZa) to the olfactory bulb (OB) in infant mice using immunostaining. Co-immunostaining for PAC1R in a variety types of cell were carried out using different markers. These included the neural stem cell markers, nestin and glial fibrillary acidic protein (GFAP), a marker for migrating neuroblasts (doublecortin, DCX), a marker for immature neurons betaIII-tubulin, (Tuj1), and a marker for mature neurons, neuronal nuclei (NeuN). PAC1R-like immunoreactivity (LI) was observed in the RMS. However, the intensity of PAC1R- LI was different depending on the regions which were investigated. PAC1R-LI was strong in nestin- and GFAP-positive cells in the SVZa and was also observed in NeuN-positive cells in the OB. However, the intensities of PAC1R-LI in DCX- and Tuj1-positive cells were weaker than the other markers. These results suggest that PACAP may participate in the neurodevelopment with the stage-specific expression of PAC1R and that PACAP plays important roles in neurons as well as in glial cells.
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Affiliation(s)
- Ryosuke Matsuno
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
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11
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Rácz B, Gasz B, Gallyas F, Kiss P, Tamás A, Szántó Z, Lubics A, Lengvári I, Tóth G, Hegyi O, Roth E, Reglodi D. PKA-Bad-14-3-3 and Akt-Bad-14-3-3 signaling pathways are involved in the protective effects of PACAP against ischemia/reperfusion-induced cardiomyocyte apoptosis. ACTA ACUST UNITED AC 2007; 145:105-15. [PMID: 17981349 DOI: 10.1016/j.regpep.2007.09.015] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The neuropeptide PACAP (pituitary adenylate cyclase activating polypeptide) and its receptors are widely expressed in the nervous system and various other tissues. PACAP has well-known anti-apoptotic effects in neuronal cell lines. Recent data suggest that PACAP exerts anti-apoptotic effects also in non-neuronal cells. The peptide is present in the cardiovascular system, and has various distinct effects. The aim of the present study was to investigate whether PACAP is protective against in vitro ischemia/reperfusion-induced apoptosis in cardiomyocytes. Cultured cardiomyocytes were exposed to 60 min ischemia followed by 120 min reperfusion. The addition of PACAP1-38 significantly increased cell viability and decreased the ratio of apoptotic cells as measured by MTT test and flow cytometry. PACAP induced the phosphorylation of Akt and protein kinase A. In the present study we also examined the possible involvement of Akt- and protein kinase A-induced phosphorylation and thus inactivation of Bad, a pro-apoptotic member of the Bcl-2 family. It was found that ischemia significantly decreased the levels of phosphorylated Bad, which was counteracted by PACAP. Furthermore, PACAP increased the levels of Bcl-xL and 14-3-3 protein, both of which promote cell survival, and decreased the apoptosis executor caspase-3 cleavage. All effects of PACAP1-38 were inhibited by the PACAP antagonist PACAP6-38. In summary, our results show that PACAP has protective effects against ischemia/reperfusion-induced cardiomyocyte apoptosis and provides new insights into the signaling mechanisms involved in the PACAP-mediated anti-apoptotic effects.
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Affiliation(s)
- B Rácz
- Department of Surgical Research and Techniques, University of Pecs, Hungary
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12
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Squillacioti C, Mirabella N, De Luca A, Paino G. Expression of pituitary adenylate cyclase-activating polypeptide in the primary lymphoid organs of the duck Anas platyrhynchos. J Anat 2007; 209:51-8. [PMID: 16822269 PMCID: PMC2100303 DOI: 10.1111/j.1469-7580.2006.00592.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The expression of pituitary adenylate cyclase-activating polypeptide (PACAP) was studied in the thymus and bursa of Fabricius of the duck Anas platyrhynchos, at different ages, using immunohistochemistry, Western blotting, RT-PCR and sequencing. In the thymus, PACAP immunoreactivity (-ir) was found in lymphoid cells. CD68/ and PGP 9.5/PACAP38 double labelling showed that PACAP was not expressed either in macrophages or in epithelial cells, suggesting that the PACAP-positive cells observed were lymphoid cells. Immunoreactive lymphocytes were observed in the interlobular septa. They increased in number with ageing. In the bursa, PACAP-ir was found in nerve fibres and in a few lymphoid cells. RT-PCR revealed PACAP mRNA expression in the thymus but not in the bursa. These results suggest that PACAP plays a role in the functions of the immune system in birds.
