UMLS:C0432222 - FACTA Search

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Query: UMLS:C0432222 (SEM)
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The vasodilator effect of the novel peptide pituitary adenylate cyclase activating polypeptide (PACAP) was investigated in humans. Forearm blood flow was measured in six healthy men by venous occlusion plethysmography. Infusion of PACAP into the brachial artery at 0.01, 0.1, 1, 3, and 10 pmol/min produced a dose-related increase in forearm blood flow in the cannulated arm from 2.8 +/- 0.6 to 8.6 +/- 2.4 ml/100 ml/min at the highest dose (mean +/- SEM, p less than 0.05). In a subsequent experiment, where the highest dose of PACAP was repeated after a 36 min interval, there was no tachyphylaxis of the forearm blood flow response, with the forearm blood flow increasing by 129 +/- 9% during the first infusion and 128 +/- 31% during the second infusion (N.S.). In further experiments, microvascular blood flow was measured by a laser-Doppler flow probe to compare the effects of intradermally injected PACAP, vasoactive intestinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP). When injected into the skin of normal volunteers at 10(-12) to 10(-11) mol/site, each peptide caused a rapid flare lasting 2-3 min, which became erythematous after 5 min. At 10(-12) mol/site, intradermally injected PACAP and VIP caused a maximum increase in skin blood flow at 15 min of 379 +/- 96 and 307 +/- 121% (% increase above basal +/- SEM), respectively, and these responses were not significantly affected by oral aspirin (600 mg) taken 1.5 h beforehand. The vasodilation induced by PACAP at 10(-12) mol/site lasted approximately 6 h, whereas the effect of the same dose of CGRP and VIP lasted less than 2 h. These data suggest that PACAP is a potent and long-lasting vasodilator in humans.
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PMID:Pituitary adenylate cyclase activating polypeptide is a potent vasodilator in humans. 138 35

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a novel peptide of hypothalamic origin which increases adenylate cyclase activity in rat anterior pituitary cell cultures. The 38-amino acid peptide shows a close sequence homology to vasoactive intestinal peptide (VIP). Binding sites for PACAP in membranes from postmortem human brain tissue were studied using [125I]PACAP27 as the radioligand. High specific binding sites (amount of specific binding measured at 0.25 nM [125I]PACAP27 in femtomoles per mg protein +/- SEM; n = 4) were present in hypothalamus (344.5 +/- 13.0), brain stem (343.0 +/- 29.3), cerebellum (292.0 +/- 21.1), cortex (259.6 +/- 19.8), and basal ganglia (259.2 +/- 50.3). Specific binding sites in pituitary, although present, were less abundant (35.0 +/- 8.9). Binding of [125I]PACAP27 was reversible and time, pH, and temperature dependent. Despite the homology with VIP, VIP was a poor inhibitor of [125I]PACAP27 binding (IC50, greater than 1 microM) compared with PACAP27 (IC50, 0.5-1.3 nM) and PACAP38 (IC50, 0.2-1.3 nM). Scatchard plots of [125I]PACAP27 binding showed the presence of both high and lower affinity sites. Chemical cross-linking of PACAP-binding sites revealed that [125I]PACAP27 was bound to polypeptide chains of 67,000 and 48,000 mol wt. Thus, we have demonstrated the presence of PACAP-specific receptors in human brain which are not VIP receptors. This opens the possibility of PACAP functioning as a novel neurotransmitter/neuromodulator in human brain.
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PMID:Investigation and characterization of receptors for pituitary adenylate cyclase-activating polypeptide in human brain by radioligand binding and chemical cross-linking. 167 86

