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R N Saunders

Publications and source records attributed to R N Saunders.

At least 37 records · Page 2Linked to original sources
PubMed1987

Release of platelet-activating factor from rabbit heart perfused in vitro by sera with transplantation alloantibodies.

During "hyperacute rejection" of rabbit heart perfused with transplantation alloantibodies, platelet activating factor (PAF) was released into the coronary effluent, which appeared to have physicochemical and functional properties similar to the 1-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (synthetic PAF) and to PAF obtained from IgE-sensitized rabbit basophils. The release of PAF was associated with an early tachycardia, followed by increasing bradycardia and conduction arrhythmias, as well as decrease of coronary flow and of amplitude of electrogram. The heart stopped beating within 30 min. The release of PAF as well as the "rejection" required the presence of fresh rabbit serum as a source of complement. The PAF receptor antagonist SRI 63-072 in a dose of 0.6 mg, reversed by 70% the reduction of coronary flow within 2-4 min after its addition to the perfusate; ED50 was 0.4 mg. Bradycardia and arrhythmia were reduced; however, the normal electrical activity was only occasionally restored. The cessation of heart action was delayed up to 50 min after the beginning of perfusion with transplantation alloantibodies and complement, but it was not prevented. These results suggest that PAF is released during "rejection" of the heart perfused in vitro with serum containing transplantation alloantibodies in the absence of inflammatory cells and that this mediator is at least in part responsible for the deterioration of cardiac function.

Animals↗
PubMed1987

Platelet-activating factor antagonists.

Over the past decade platelet-activating factor has achieved the status of an important inflammatory mediator. The scientific enthusiasm and number of research investigators, publications, and meetings recently devoted to PAF suggest that this mediator will be the subject of continued study in the foreseeable future. The potential for the presence and involvement of PAF in human disease is easily concluded from the reports described in this review. Both the need for low concentrations for cellular response and the rapid biological clearance mechanisms have made the proof of the involvement of PAF in human disease difficult. The discovery of PAF receptor antagonists and structure-activity relationships of such antagonists (159) will make this determination possible in the near future. The current PAF antagonists may be considered as first generation agents, since the most potent antagonist is still less than 1/100th as potent as PAF is as an agonist. The wide diversity of clinical applications from asthma to septic shock may also require antagonists with selective attributes such as delivery route (oral vs intravenous vs topical) or biological half-life (prolonged vs short). PAF may prove to be the key mediator of several poorly understood disease syndromes such as hyperacute organ transplant rejection, ischemic bowel necrosis (160), and adult respiratory distress syndrome. We must wait for clinical results to draw further conclusions.

Animals↗
PubMed1987

Evaluation of the effect of a platelet activating factor antagonist on platelet activating factor and Ascaris antigen-induced airway responses in rhesus monkeys.

An acute airway response to aerosolized platelet activating factor (PAF) can be induced in certain rhesus monkeys. This PAF airway response is completely inhibited by the PAF antagonist, SRI 63-441, in normal monkeys. After the completion of these studies showing inhibition of the PAF airway response, we evaluated whether the PAF antagonist could inhibit three types of acute IgE-mediated airway responses to Ascaris suum (A) in rhesus monkeys. The A aerosol test protocols used the following: a single A aerosol challenge system; a threshold dose of A challenge system, which consists of increasing A aerosol exposure until an airway response occurs; and two sequential A challenges in which the response to the second A challenge always occurs if there is a response to the first A challenge. When SRI 63-441 was tested as a potential antagonist of the A airway response in any of these three systems, no inhibition was shown.

Aerosols↗
PubMed1986

Inhibition of PAF-induced systemic responses in the rat, guinea pig, dog and primate by the receptor antagonist SRI 63-441.