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Affiliation(s)
- Caterina Squillacioti
- Department of Structure, Functions and Biological Technologies, University of Naples Federico II, Italy
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13
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Girard BA, Lelievre V, Braas KM, Razinia T, Vizzard MA, Ioffe Y, El Meskini R, Ronnett GV, Waschek JA, May V. Noncompensation in peptide/receptor gene expression and distinct behavioral phenotypes in VIP- and PACAP-deficient mice. J Neurochem 2006; 99:499-513. [PMID: 17029602 DOI: 10.1111/j.1471-4159.2006.04112.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are closely related neurotrophic peptides of the secretin/glucagon family. The two peptides are derived from a common ancestral gene and share many functional attributes in neuronal development/regeneration which occur not only from overlapping receptor subtype signaling but also through common mechanisms regulating their expression. Although PACAP or VIP null mice have been generated for study, it is unclear whether the expression of the complementary peptide or their receptor systems are altered in a compensatory manner during nervous system development. By radioimmunoassay and quantitative PCR measurements, we first show that PACAP and VIP have very different temporal patterns of expression in developing postnatal mouse brain. In wild-type animals, PACAP transcript and peptide levels increased rapidly 2- and 5-fold, respectively, within 1 week of age. These levels at 1 week of age were maintained through adulthood. VIP transcript and peptide levels, by contrast, increased 25- and 50-fold, respectively, over a later time course. In parallel studies of development, there were no apparent compensatory increases in brain VIP expression in the PACAP knockout animals, PACAP expression in the VIP-deficient animals, or receptor mRNA levels in either genotype. To the contrary, there was evidence for developmental delays in the expression of peptide and receptor transcripts in the knockout animals. A series of behavioral and neurological tests demonstrated differences between the knockout genotypes, revealing some functional distinctions between the two genes. These results suggest that the PACAP and VIP have evolved to possess distinct biological activities and intimate that the respective knockout phenotypes represent deficits unmitigated by the actions of the complementary related peptide.
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Affiliation(s)
- Beatrice A Girard
- Department of Anatomy, University of Vermont College of Medicine, Burlington, 05405, USA
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Ohtaki H, Nakamachi T, Dohi K, Aizawa Y, Takaki A, Hodoyama K, Yofu S, Hashimoto H, Shintani N, Baba A, Kopf M, Iwakura Y, Matsuda K, Arimura A, Shioda S. Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Proc Natl Acad Sci U S A 2006; 103:7488-93. [PMID: 16651528 PMCID: PMC1464366 DOI: 10.1073/pnas.0600375103] [Citation(s) in RCA: 162] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) has been reported to decrease ischemic neuronal damage and increase IL-6 secretion in rats. However, the mechanisms underlying neuroprotection are still to be fully elucidated. The present study was designed to investigate the role played by PACAP and IL-6 in mediating neuroprotection after ischemia in a null mouse. Infarct volume, neurological deficits, and cytochrome c in cytoplasm were higher in PACAP(+/-) and PACAP(-/-) mice than in PACAP(+/+) animals after focal ischemia, although the severity of response was ameliorated by the injection of PACAP38. A decrease in mitochondrial bcl-2 was also accentuated in PACAP(+/-) and PACAP(-/-) mice, but the decrease could be prevented by PACAP38 injection. PACAP receptor 1 (PAC1R) immunoreactivity was colocalized with IL-6 immunoreactivity in neurons, although the intensity of IL-6 immunoreactivity in PACAP(+/-) mice was less than that in PACAP(+/+) animals. IL-6 levels increased in response to PACAP38 injection, an effect that was canceled by cotreatment with the PAC1R antagonist. However, unlike in wild-type controls, PACAP38 treatment did not reduce the infarction in IL-6 null mice. To clarify the signaling pathway associated with the activity of PACAP and IL-6, phosphorylated STAT (signal transducer and activator of transcription) 3, ERK (extracellular signal-regulated kinase), and AKT levels were examined in PACAP(+/-) and IL-6 null mice after ischemia. Lower levels of pSTAT3 and pERK were observed in the PACAP(+/-) mice, whereas a reduction in pSTAT3 was recorded in the IL-6 null mice. These results suggest that PACAP prevents neuronal cell death after ischemia via a signaling mechanism involving IL-6.