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a newly discovered neuropeptide that is present in high amounts in hypothalamic neuroendocrine neurons and potently stimulates the accumulation of cAMP within cells of the anterior pituitary. We have employed several specific antisera recognizing different parts of the PACAP precursor to elucidate the distribution of PACAP-like immunoreactivities in the hypothalamic components of the hypothalamo-pituitary-adrenocortical axis in sections obtained from normal and colchicine-treated rats. Using immunohistochemistry with avidin-biotin-coupled peroxidase as a reporter system, high numbers of PACAP-immunoreactive perikarya were found in colchicine-pretreated rats in many of the parvicellular subdivisions of the hypothalamic paraventricular nucleus (PVN). A few cells were also found in the magnocellular subdivisions of the nucleus, and a similar small population of cells was observed in the dorsolateral aspect of the supraoptic nucleus. Using indirect immunofluorescence, the relation between CRF- and PACAP-containing neurons in the various parvicellular subnuclei of the PVN was studied, and a high degree of colocalization was demonstrated in the neurons of the medial parvicellular part of PVN. To further study the functional implications of PACAP in the hypothalamo-pituitary-adrenocortical axis, we examined the expression of PACAP messenger RNA (mRNA) in the PVN in response to five different stimulatory paradigms that previously have been shown to stimulate CRF mRNA expression in the medial parvicellular part of the PVN. The stimulatory challenges of adrenalectomy, restraint stress, ip injection of hypertonic saline, ether stress, and intracerebroventricular injection of colchicine induced significant elevations of CRF mRNA expression in the medial parvicellular part of the PVN. In contrast, the expression of PACAP mRNA, which is hardly detectable within the medial parvicellular part of the PVN, was induced only by colchicine treatment (from undetectable levels to 177 +/- 21 dpm/g; mean +/- SEM), whereas PACAP mRNA remained undetectable in this region of the PVN after exposure to any of the other stimulatory paradigms. The onset of colchicine-induced PACAP mRNA expression in the PVN was rapid (3 h), and PACAP mRNA levels remained elevated throughout the 48-h observation period. Considering the different topography and connections of the parvicellular subnuclei of the PVN, the current observations suggest that PACAP present in parvicellular neurons of the PVN may act not only as a neuroendocrine transmitter/modulator in the hypothalamo-pituitary-adrenocortical axis, but also as transmitter mediating neurotransmission conveyed from the PVN to preganglionic neurons of the autonomic system.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pituitary adenylate cyclase-activating peptide gene expression in corticotropin-releasing factor-containing parvicellular neurons of the rat hypothalamic paraventricular nucleus is induced by colchicine, but not by adrenalectomy, acute osmotic, ether, or restraint stress. 764 20

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) is a neuropeptide related to vasoactive intestinal peptide-secretin-glucagon which stimulates adenylate cyclase in cultured rat pituitary cells and stimulates LH and FSH release in vitro and in vivo. Because the cAMP-protein kinase-A pathway regulates the gonadotropin subunit messenger RNAs (mRNAs) and modulates GnRH-stimulated gonadotropin secretion in vitro, we examined the effects of PACAP38 on gonadotropin secretion and subunit mRNA levels. Anterior pituitary cells were prepared from 7-week-old male rats castrated at 5 weeks of age. In monolayer cultures stimulated with GnRH, 0.1-10 nM PACAP38 decreased (P < 0.05) the EC50 for GnRH dose-dependently without affecting the maximum LH secretory response. Cells were next stimulated with 1-min pulses of 2.5 nM GnRH every hour for 9 h in the absence or presence of 10 nM PACAP38, which was perifused continuously. The amplitude of GnRH-induced LH, FSH, and alpha-subunit secretory episodes from PACAP38-treated cells rose (P < 0.01) gradually to 233 +/- 54%, 197 +/- 44%, and 378 +/- 104%, respectively (mean +/- SEM; n = 5 experiments), of the value for control cells lacking PACAP38. This enhancement was sustained for at least 3 h after PACAP38 was removed from the perifusion medium. With PACAP treatment, interpulse secretion of LH and alpha-subunit increased gradually (P < 0.01) to 174 +/- 21% and 212 +/- 64% of the value for chambers stimulated with GnRH alone (control), respectively, whereas interpulse secretion of FSH declined (P < 0.001) to 75 +/- 7% of the control value. In contrast to the gradual effect of PACAP38 to enhance GnRH-induced hormone secretion, PACAP38 alone produced a transient burst of gonadotropin secretion. At the completion of the perifusions, total RNA was extracted and gonadotropin subunit mRNA levels were determined by Northern analysis. GnRH increased (P < 0.01) FSH beta mRNA to 438 +/- 52% of the level in cells stimulated with medium alone (control). Adding PACAP38 to the perifusion medium partially blocked (P < 0.01) the effect of GnRH (178 +/- 20% of the control value), and PACAP38 alone reduced (P < 0.01) FSH beta mRNA levels to 31 +/- 3% of the control value. By contrast, alpha-subunit mRNA levels were increased by both PACAP38 (143 +/- 4% of the control value; P < 0.01) and GnRH (121 +/- 2% of the control value; P < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of pituitary adenylate cyclase-activating polypeptide on gonadotropin secretion and subunit messenger ribonucleic acids in perifused rat pituitary cells. 791 30

