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Biomedical subjects

S I Said

Publications and source records attributed to S I Said.

At least 37 records · Page 2Linked to original sources
PubMed1996

Characterization of VIP-and helodermin-preferring receptors on rat platelets.

We have examined the binding of radio-iodinated vasoactive intestinal peptide (VIP) to rat platelets. The binding was time- and temperature-dependent and was reversible, saturable and specific. Scatchard analysis of binding data suggested the presence of a single class of binding sites, with Kd = 2.49 +/- 0.76 nM and Bmax = 112.1 +/- 54.6 fmol/10(8) cells. Several VIP-related peptides inhibited 125I-VIP binding to rat platelets with the following order of potency: helodermin > or = VIP > peptide histidine isoleucine. Glucagon, secretin, growth hormone-releasing hormone (GHRH), and gastric inhibitory peptide (GIP) were ineffective. VIP and the other peptides increased cyclic AMP production with the same order of potency as the inhibition of binding, but the stimulation by VIP was less marked than that by prostacyclin (PGI2). We conclude that rat platelets have functional, adenylate cyclase-linked, receptors that bind preferentially to helodermin and VIP.

Animals↗
PubMed1996

Excitotoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase.

Excitatory amino acid toxicity, resulting from overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors, is a major mechanism of neuronal cell death in acute and chronic neurological diseases. We have investigated whether excitotoxicity may occur in peripheral organs, causing tissue injury, and report that NMDA receptor activation in perfused, ventilated rat lungs triggered acute injury, marked by increased pressures needed to ventilate and perfuse the lung, and by high-permeability edema. The injury was prevented by competitive NMDA receptor antagonists or by channel-blocker MK-801, and was reduced in the presence of Mg2+. As with NMDA toxicity to central neurons, the lung injury was nitric oxide (NO) dependent: it required L-arginine, was associated with increased production of NO, and was attenuated by either of two NO synthase inhibitors. The neuropeptide vasoactive intestinal peptide and inhibitors of poly(ADP-ribose) polymerase also prevented this injury, but without inhibiting NO synthesis, both acting by inhibiting a toxic action of NO that is critical to tissue injury. The findings indicate that: (i) NMDA receptors exist in the lung (and probably elsewhere outside the central nervous system), (ii) excessive activation of these receptors may provoke acute edematous lung injury as seen in the "adult respiratory distress syndrome," and (iii) this injury can be modulated by blockade of one of three critical steps: NMDA receptor binding, inhibition of NO synthesis, or activation of poly(ADP-ribose) polymerase.

Animals↗
PubMed1996

Neurochemical characterization of intrinsic neurons in ferret tracheal plexus.

Although neuroanatomical and neurophysiological features of neurons in the ferret trachea have been studied, the neural mediators associated with this plexus have not been completely characterized. The purpose of this study was to examine the occurrence of choline acetyltransferase (ChAT), nitric oxide synthase (NOS), vasoactive intestinal peptide (VIP), and substance P(SP) in the intrinsic neurons of this plexus. The distribution of double- and triple-labeled neurons was quantified in cryostat sections and in whole mounted specimens to evaluate the neurochemical profiles. About 85% of the nerve cell bodies with ChAT immunoreactivity (ChAT-IR) were located in ganglia of the longitudinal trunks or the closely associated bridge ganglia. Approximately 15% of ChAT-positive neurons were in ganglia of the superficial muscular plexus. Conversely, VIP-IR neurons were most frequent in the superficial muscular plexus (>75%) and, <10% were observed in the longitudinal trunks or bridge neurons. Most NOS- and SP-IR neurons were also located in the superficial muscular plexus. The following distribution of neurochemical profiles was determined for neurons of the superficial muscular plexus: 11% only NOS, 20% only VIP, 5% only SP, 67% NOS and VIP, and 40% VIP and SP. NOS, VIP, and SP were frequently localized in the same nerve cell body. The occurrence of nerve terminals containing only SP located around the borders of individual NOS/VIP/SP-containing neurons suggests possible sensory innervation to the airway neurons. The results demonstrate that: (1) most cholinergic nerves do not contain VIP, NOS, or SP; (2) cholinergic neurons are predominantly located in the longitudinal trunk ganglia; (3) VIP, NOS, and SP are predominantly located in the superficial muscular plexus ganglia; and (4) nerve terminals containing exclusively SP, suggesting possible sensory origin, are closely associated with some neurons in the plexus.