Systemic administration of synthetic PAF produces a number of dose-dependent circulatory effects in a variety of species. We have evaluated a novel PAF antagonist, SRI 63-441, for its ability to inhibit PAF-induced effects in the rat, guinea pig, dog and primate. In the rat, a 100 ng kg-1 i.v. PAF challenge produced a (mean +/- 1 S.D.) 39 +/- 5% decrease in carotid blood pressure. Prior injection of SRI 63-441 inhibited this hypotensive response in a dose-dependent manner, with an ED50 of 0.15 mg kg-1 i.v. In the guinea pig, PAF at 100 ng kg-1 elicited a 50 +/- 8% increase in hematocrit and a 50 +/- 11% elevation in bronchial resistance. The ED50 values for inhibition by SRI 63-441 of these two physiological parameters were 0.012 mg kg-1 and 0.035 mg kg-1 i.a., respectively. Dogs challenged with 1.5 micrograms kg-1 PAF i.v. exhibited 28.7 +/- 6.5% increase in hematocrit 10 min after injection. The ED50 value for SRI 63-441 inhibition of hemoconcentration in the dog was 0.18 mg kg-1 i.v. In the primate model of PAF-induced hemoconcentration, controls responded to 3.5 micrograms kg-1 i.v. PAF with a 30 +/- 6% increase in hematocrit. Using the primates in a cross-over design, the ED50 of SRI 63-441 was 0.11 mg kg-1 i.v. At this ED50 value, the ratio of nmol kg-1 PAF used versus nmol kg-1 antagonist is approximately 1:25. The effectiveness of SRI 63-441 in these models suggest potential clinical applications in disease states involving hyperpermeability and pulmonary dysfunction.

Animals↗
PubMed1986

Vascular responses of platelet-activating factor in the Cebus apella primate and inhibitory profiles of antagonists SRI 63-072 and SRI 63-119.

We have evaluated several effects of intravenous administration of synthetic platelet-activating factor (PAF) in the non-human primate Cebus apella. Parameters measured were hemoconcentration (monitored by changes in hematocrit), thrombocytopenia (platelet counts), leukopenia (loss of buffy coat), bronchoconstriction (increased airway resistance to fixed airway ventilation), thromboxane A2 production (radioimmunoassay to thromboxane B2) and in vitro aggregation responses of platelets in platelet-rich plasma. Cebus platelets were refractory to PAF-induced aggregation (up to 50 microM) and there was no evidence of thrombocytopenia, elevated thromboxane B2 levels, loss of buffy coat or bronchoconstriction following systemic PAF injection. Animals exhibited reproducible but varying sensitivities to PAF-induced hemoconcentration, where 3.5-30 micrograms/kg PAF (6.6-57 nmol/kg) was required to produce 28-32% increased hematocrit range for the colony. Hemoconcentration induced by PAF in baboons and rhesus occurred at similar doses, suggesting comparable sensitivity. Prior administration of PAF receptor antagonists SRI 63-072 or SRI 63-119 at 3 mg/kg inhibited cebus hemoconcentration responses to 3.5 micrograms/kg PAF by 96% and 100%, respectively. The ED50 values were 0.95 and 0.60 mg/kg, respectively. These results suggest that the cebus exhibits a reproducible hemoconcentration effect to PAF and that these vascular responses can be inhibited by a PAF receptor antagonist.

Animals↗
PubMed1986

Inhibition and reversal of endotoxin-, aggregated IgG- and paf-induced hypotension in the rat by SRI 63-072, a paf receptor antagonist.

Platelet activating factor (paf) given intravenously produces systemic hypotension in the rat. Similar effects can be induced using endotoxin or heat-aggregated IgG challenges, which are thought to involve endogenous paf release. Extending this concept, we have examined the ability of the paf antagonist SRI 63-072 to inhibit or reverse systemic hypotension induced with paf, heat-aggregated IgG or endotoxin 0111-B4 in rats. At 100 ng kg-1 paf, there occurred a 38.6 +/- 5.1% decrease in carotid mean arterial pressure (MAP) followed by a 3.2 +/- 0.7 min recovery period (RP) to return to normal pressure values. The ED50 of SRI 63-072 was 0.16 mg kg-1 i.v. (MAP) and 0.25 mg kg-1 (RP) when given 1-5 min before the paf challenge. Endotoxin (15 mg kg-1 i.v.) produced a hypotensive response (54 +/- 8% decrease in MAP) and a corresponding 80% decrease in mesenteric artery blood flow. When given 2-8 min after endotoxin, 1.0 mg kg-1 i.v. SRI 63-072 totally restored blood pressure and artery blood flow. SRI 63-072 similarly reversed heat-aggregated IgG (10 mg kg-1) induced reduction of MAP, with an ED50 of 0.05 mg kg-1 i.v. The observations that SRI 63-072 can inhibit or reverse systemic vascular effects produced from paf and other provocators of endogenous paf release strongly implicates paf as a common final mediator of hypotension and shock. As SRI 63-072 is a competitive receptor antagonist, the hypotensive effects of these provocators appear to be mediated by vascular receptors for paf.