To establish the role of pituitary adenylate cyclase activating polypeptide (PACAP), a member of vasoactive intestinal polypeptide (VIP) family, as a neurotransmitter/neuromodulator in the central nervous system, the effects of PACAP38, PACAP27 and VIP on the single neuron activity in the magnocellular portion of the hypothalamic paraventricular nucleus (mg.PVN) were examined in rat brain slice preparations. Extracellular recordings were made from 111 neurons in the mg.PVN, which fired spontaneously at an average rate of 1.85 +/- 0.2 spikes/s (mean +/- SEM). PACAP38 and PACAP27 were applied to 78 and 33 of the 111 neurons, respectively. Perfusion with PACAP38 in doses between 10 nM and 1 microM increased the firing rate of 56 (71.8%) of the 78 neurons in a dose-dependent manner. The threshold dose of PACAP38 to excite the neurons seemed to lie below 10 nM. The application of PACAP27 (1 microM) also increased the firing rate of 19 (57.6%) of the 33 neurons tested. Eleven (52.4%) of 21 neurons which were excited by PACAP38 also showed excitation following perfusion with VIP (1 microM). The responses to PACAP38 in 12 of 20 neurons and those to VIP in 6 of 9 neurons tested were still observed in a low Ca2+ and high Mg2+ medium. Although there was no difference in the mean latency between the responses to PACAP38 (1 microM) and VIP (1 microM) (2.1 +/- 0.1 min and 2.4 +/- 0.4 min, respectively), the duration of the PACAP38-induced excitation (59.0 +/- 5.0 min) was much longer than that of the VIP-induced one (18.8 +/- 3.1 min). The PACAP38 (30 nM)-induced excitation was reversibly blocked by a concurrent application of PACAP5-38 (300 nM), a PACAP receptor antagonist. While a selective VIP receptor antagonist, [Lys1, Pro2,5, Arg3,4, Tyr6]-VIP (1 microM), did not affect the excitatory responses to PACAP38 (300 nM), it completely blocked the VIP (1 microM)-induced excitation. These findings suggest that PACAP may therefore modulate the secretion of the pituitary hormones at least partly by its action on the neurons in the mg.PVN through the activation of specific receptors for PACAP.
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PMID:Facilitatory effects of pituitary adenylate cyclase activating polypeptide (PACAP) on neurons in the magnocellular portion of the rat hypothalamic paraventricular nucleus (PVN) in vitro. 886 61

Pituitary adenylate cyclase-activating polypeptide (PACAP) is synthesized in developing germ cells in the testis and may act as a paracrine modulator of spermatogenesis and/or participate in tubule-interstitial interactions. Despite the abundance of PACAP in the organ, its role in testicular function has not yet been studied in vivo. Using laser Doppler flowmetry, the effects of PACAP on blood flow in the testis and caput epididymidis were studied on anesthetized adult rats. When given intratesticularly as 5- and 50-ng doses, PACAP increased blood flow by 55+/-21% (mean +/- SEM, P < 0.05) and by 68+/-11% at 5 mm from the injection site, respectively. Whereas 5 ng PACAP did not influence blood flow 15 mm from the site of injection, flow was reduced (-7+/-3; P < 0.05) at this site following treatment with 50 ng. Injection of 50 ng PACAP into the caput epididymidis increased epididymal blood flow by 18+/-4% (P < 0.05) at 1 mm from the injection site. None of the treatments above significantly affected the mean arterial blood pressure. Using immunohistochemistry, PACAP was observed in elongated spermatids and in the acrosomes of round spermatids in some, but not all, seminiferous tubules. Also, distinct PACAP immunoreactivity was seen in epithelial cells, particularly in clear cells, of the caput epididymidis. In conclusion, PACAP can induce vasodilatation in both testicular and epididymal microvessels and may be involved in regulating blood flow in these organs. Whereas the vasodilatory effect of PACAP is strong in the testis, the epididymal response appears to be more moderate.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP): effects on blood flow in the testis and caput epididymidis of the rat. 1038 16

The effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on neuronal excitability in the CA1 region of rat hippocampus were studied using in vivo and in vitro electrophysiological techniques. Extracellularly recorded spontaneous firing of CA1 neurons was transiently (2-7 min) increased by PACAP (106+/-32% enhancement, mean+/-SEM, n=11). Using whole-cell patch clamp, PACAP was tested on the resting membrane current of CA1 pyramidal neurons: PACAP activated a slow-onset (20-30 s) and long-lasting (over 20 min) inward current with a mean amplitude of 99+/-34 pA (mean+/-SD, n=8). These results indicate that PACAP induces depolarizing effects on CA1 hippocampal neurons. PACAP-induced long-lasting facilitation in the CA1 region might modify neuronal excitability and/or modulate the effect of other neurotransmitters.
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PMID:Pituitary adenylate cyclase-activating polypeptide modifies the electrical activity of CA1 hippocampal neurons in the rat. 1252 97