Animals↗
PubMed1995

Enhancement of extended lung preservation with a vasoactive intestinal peptide-enriched University of Wisconsin solution.

Vasoactive intestinal peptide (VIP) is a known pulmonary and bronchial vasodilator as well as an oxygen free radical scavenger. Since its effect as an additive to University of Wisconsin (UW) solution for lung preservation has been shown previously, the aim of this study was to determine the ability of VIP to improve lung preservation followed by reperfusion. Four groups of excised Sprague-Dawley rat lungs (n = 24) were studied using an isolated blood perfused working lung model. The first 3 groups of lungs were flushed and stored in UW solution at 4 degrees C for: (1) 4 hr, (2) 18 hr, and (3) 24 hr. Group 4 lungs were flushed with UW solution + VIP (1 microgram/ml) and stored in UW solution + VIP (0.5 microgram/ml) for 24 hr. After preservation, the lungs were reperfused to evaluate their functions for 2 hr or until lung failure occurred (arterial oxygen saturation less than 90% and/or appearance of bronchial fluid in the bronchial cannula). In the lungs stored in UW solution for 24 hr, failure occurred after 10 min of reperfusion and all functions were significantly altered. The addition of VIP to UW solution maintained the functional capacity of the lungs, recorded by lung resistance, lung compliance, elastic work, flow resistive work, shunt fraction, and blood oxygen tension. No statistical difference in these parameters other than shunt fraction was found when the VIP group was compared with the group preserved for 4 hr in UW solution. We conclude that lung preservation can be extended to 24 hr with the maintenance of lung functional capacity if VIP is added to UW solution.

Adenosine↗
PubMed1995

Pituitary adenylate cyclase-activating peptide (PACAP), a VIP-like peptide, has prolonged airway smooth muscle relaxant activity.

Pituitary adenylate cyclase-activating peptide (PACAP), a widely distributed peptide belonging to the vasoactive intestinal peptide (VIP) family of peptides, stimulates the accumulation of cyclic adenosine monophosphate (cAMP) in many tissues, with greater potency and efficacy than VIP. We report that PACAP-38 was one-third as potent and 70% as efficacious as VIP in producing relaxation of isolated perifused guinea pig strips, although it was approximately twice as effective in stimulating cAMP accumulation. The PACAP-38-induced relaxation, however, was five to eight times as prolonged as that of VIP, and its cAMP stimulation was also more sustained. The prolonged action of PACAP-38 is probably due to its greater resistance to enzymatic degradation. The data suggest that airway relaxation is not solely dependent on the total content of cAMP in airways. PACAP-38 exhibits properties that may be useful in the management of airway constriction.

Adenylyl Cyclases↗
PubMed1995

N-methyl-D-aspartate receptors outside the central nervous system: activation causes acute lung injury that is mediated by nitric oxide synthesis and prevented by vasoactive intestinal peptide.

N-methyl-D-aspartate receptors, found throughout the mammalian brain, are a component of the major excitatory transmitter system. Strong evidence exists that N-methyl-D-aspartate receptors, by promoting excessive entry of Ca2+ into neurons, play a role in neuronal damage that follows head injury, strokes, and epileptic seizures, and is associated with degenerative diseases such as Alzheimer's disease. Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We have investigated whether N-methyl-D-aspartate receptors exist in peripheral neurons, and, if so, whether their activation may result in tissue injury. We report that N-methyl-D-aspartate receptors exist in the lung, that their activation triggers acute injury, and that, as in toxicity to central neurons, this injury is associated with stimulation of nitric oxide synthesis, and can be attenuated by inhibition of this synthesis. Finally, vasoactive intestinal peptide, which protects the lung and heart against oxidant injury and promotes neuronal survival and differentiation also prevented N-methyl-D-aspartate lung injury, apparently by inhibiting a key neurotoxic action of nitric oxide, but not its production. The findings suggest that N-methyl-D-aspartate receptors exist in the peripheral nervous system and that activation of these receptors, resulting in damage to peripheral neurons, may be a novel mechanism of lung and other organ injury.