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Affiliation(s)
- Hirokazu Ohtaki
- *Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan
| | - Tomoya Nakamachi
- *Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan
- U.S.–Japan Biomedical Research Laboratories, F. Edward Hebert Research Center, Tulane University, New Orleans, LA 70037
| | - Kenji Dohi
- *Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan
| | - Yoichi Aizawa
- *Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan
| | - Atsushi Takaki
- Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kei Hodoyama
- *Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan
| | - Sachiko Yofu
- *Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan
| | - Hitoshi Hashimoto
- Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Norihito Shintani
- Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Akemichi Baba
- Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Manfred Kopf
- Institute of Integrative Biology, Eidgenössische Technische Hochschule, 8092 Zürich, Switzerland
| | - Yoichiro Iwakura
- **Institute of Medical Science, Laboratory of Animal Research, University of Tokyo, Minato-Ku, Tokyo 108-8639, Japan; and
| | - Kouhei Matsuda
- Laboratory of Regulatory Biology, Graduate School of Science and Engineering, Toyama University, Gofuku, Toyama 930-8555, Japan
| | - Akira Arimura
- U.S.–Japan Biomedical Research Laboratories, F. Edward Hebert Research Center, Tulane University, New Orleans, LA 70037
| | - Seiji Shioda
- *Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan
- To whom correspondence should be addressed at:
Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan. E-mail:
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Ohtaki H, Dohi K, Yofu S, Nakamachi T, Kudo Y, Endo S, Aruga T, Goto N, Watanabe J, Kikuyama S, Shioda S. Effect of pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) on tissue oxygen content—Treatment in central nervous system of mice. ACTA ACUST UNITED AC 2004; 123:61-7. [PMID: 15518894 DOI: 10.1016/j.regpep.2004.05.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It has been reported that pituitary adenylate cyclase-activating polypeptide (PACAP) plays an important role in preventing neuronal cell death and is also a potent vasodilator. Cerebral hypotension and hypoperfusion during cerebral ischemia and neurodegenerative diseases are well known as some of the negative factors which aggravate neuronal cell death. Nevertheless, the effect of PACAP on the cerebral circulation was not understood well. Therefore, in the present study, we determined the mean arterial blood pressure (MBP), regional cerebral blood flow (rCBF) and cerebral oxygen content (pO2) in mice, and estimated the therapeutically useful doses of PACAP. Under barbiturate anesthesia, polyethylene tubes were inserted into mice to monitor MBP and to administer PACAP (5 x 10(-13)-5 x 10(-8) mol/kg) or vasoactive intestinal peptide (VIP; 5 x 10(-12) and 5 x 10(-9) mol/kg). Then, MBP, rCBF and cerebral pO2 were simultaneously measured in the mice. PACAP (5 x 10(-10)-5 x 10(-9) mol/kg) injections transiently decreased MBP, and cerebral pO2. PACAP (5 x 10(-8) mol/kg) injections produced a long-lasting potent decline of MBP, rCBF and cerebral pO2. Therefore, PACAP should be applied at low doses which do not influence the MBP and cerebral circulation to determine the therapeutically useful doses of PACAP for neuroprotection.
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Affiliation(s)
- Hirokazu Ohtaki
- Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan.