Animals↗
PubMed1986

Evidence for distinct systemic extravasation effects of platelet activating factor, leukotrienes B4, C4, D4 and histamine in the guinea pig.

The relative potencies of platelet-activating factor (PAF), leukotrienes B4 (LTB4), C4 (LTC4), D4 (LTD4) and histamine to induce hemoconcentration (HC) were evaluated in the guinea pig. The maximal hematocrit increase (MHI) from PAF, LTD4 and histamine occurred 5-7 min after i.v. injection, whereas the MHI of LTC4 occurred 13-15 min after injection. LTB4 (2.97-5.95 nmol kg-1) did not produce HC. The magnitude of PAF-induced MHI was 2-fold that of LTC4 or LTD4, regardless of the dose of leukotrienes used. The doses (nmol kg-1) needed to produce 30% HC were: 0.14-PAF, 0.71-LTD4 and 3.37-LTC4 and 2,400 histamine. The HC effects of LTD4 were markedly reduced by prior administration of FPL-55712. However, neither LTC4 or LTD4 HC effects were significantly reduced by prior i.v. injection of CV-3988 (3.4 mg kg-1), a competitive receptor antagonist to PAF which is 98% effective in abolishing HC response to 0.14 nmol kg-1 PAF. Diphenhydramine abolished histamine-induced hemoconcentration but was without effect on PAF or LTD4. These results suggest that the responses of PAF, leukotrienes and histamine differ in their potency and may involve separate vascular recognition sites related to acute increases in vascular permeability.

Animals↗
PubMed1986

Suppression of rat carotid lesion development by the calcium channel blocker PN 200-110.

Balloon catheter damage of the rat carotid artery endothelium results in an extensive and reproducible neointimal lesion composed of smooth muscle cells and connective matrix. The authors have examined two calcium channel blockers, PN 200-110 and PY 108-068, for their ability to inhibit neointimal lesion development in the rat carotid model. When given subcutaneously (1.0 mg/kg day) both compounds produced rapidly acting and long-lasting hypotension, reducing blood pressure 25-29%. At this dose given daily, PN 200-110 reduced lesion cross-sectional area by 44%, compared with only 25% seen by PY 108-068, which suggests that the antiatherosclerotic effect may not be related to lowering of blood pressure. Furthermore, PN 200-110 did not reduce the extent of platelet deposition (compared with controls) occurring at the denuded vessel surface 1 hour or 24 hours after balloon catheterization, which indicates that the inhibition of lesion development may not reflect an antiplatelet mechanism. The observed inhibition by PN 200-110 may relate to mitogen responses of the smooth muscle cell in the vessel wall (migration and proliferation) involved in lesion progression after endothelial damage.

Angioplasty, Balloon↗
PubMed1985

Evidence for a direct effect on vascular permeability of platelet-activating factor induced hemoconcentration in the guinea pig.

The ability of synthetic platelet-activating factor (PAF) given intravenously to produce loss (extravasation) of protein rich plasma (resulting in hemoconcentration) has been examined using guinea pigs. Hemoconcentration induced by PAF was not prevented by prior administration of inhibitors of thromboxane synthetase (7-(3-pyridyl)heptanoic acid, UK-37,248-01), PGI2, aspirin, indomethacin or antiserum induced thrombocytopenia. Calcium channel blockers (nifedipine, verapamil, diethylamino octyltrimethoxybenzoate, diltiazem), antihistamines (pyrilamine, cimetidine, diphenhydramine), or the elevator of cAMP IBMX were ineffective in blocking PAF-induced hemoconcentration. In contrast, CV-3988, reported to be a specific antagonist to PAF, was 98% inhibitory of PAF extravasation when given i.a. at 3.5 mg/kg. The ED50 was 0.14 mg/kg I.A. and 15 mg/kg p.o. against 75 ng/kg PAF. These data suggest that PAF-induced hemoconcentration involves receptor mediated alterations of vascular permeability that are inhibited by a specific PAF antagonist.