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a cerebrovascular dilator and was found neuroprotective in numerous in vitro and in vivo models of cerebral ischemia. However, the mechanism of its cerebrovascular action is poorly known, especially in newborns. Therefore, we tested pial arteriolar responses to the two naturally occurring forms PACAP27 and 38 as well as to shorter sequences (PACAP6-27, 6-38, 1-15, 6-15, 20-31). We also investigated the involvement of nitric oxide synthase (NOS), cyclooxygenase-1 and -2 (COX-1 and -2) activity in PACAP-induced pial arteriolar responses using the NOS inhibitor N-omega-nitro-l-arginine methyl ester (L-NAME 15 mg/kg iv), the non-selective COX inhibitor indomethacin (5 mg/kg iv), and the selective COX-1 and COX-2 inhibitors SC-560 (1 mg/kg iv) and NS-398 (1 mg/kg iv), respectively. Anesthetized, ventilated piglets (n=127) were equipped with closed cranial windows, and pial arteriolar diameters were determined via intravital microscopy. Topical application of both natural PACAPs, but none of the PACAP segments, resulted in prominent, repeatable, dose-dependent vasodilation. Percentage changes ranged 5+/-1-29+/-6 (n=7) and 4+/-1-36+/-7 (n=9) to 10(-)(8) to 10(-)(6) M PACAP27 and 38 (mean+/-SEM), respectively. Vasodilation to both natural PACAPs was significantly reduced by co-application with PACAP6-27 or 6-38, but not by L-NAME. Indomethacin abolished PACAP38 but not PACAP27-induced vasodilation. Arteriolar responses to PACAP38 were also sensitive to SC-560 but not to NS-398 suggesting the unique involvement of COX-1 activity in this response. In summary, PACAP27 and 38 are potent vasodilators in the neonatal cerebral circulation with at least two distinct mechanisms of action: a COX-dependent and a COX-independent pathway.
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PMID:Pituitary adenylate cyclase-activating polypeptide induces pial arteriolar vasodilation through cyclooxygenase-dependent and independent mechanisms in newborn pigs. 1765 92

Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective in numerous models. Impairment of cerebrovascular reactivity (CR) contributes to ischemia/reperfusion (I/R)-induced neuronal damage. We tested whether PACAP and/or VIP preserve CR to I/R-sensitive dilator responses dependent on endothelial and/or neuronal function. Accordingly, changes in pial arteriolar diameters in response to hypercapnia (5-10% CO(2) ventilation) or topical N-methyl-d-aspartate (NMDA, 10(-4) M) were determined before and after I/R via intravital microscopy in anesthetized/ventilated piglets. Local pretreatment with non-vasoactive doses of PACAP (10(-8) M) and VIP (10(-9) M) prevented the attenuation of postischemic CR to hypercapnia; to 10% CO(2), the CR values were 27+/-8% vs 92+/-5% vs 88+/-13% (vehicle vs PACAP38 vs VIP, CR expressed as a percentage of the response before I/R, mean+/-SEM, n=8-8, p<0.05). PACAP, but not VIP, preserved CR to NMDA after I/R, with CR values of 31+/-10% vs 87+/-8% vs 35+/-12% (vehicle vs PACAP38 vs VIP, n=6-6). Unlike PACAP, VIP-induced vasodilation has not yet been investigated in the piglet. We tested whether VIP-induced arteriolar dilation was sensitive to inhibitors of cyclooxygenase (COX)-1 (SC-560, 1 mg/kg), COX-2 (NS-398, 1 mg/kg), indomethacin (5 mg/kg), and nitric oxide synthase (L-NAME, 15 mg/kg). VIP (10(-8)-10(-7)-10(-6) M, n=8) induced reproducible, dose-dependent vasodilation of 16+/-3%, 33+/-6%, and 70+/-8%. The response was unaffected by all drugs, except that the vasodilation to 10(-8) M VIP was abolished by SC-560 and indomethacin. In conclusion, PACAP and VIP differentially preserve postischemic CR; independent of their vasodilatory effect.
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PMID:PACAP and VIP differentially preserve neurovascular reactivity after global cerebral ischemia in newborn pigs. 1953 45