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16
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Tsueshita T, Gandhi S, Onyüksel H, Rubinstein I. Phospholipids modulate the biophysical properties and vasoactivity of PACAP-(1--38). J Appl Physiol (1985) 2002; 93:1377-83. [PMID: 12235038 DOI: 10.1152/japplphysiol.00277.2002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The purpose of this study was to elucidate the interactions between pituitary adenylate cyclase-activating peptide (PACAP)-(1--38) and phospholipids in vitro and to determine whether these phenomena modulate, in part, the vasorelaxant effects of the peptide in the intact peripheral microcirculation. We found that the critical micellar concentration of PACAP-(1--38) was 0.4-0.9 microM. PACAP-(1--38) significantly increased the surface tension of a dipalmitoylphosphatidylcholine monolayer and underwent conformational transition from predominantly random coil in saline to alpha-helix in the presence of distearoyl-phosphatidylethanolamine-polyethylene glycol (molecular mass of 2,000 Da) sterically stabilized phospholipid micelles (SSM) (P < 0.05). Using intravital microscopy, we found that aqueous PACAP-(1--38) evoked significant concentration-dependent vasodilation in the intact hamster cheek pouch that was significantly potentiated when PACAP-(1--38) was associated with SSM (P < 0.05). The vasorelaxant effects of aqueous PACAP-(1--38) were mediated predominantly by PACAP type 1 (PAC(1)) receptors, whereas those of PACAP-(1--38) in SSM predominantly by PACAP/vasoactive intestinal peptide type 1 and 2 (VPAC(1)/VPAC(2)) receptors. Collectively, these data indicate that PACAP-(1--38) self-associates and interacts avidly with phospholipids in vitro and that these phenomena amplify peptide vasoactivity in the intact peripheral microcirculation.
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Affiliation(s)
- Takaya Tsueshita
- Department of Biopharmaceutical Sciences, University of Illinois at Chicago, West Side Division, Chicago, Illinois 60612, USA
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17
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Sherwood NM, Krueckl SL, McRory JE. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 2000; 21:619-70. [PMID: 11133067 DOI: 10.1210/edrv.21.6.0414] [Citation(s) in RCA: 160] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The pituitary adenylate cyclase-activating polypeptide (PACAP)/ glucagon superfamily includes nine hormones in humans that are related by structure, distribution (especially the brain and gut), function (often by activation of cAMP), and receptors (a subset of seven-transmembrane receptors). The nine hormones include glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, glucose-dependent insulinotropic polypeptide (GIP), GH-releasing hormone (GRF), peptide histidine-methionine (PHM), PACAP, secretin, and vasoactive intestinal polypeptide (VIP). The origin of the ancestral superfamily members is at least as old as the invertebrates; the most ancient and tightly conserved members are PACAP and glucagon. Evidence to date suggests the superfamily began with a gene or exon duplication and then continued to diverge with some gene duplications in vertebrates. The function of PACAP is considered in detail because it is newly (1989) discovered; it is tightly conserved (96% over 700 million years); and it is probably the ancestral molecule. The diverse functions of PACAP include regulation of proliferation, differentiation, and apoptosis in some cell populations. In addition, PACAP regulates metabolism and the cardiovascular, endocrine, and immune systems, although the physiological event(s) that coordinates PACAP responses remains to be identified.
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Affiliation(s)
- N M Sherwood
- Department of Biology, University of Victoria, British Columbia, Canada.