2-Amino-5-phosphonovalerate↗
PubMed1995

VIP inhibits basal and histamine-stimulated proliferation of human airway smooth muscle cells.

Airway smooth muscle (ASM) cell proliferation contributes to increased airway resistance in bronchial asthma. We have examined the modulation of ASM proliferation by vasoactive intestinal peptide (VIP), a cotransmitter of airway relaxation. Human ASM cells were grown in culture as a monolayer. VIP (1.0 nM-1.0 microM) inhibited proliferation in a dose-dependent manner by up to 82% on day 2, but the related peptide glucagon had no effect. Histamine (100 nM-100 microM) increased cell counts by 66%, but in the presence of VIP, cell counts and [3H]thymidine incorporation were reduced by up to 55%. Adenosine 3',5'-cyclic monophosphate (cAMP)-promoting agents, including 3-isobutyl-1-methylxanthine, forskolin, and 8-bromo-adenosine 3',5'-cyclic monophosphate, alone and especially combined with VIP, reduced cell counts and [3H]thymidine incorporation, in correlation with cAMP levels. KT-5720 (1.0 nM-1.0 microM), a selective inhibitor of cAMP-dependent protein kinase A (PKA), abolished the inhibitory effect of VIP. The results show that VIP selectively and potently inhibits human ASM cell growth and multiplication, and nullifies the mitogenic effect of histamine, by a PKA-mediated mechanism. A deficiency of VIP may lead to ASM hyperplasia due to unopposed stimulation by endogenous mitogens.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Nitric oxide as a mediator of oxidant lung injury due to paraquat.

At low concentrations, nitric oxide is a physiological transmitter, but in excessive concentrations it may cause cell and tissue injury. We report that in acute oxidant injury induced by the herbicide paraquat in isolated guinea pig lungs, nitric oxide synthesis was markedly stimulated, as evidenced by increased levels of cyclic GMP in lung perfusate and of nitrite and L-citrulline production in lung tissue. All signs of injury, including increased airway and perfusion pressures, pulmonary edema, and protein leakage into the airspaces, were dose-dependently attenuated or totally prevented by either NG-nitro-L-arginine methyl ester or N omega-nitro-L-arginine, selective and competitive inhibitors of nitric oxide synthase. Protection was reversed by excess L-arginine but not by its enantiomer D-arginine. When blood was added to the lung perfusate, the paraquat injury was moderated or delayed as it was when paraquat was given to anesthetized guinea pigs. The rapid onset of injury and its failure to occur in the absence of Ca2+ suggest that constitutive rather than inducible nitric oxide synthase was responsible for the stimulated nitric oxide synthesis. The findings indicate that nitric oxide plays a critical role in the production of lung tissue injury due to paraquat, and it may be a pathogenetic factor in other forms of oxidant tissue injury.

Amino Acid Oxidoreductases↗
PubMed1994

VIP enhances and nitric oxide synthase inhibitor reduces survival of rat lungs perfused ex vivo.

VIP delayed the onset of edematous lung injury in isolated perfused rat lungs by 64%, and was more effective than PGI2 in prolonging lung survival ex vivo. While PGI2 increased survival by 37 min versus Krebs/BSA only, VIP increased it by 2 h and 17 min. On the other hand, inhibition of NO. synthase, which protected the lung against oxidant injury caused by paraquat or X/XO,3 actually hastened the onset of injury caused by prolonged perfusion ex vivo, suggesting opposite roles for NO. in different forms of oxidant injury.

Amino Acid Oxidoreductases↗
PubMed1994

Nitric oxide mediates oxidant tissue injury caused by paraquat and xanthine oxidase.

In both paraquat and X/XO models of lung injury, the injury, previously attributed to the generation of reactive oxygen species, was related to the induction of NO. synthesis, and was totally preventable by inhibition of this synthesis. The results support the view that the NO. radical itself is an essential intermediary in the pathogenesis of at least some forms of oxidant tissue damage. Another form of oxidant injury, caused by prolonged perfusion of the lung ex vivo, is not mediated by NO. however.

Animals↗
PubMed1994

Characterization of vasoactive intestinal peptide receptors on rat alveolar macrophages.