Animals↗
PubMed1984

Evaluation of dose and route effects of platelet activating factor-induced extravasation in the guinea pig.

Platelet-activating factor (PAF) is a naturally occurring lipid that is reported to induce vessel hyperpermeability leading to loss of protein-rich plasma (extravasation). We have quantitated the systemic extravasation effects of synthetic PAF in the guinea pig by monitoring increases in hematocrit. When given intravenously (10-170 ng/kg), PAF produced dose-dependent increases in hematocrit, with maximal hemoconcentration developing in 5-7 min. In leukopenic animals the expected hematocrit increase was reduced by 57%. PAF given intra-arterially produced the dose-dependent changes in hematocrit similar to the intravenous effects of PAF. However, PAF given intraperitoneally (10-2500 micrograms/kg) was 800-1100-fold less effective than the other routes and hemoconcentration continued for 30-45 min until a maximal hematocrit was observed. These results show that PAF may markedly influence extravasation of plasma in a dose and route-dependent manner.

Animals↗
PubMed1984

Effect of platelet activating factor on endothelial permeability to plasma macromolecules.

We have examined the effect of intrajugular administration of platelet activating factor (PAF-C16) on vascular permeability in the guinea pig. To examine the loss of selective endothelial permeability, the extravasative effect of PAF was assessed by monitoring hemoconcentration and the plasma loss of 125I-albumin (6.7 nm), 125I-low density lipoproteins (22.0 nm) or 125I-very low density lipoproteins (62.1 nm). Extravasation was dose-dependent and began 1 min after PAF administration, continuing for 5-7 min. During extravasation, there was no evidence for selective plasma retention of any of the labeled plasma tracers, as measured by plasma radioactivity. These results suggest that PAF-induced extravasation is dose-dependent, with increases in vascular permeability sufficient to permit similar plasma efflux rates of albumin, low density lipoproteins and very low density lipoproteins.

Animals↗
PubMed1983

Suppression of fibroblast proliferation in vitro and of myointimal hyperplasia in vivo by the triazolopyrimidine, Trapidil.

Platelet derived growth factor (PDGF) is a mitogen capable of stimulating the proliferation of both vascular smooth muscle cells (SMC) and fibroblasts in tissue culture. Recently, it was reported that this in vitro stimulatory effect is significantly reduced by Trapidil, a triazolopyrimidine. We confirm this, and also that similar inhibition occurs in vivo, in balloon catheter deendothelialized aorta of male, Sprague-Dawley rats treated with Trapidil. Two groups of rats, of 8 animals each, were treated daily with oral doses of either 45 mg or 90 mg Trapidil. A third group of 9 control animals were treated identically, but received only the diluent used to dissolve the drug. ADP or collagen-induced platelet aggregation, and endothelial cell regrowth were unaffected by Trapidil administration, but the degree of myointimal hyperplasia was significantly reduced in all animals receiving the drug. Thus, Trapidil seems to possess the selective ability to alter the SMC proliferative response which normally follows deendothelialization.

Animals↗
PubMed1980

Synthesis and biological activities of arachidonic and alpha- and beta-alkyl-substituted arachidonic acid derivatives.

In the male retired breeder rat, arachidonic acid 1a and 2,2-dimethylarachidonic acid 3a exhibited plasma platelet disaggregation as measured after 3 hr after the compounds were administered intragastrically at 15 and 13 mg/kg/rat mean effective dose (MED), respectively. The corresponding p-t-butylphenol ester of the acids showed a remarkable potentiation of platelet disaggregation. The MED for p-t-butylphenol ester of AA was 1.1 mg/kg/rat.

Alkylation↗
PubMed1979

In vivo effect of suloctidil as an antiplatelet agent.

The relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5-HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

Animals↗