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18
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Kis B, Mezei Z, Dancsó G, Pataricza J, Gecse A, Papp JG, Telegdy G. Effects of pituitary adenylate cyclase-activating polypeptide on the cyclooxygenase pathway of rat platelets and on platelet aggregation. Prostaglandins Other Lipid Mediat 1999; 58:103-12. [PMID: 10560613 DOI: 10.1016/s0090-6980(99)00039-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Several data suggest that pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in the regulation of local circulation. One possible role of PACAP in the regulation of circulation is that, it may modify the cyclooxygenase pathway of the arachidonate cascade in platelets. Our study was designed to study the effect of PACAP on the cyclooxygenase pathway of rat platelets and on platelet aggregation. PACAP (10(-7) and 10(-6) M) significantly inhibited the cyclooxygenase pathway of platelets, mostly the thromboxane synthesis. Pretreatment with a PACAP receptor antagonist, PACAP(6-38), or with an inhibitor of protein kinase A, H-89, shows that the effects of PACAP on the cyclooxygenase pathway were diminished. In the aggregation studies, PACAP inhibited both the arachidonic acid-induced and the thrombin-induced platelet aggregation. It can be concluded that PACAP inhibits the cyclooxygenase pathway of rat platelets via a specific PACAP receptor-activated, cAMP-dependent pathway, and these effects of PACAP are involved in the inhibition of platelet aggregation.
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Affiliation(s)
- B Kis
- Department of Pathophysiology, Albert Szent-Györgyi Medical University, Szeged, Hungary
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19
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Naruse S, Ito O, Kitagawa M, Ishiguro H, Nakajima M, Hayakawa T. Effects of PACAP/VIP/secretin on pancreatic and gastrointestinal blood flow in conscious dogs. Ann N Y Acad Sci 1998; 865:463-5. [PMID: 9928050 DOI: 10.1111/j.1749-6632.1998.tb11216.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- S Naruse
- Department of Internal Medicine II, Nagoya University School of Medicine, Japan.
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20
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Ito O, Naruse S, Kitagawa M, Ishiguro H, Ko S, Nakajima M, Hayakawa T. The effect of VIP/PACAP family of peptides on pancreatic blood flow and secretion in conscious dogs. REGULATORY PEPTIDES 1998; 78:105-12. [PMID: 9879753 DOI: 10.1016/s0167-0115(98)00135-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The effects of PACAP-38, PACAP-27, VIP and secretin on pancreatic blood flow were compared with those of meals in five conscious dogs using an ultrasound transit-time blood flow meter. All peptides (1-100 pmol/kg) induced dose-related increases of pancreatic blood flow, and fluid and bicarbonate secretion. Only PACAPs stimulated protein secretion. Both PACAPs at doses which did not stimulate pancreatic secretion, induced significant pancreatic vasodilatation. VIP was less potent than PACAP-38 and PACAP-27 at lower doses (1-25 pmol/kg), but was similar to PACAPs at higher doses. The maximal effects of PACAPs and VIP were comparable to those observed after meals. Secretin was a significant but weak vasodilator. When pancreatic secretion was maximally stimulated by secretin, a reduction of vascular resistance was 75% of postprandial peak levels. PACAP(6-38), a competitive antagonist of PACAP, inhibited pancreatic vascular responses to PACAPs, but not those to VIP and secretin. Its inhibitory effects on protein response to PACAPs were not significant. Atropine inhibited pancreatic protein but not the vascular effect of PACAP-27. Pancreatic vasodilatation by PACAPs appears to be mediated by both PACAP-specific and VIP/PACAP common receptors in dogs. PACAP, like VIP, is a good candidate for a mediator of atropine-resistant vasodilatation of the pancreas.
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Affiliation(s)
- O Ito
- Department of Internal Medicine II, School of Medicine, Nagoya University, Japan
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21
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Naruse S, Nakamura T, Wei M, Ando E, Nokihara K, Wray V, Ozaki T, Kitagawa M, Hayakawa T. Effects of PACAP-VIP hybrid peptides on gastric blood flow in conscious dogs. Ann N Y Acad Sci 1996; 805:511-5. [PMID: 8993432 DOI: 10.1111/j.1749-6632.1996.tb17512.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- S Naruse
- Department of Internal Medicine II, Nagoya University School of Medicine, Japan.
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22
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Abstract
AIM: To investigate the structure-activity relationship of pituitary adenylate cyclase activating polypeptide (PACAP) in guinea pig gallbladder using a synthetic PACAP/vasoactive intestinal peptide (VIP) hybrid.