In view of the evidence that vasoactive intestinal peptide (VIP) may modulate acute inflammatory injury in the lung, we investigated the presence and characteristics of VIP receptors on alveolar macrophages (AMs). We examined the binding of monoiodinated [Tyr(125I)10]-labeled VIP (125I-VIP) to rat AMs (> 96% pure), obtained from Sprague-Dawley rats by bronchoalveolar lavage (BAL). At 23 degrees C, the interaction of 125I-VIP with AMs was rapid, reversible, saturable, and linearly proportional to the number of cells. At equilibrium, the binding was competitively inhibited by 10(-11)-10(-6) M of native peptide [half-maximal inhibition (IC50) = 0.53 +/- 0.34 nM, n = 8], with evidence for two classes of binding sites: one with a high affinity (Kd = 0.20 +/- 0.09 nM) and a low capacity (1,190 +/- 640 sites/cell) and another with a low affinity (Kd = 43.2 +/- 13.8 nM) and a high capacity (51,700 +/- 14,000 sites/cell). VIP-related peptides inhibited the binding with the order of potency: VIP > peptide histidine isoleucine > helodermin >> secretin; glucagon was ineffective. In the presence of 3-isobutyl-1-methylxanthine, VIP dose dependently stimulated adenosine 3',5'-cyclic monophosphate accumulation in intact AMs, with maximal stimulation (6.3 times basal level) at 1 nM, and half-maximal accumulation at 0.23 +/- 0.11 nM VIP (Kd for high-affinity sites). For determination of the mass of the VIP receptor, 125I-VIP was covalently bound to AMs with the cross-linking agent dithiobis succinimidyl propionate. Autoradiographic studies after sodium dodecyl sulfate/polyacrylamide gel electrophoresis of solubilized affinity-labeled cells revealed a single major band of M(r) 76,400. We conclude that VIP binds to specific receptors on rat AMs that are coupled to adenylate cyclase, through which VIP may modulate inflammatory responses within the lung.

Animals↗
PubMed1993

Vasoactive intestinal peptide and helodermin inhibit phospholipase A2 activity in vitro.

We recently reported that the widely distributed neuropeptide vasoactive intestinal peptide (VIP) reduces inflammatory lung injury due to a variety of agents and inhibits the associated generation of cyclo-oxygenase and lipoxygenase products. We therefore investigated whether VIP may inhibit phospholipase A2 activity, thus reducing the release of arachidonic acid, the common precursor of all eicosanoids. VIP dose-dependently inhibited PLA2 of porcine pancreas and of Naja naja venom, as assessed by the release of free [3H]oleic acid from labeled Escherichia coli phospholipids. The potency of VIP was similar to that of mepacrine, with 50% inhibition at 400-500 microM. The closely related peptide helodermin produced 50% inhibition at 200 microM, but secretin and peptide histidine isoleucineamide produced little or no inhibition. The results suggest that VIP and helodermin selectively inhibit PLA2 in vitro. If this activity is exerted in vivo, it may contribute to the anti-inflammatory activity of these two peptides.

Animals↗
PubMed1993

Small-cell lung carcinoma: inhibition of proliferation by vasoactive intestinal peptide and helodermin and enhancement of inhibition by anti-bombesin antibody.

Small-cell lung cancer (SCLC) is a common and highly fatal malignancy for which there is no satisfactory treatment. The amphibian peptide bombesin and its mammalian counterpart, gastrin-releasing peptide, serve as autocrine growth factors for the SCLC cells, but little is known about endogenous substances that inhibit the growth and proliferation of these tumor cells. We report that the neuropeptide vasoactive intestinal peptide (VIP) markedly inhibits the growth and multiplication of SCLC cell lines NCI-H345 and NCI-H69, and that the closely related peptide helodermin inhibits the proliferation of NCI-H345 cells with even higher efficacy. In the latter cells, the inhibition by VIP and isobutyl methyl xanthine paralleled their ability to stimulate cyclic adenosine monophosphate production within the cells. The peptide-induced suppression of SCLC proliferation is enhanced in the presence of an anti-bombesin monoclonal antibody. The antimitogenic activities of VIP and helodermin, and their enhancement by anti-bombesin antibody, offer the potential for a new approach to the pharmacologic control of SCLC.

Antibodies, Monoclonal↗