METHODS: We synthesized PACAP-VIP hybrid peptides using the Fmoc strategy and a simultaneous multiple solid-phase peptide synthesizer. The peptides were tested in isolated guinea pig gallbladders using an improved horizontal type organ bath.
RESULTS: VIP induced relaxation of gallbladder smooth muscle strips, while PACAP27 contracted them. Amino acids at positions 4, 5, 9, and 24-26 were replaced without significant loss of activity. [Leu13]-PACAP27, a substitution in the α-helix domain, also had no significant loss in activity (P < 0.05). It was more potent than [Gly8]- and [DAsp8]-PACAP27 and could substitute peptides at position 21. Des-[His1] and [Ala6]-PACAP27 had no activity at 10-7 mol/L. [Gly8]-, [DAsp8]-, [Phe21]- and [Pro21]-PACAP27 at 10-7 mol/L had about 25% of the activity of PACAP27 at 10-7 mol/L (P < 0.05).
CONCLUSION: The N-terminal disordered region is more important than other regions for determining the physiological activity of PACAP in the guinea pig gallbladder.
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23
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Steenstrup BR, Jørgensen JC, Alm P, Hannibal J, Junge J, Fahrenkrug J, Ottesen B. Pituitary adenylate cyclase activating polypeptide (PACAP): occurrence and vasodilatory effect in the human uteroplacental unit. REGULATORY PEPTIDES 1996; 61:197-204. [PMID: 8701036 DOI: 10.1016/0167-0115(95)00156-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
UNLABELLED Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide which was originally isolated from ovine hypothalamus. PACAP exists in at least two biologically active forms, PACAP-38 and PACAP-27. The aim of this study was to establish the distribution, localization and smooth muscle effects of PACAP-38 and PACAP-27 in the human uteroplacental unit. For this purpose we used radioimmunoassay, immunocytochemistry and in vitro studies of the effect of the peptides on smooth muscle activity. RESULTS By radioimmunoassay both peptides were detected throughout the uteroplacental unit. The concentrations of PACAP-27 were in general low, ranging from 1/6-1/25 of the corresponding PACAP-38 concentrations. PACAP-immunoreactivity was localized in nerve fibres of the lower segment of the pregnant uterus, but the number of PACAP-immunoreactive nerves was very clearly reduced compared to the corresponding isthmic region of non-pregnant myometrial tissue. PACAP-immunoreactive fibres were not observed in placenta or in the umbilical cord. Both PACAP-38 and PACAP-27 caused a concentration-dependent relaxation on stem villous arteries and on the intramyometrial arteries. Neither of the peptides displayed any effect on non-vascular smooth muscle specimens from the term pregnant myometrium. In conclusion the findings suggest a vasoregulator role of PACAP in the human uteroplacental unit.
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Affiliation(s)
- B R Steenstrup
- Department of Gynaecology and Obstetrics, Huidoure Hospital, University of Copenhagen, Denmark
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24
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Abstract
1. Neuropeptides are present in the majority of autonomic neurons projecting to blood vessels, where they are co-localized with non-peptide transmitters and sometimes with other peptides. 2. Neuropeptides are released from vasoconstrictor and vasodilator nerve terminals after high frequency stimulation ( > 2-5Hz) with trains of impulses. 3. Neuropeptides can have potent post-synaptic effects on vascular tone, but often these effects are restricted to selected regions of the vasculature. 4. Post-synaptic effects of neuropeptides tend to be more slowly-developing and more long-lasting than those of non-peptide transmitters. 5. Autonomic vasoconstrictor and vasodilator responses often have multiple phases, with the faster phases being mediated by non-peptide transmitters and the slower phases medicated predominantly by one or more neuropeptides. 6. Some neuropeptides do not seem to have post-synaptic effects in a particular vascular bed, but can have presynaptic actions on neurotransmitter release. 7. Neuropeptides form an important component of the repertoire of neurotransmitters used by vascular autonomic neurons to regulate regional blood flow in response to a range of physiological stimuli.
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Affiliation(s)
- J L Morris
- Department of Anatomy & Histology, School of Medicine, Flinders University of South Australia, Adelaide, Australia
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25
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Hedlund P, Alm P, Ekström P, Fahrenkrug J, Hannibal J, Hedlund H, Larsson B, Andersson KE. Pituitary adenylate cyclase-activating polypeptide, helospectin, and vasoactive intestinal polypeptide in human corpus cavernosum. Br J Pharmacol 1995; 116:2258-66. [PMID: 8564257 PMCID: PMC1908961 DOI: 10.1111/j.1476-5381.1995.tb15062.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
1. The distribution and effects of pituitary adenylate cyclase-activating polypeptide (PACAP-27 and -38), helospectin (Hel-1 and Hel-2), and vasoactive intestinal polypeptide (VIP), were investigated in isolated preparations of human corpus cavernosum (CC). 2. Immunohistochemistry revealed coinciding profiles of nerve structures that showed immunoreactivities for VIP and PACAP, and VIP and Hel. Confocal microscopy showed the co-existence of VIP- and PACAP-immunoreactivities, and VIP- and Hel-immunoreactivities in most (90%) varicose nerve structures. 3. As determined by radioimmunoassay, the amounts of VIP, PACAP-27, and PACAP-38 in the preparations were 61.7 +/- 11.6, 0.1 +/- 0.05, and 3.7 +/- 0.5 pmol g-1 wet weight of tissue (pmol g-1 wet wt.), respectively. In tissue from patients with diabetes, the content of VIP was lower (13.7 +/- 0.5 pmol g-1 wet wt.), whereas that of PACAP (-27 and -38) was unchanged. 4. Cyclic nucleotide levels were determined in preparations exposed to PACAP-27, PACAP-38, Hel-1, Hel-2, and VIP. All the peptides, but Hel-2, significantly increased the concentrations of cyclic AMP, whereas the levels of cyclic GMP were unchanged. 5. The peptides concentration-dependently relaxed noradrenaline-contracted preparations. The order of potency was VIP > PACAP 27 > Hel-1 > Hel-2 > PACAP-38. 6. Hel-1, VIP and PACAP-27 effectively counteracted electrically induced contractions. At 10(-6) M, the highest peptide concentration used, the inhibitory effects obtained reached 96 +/- 3%, 87 +/- 6%, and 80 +/- 3%, respectively. 7. The results suggest that PACAP and Hel-1 are co-localized with VIP in nerve structures within the human cavernous tissue, and that the peptides are effective relaxants of CC preparations in vitro. The role of the investigated peptides for penile erection remains to be established.
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Affiliation(s)
- P Hedlund
- Department of Clinical Pharmacology, Lund University Hospital, Sweden
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26
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Steenstrup BR, Alm P, Hannibal J, Jørgensen JC, Palle C, Junge J, Christensen HB, Ottesen B, Fahrenkrug J. Pituitary adenylate cyclase-activating polypeptide: occurrence and relaxant effect in female genital tract. THE AMERICAN JOURNAL OF PHYSIOLOGY 1995; 269:E108-17. [PMID: 7631765 DOI: 10.1152/ajpendo.1995.269.1.e108] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The distribution, localization, and smooth muscle effects of pituitary adenylate cyclase-activating polypeptide (PACAP) were studied in the human female genital tract. The concentrations of PACAP-38 and PACAP-27 were measured by radioimmunoassays, and both peptides were found throughout the genital tract. The highest concentrations of PACAP-38 were detected in the ovary, the upper part of vagina, and the perineum. The concentrations of PACAP-27 were generally low, in some regions below the detection limit and in other regions 1 to 5% of the PACAP-38 concentrations. Immunocytochemistry revealed that PACAP was located in delicate varicose nerve fibers that were most abundant in the internal cervical os, where they mainly seemed to innervate blood vessels and smooth muscle cells. PACAP-38 and PACAP-27 (10(-10)-10(-6) M) caused a concentration-dependent relaxation of the spontaneous activity of the nonvascular smooth muscle strips from fallopian tube and myometrium in vitro. Likewise, both peptides (10(-10)-10(-6) M) caused relaxation of nonrepinephrine (10(-6) M)-precontracted intramyometrial arteries. No effect of the PACAP sequences, PACAP-(6-27), PACAP-(16-38), and PACAP-(18-27), on fallopian tube was observed. The findings suggest a smooth muscle regulatory role of PACAP in the human female reproductive tract.
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Affiliation(s)
- B R Steenstrup
- Department of Gynaecology and Obstetrics, Hvidovre Hospital, Sweden
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27
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Ishizuka O, Alm P, Larsson B, Mattiasson A, Andersson KE. Facilitatory effect of pituitary adenylate cyclase activating polypeptide on micturition in normal, conscious rats. Neuroscience 1995; 66:1009-14. [PMID: 7651605 DOI: 10.1016/0306-4522(95)00038-k] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
In unanaesthetized, normal rats, continuous cystometry revealed that pituitary adenylate cyclase activating peptide (PACAP-27), administered intrathecally or intra-arterially near the bladder, stimulated micturition. The localization of PACAP-27 in the rat lower urinary tract was studied by immunohistochemistry, and the direct effects on the smooth muscles of the rat detrusor and urethra were investigated in vitro. In the intact rat, 1.0 nmol of PACAP-27 administered intrathecally as well as intra-arterially close to the bladder, but not intravenously, increased micturition pressure, decreased micturition volume and bladder capacity, and facilitated spontaneous bladder contractions. PACAP-27 immunoreactive structures were extremely scarce in the lower urinary tract, and the peptide had negligible effects on isolated detrusor muscle contracted by carbachol or stimulated electrically, or on urethral preparations contracted by noradrenaline. These results suggest that PACAP-27 has facilitatory actions on micturition both at the spinal cord and peripheral ganglionic levels.
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Affiliation(s)
- O Ishizuka
- Department of Urology, Lund University Hospital, Sweden
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28
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Tobin G, Asztély A, Edwards AV, Ekström J, Håkanson R, Sundler F. Presence and effects of pituitary adenylate cyclase activating peptide in the submandibular gland of the ferret. Neuroscience 1995; 66:227-35. [PMID: 7637871 DOI: 10.1016/0306-4522(94)00622-c] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Pituitary adenylate cyclase activating peptide (PACAP), a recently described vasoactive intestinal peptide-like neuropeptide, was found to be present in neurons in the submandibular gland of the ferret, where PACAP-immunoreactive nerve fibers were distributed around blood vessels, acini and ducts. Most of the PACAP-immunoreactive fibres were distinct from those storing vasoactive intestinal peptide. PACAP occurs in tissues as PACAP1-38 and PACAP1-27. PACAP1-38 and PACAP1-27 but not PACAP16-38 displayed biological activity with about the same potency. They exerted vasodilator effects on the submandibular vasculature, which resulted in a greater fall in vascular resistance than an equimolar dose of vasoactive intestinal peptide. The vasodilator response was independent of muscarinic receptor activation. Neither vasoactive intestinal peptide nor PACAP alone evoked any flow of saliva. However, both vasoactive intestinal peptide and PACAP enhanced the fluid response to acetylcholine, and the flow of saliva as well as the output of protein in response to parasympathetic nerve stimulation, vasoactive intestinal peptide being more potent than PACAP. In vitro, protein was released from submandibular gland tissue in response to both vasoactive intestinal peptide and PACAP, vasoactive intestinal peptide being more potent than PACAP. PACAP (and vasoactive intestinal peptide) exerted its in vitro effect following adrenoceptor and muscarinic blockade and following degeneration of sympathetic nerves. Sympathetic denervation combined with parasympathetic preganglionic denervation resulted in supersensitivity to both vasoactive intestinal peptide and PACAP. The fact that PACAP and vasoactive intestinal peptide occur in different nerve fibre populations suggests different roles for the two peptides in the submandibular gland.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- G Tobin
- Department of Physiology and Pharmacology, Göteborg University, Sweden
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