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Biomedical subjects

R N Pinckard

Publications and source records attributed to R N Pinckard.

At least 55 records · Page 3Linked to original sources
PubMed1982

Vasoactive properties of acetyl glyceryl ether phosphorylcholine and analogues.

Intradermal injection of 0.1 pmole (52 pg.) of acetyl glyceryl ether phosphorylcholine (AGEPC) in guinea pigs induced increased vascular permeability as assessed by a skin-blueing model. Rabbits and rats showed increased vascular permeability with 1.0 pmole (520 pg.) of AGEPC. On a molar basis, from 1,000 to 10,000 times more histamine was required to induce skin blueing in the same animals. In rabbits and guinea pigs, the increased vascular permeability induced by AGEPC occurred as an early, transient phase and as a delayed, prolonged phase. The early, transient phase was not inhibited by chlorpheniramine doses which markedly reduced or abrogated histamine-induced blueing. AGEPC was 100 to 1000 times more potent than histamine on a molar basis for the induction of vasoconstriction in a blued skin assay in guinea pigs. These studies demonstrate that AGEPC has potent vasoactive properties and provide additional information that implicates this acetylated alkyl phosphoglyceride as a mediator of the acute inflammatory process.

Animals↗
PubMed1982

Induction of leukocytic infiltrates in rabbit skin by acetyl glyceryl ether phosphorylcholine.

Intracutaneous injection of 5 to 50 pmoles of acetyl glyceryl ether phosphorylcholine (AGEPC) induced neutrophil (PMN) infiltrates in rabbit skin. PMN margination and plugging were present in dermal venules within 15 minutes after AGEPC injection, and extravascular PMN were most abundant after 3 hours. There was a sharp decline in PMN numbers when sites were examined 6 hours after AGEPC injection. PMN emigration appeared to occur predominantly from venules in the deep portion of the cutaneous venous plexus, and PMN accumulation was greatest in the deep dermis. Few if any PMN were present in lyso-glyceryl ether phosphorylcholine and human serum albumin sites at all time points studied. This demonstration that extravascularly introduced AGEPC induces PMN infiltrates in vivo provides evidence that this acetylated alkyl phosphoglyceride may be a significant mediator of acute allergic and inflammatory processes with a broader role than its previously described platelet-activating properties.

Animals↗
PubMed1981

Characterization of the binding of purified human C1q to heart mitochondrial membranes.

The binding of purified, radioiodinated human C1q to baboon heart mitochondrial membranes was investigated. The interaction of C1q with heart mitochondrial membranes was shown to be readily saturable, specific for C1q, and reversible upon addition of unlabeled C1q or increasing salt concentrations. Scatchard plots of the binding data were biphasic and yielded association constants on the order of 1 X 10(10) and 1 X 10(9) M-1 and binding capacities of approximately 0.16 and 0.24 nmol of C1q/mg of mitochondrial protein. The binding of C1q to isolated cardiac-derived mitochondrial membranes is implicated in the antibody-independent activation of the classical complement pathway by cellular membranes.

Animals↗
PubMed1981

Modification of the polar head group of acetyl glyceryl ether phosphorylcholine and subsequent effects upon platelet activation.

A series of phosphoglycerides containing the same structural unit, 1-O-alkyl-2-acetyl-sn-glycerol, was prepared with the following polar head groups: -3-phosphoric acid (AGEPA), -3-phosphorylethanol (AGEPEt), -3-phosphorylethanolamine (AGEPE), -3-phosphoryl-N-monomethylethanolamine (AGEPMME), -3-phosphoryl-N,N-dimethylethanolamine (AGEPDME), and -3-phosphorylcholine (AGEPC). These compounds were synthesized primarily by phospholipase D modification of AGEPC. The characterization of these derivatives was achieved through thin layer chromatography, infrared spectrometry, gas-liquid chromatography, and combined gas-liquid chromatograph-mass spectrometry. Their ability to induce irreversible aggregation and 50% secretion of serotonin from washed rabbit platelets was investigated. The latter secretory activity, expressed on a molar basis (60 s following platelet stimulation) was shown to be particularly sensitive to the nature of the polar head group as follows: AGEPA, 8.3 X 10(-7) M; AGEPE, 6.8 X 10(-7) M; AGEPEt, 4.0 x 10(-7) M; AGEPMME, 3.7 X 10(-9) M; AGEPDME, 4.5 X 10(-10) M; and AGEPC, 1.8 X 10(-10) M. It was concluded that the polar head group of the various acetyl glyceryl ether phosphoglycerides had an important role in expressing the biological activity of this unique type of phosphoglyceride towards platelets. It appears likely that the polar head group of the various acetyl glyceryl ether phosphoglycerides had an important role in expressing the biological activity of this unique type of phosphoglyceride towards platelets. It appears likely that the recognition site (receptor site) on platelets is more reactive to the dimethylethanolamine or teh quaternary ammonium base, choline, than to any of the other polar head groups under consideration.

Animals↗
PubMed1981

Contraction of guinea pig ileal smooth muscle by acetyl glyceryl ether phosphorylcholine.

Acetyl glyceryl ether phosphorylcholine (AGEPC) is a chemical that has the biological activity of what was formerly termed platelet-activating factor. We report here that synthetic AGEPC induces the contraction of guinea pig ileal smooth muscle. Antagonists of histamine, acetylcholine, and slow-reacting substances (SRS) do not block AGEPC-induced contraction. These responses were long lasting, resistant to washing, and displayed complete agonist specific desensitization. Histamine- and SRS-induced contractions were unaffected by AGEPC. These studies show that AGEPC has the potential to produce a component of anaphylactically induced smooth muscle contraction.

Animals↗
PubMed1981

Differential effects of platelet depletion on the physiologic alterations of IgE anaphylaxis and acetyl glyceryl ether phosphorylcholine infusion in the rabbit.

Intravenously administered acetyl glyceryl ether phosphorylcholine (AGEPC) induced all of the respiratory and circulatory alterations observed during IgE anaphylaxis in the rabbit. Prior platelet depletion, however, had differential effects on these two physiologic responses. The AGEPC-induced increase in total pulmonary resistance and decrease in dynamic compliance were abrogated by prior platelet depletion, whereas these lung mechanical changes occurring as part of an IgE anaphylactic response after intravenous antigen challenge were unaffected by platelet depletion. The apneic episode observed in both the AGEPC and antigen-induced response was unaffected by platelet depletion, and the brief period of rapid shallow breathing of the AGEPC response was diminished to that characteristically seen in the anaphylactic response of both platelet-intact and platelet-depleted rabbits. Prior platelet depletion had little effect on right ventricular hypertension, bradycardia, and systemic hypotension of either the AGEPC or the anaphylactic responses. Thus, AGEPC induced lung mechanical alterations via platelet-dependent mechanisms and ventilatory and circulatory alterations by mechanisms largely independent of circulating platelets. These findings were consistent with the possibility that AGEPC released into the blood stream during IgE anaphylaxis may mediate the circulatory and ventilatory alterations but not the lung mechanical alterations of the anaphylactic response.

Anaphylaxis↗
PubMed1981

Human platelet stimulation by acetyl glyceryl ether phosphorylcholine.

Acetyl glyceryl ether phosphorylcholine (AGEPC) induced dose-dependent platelet aggregation and release of [3H]serotonin and platelet factor 4 in citrated human platelet-rich plasma. ADP scavengers or indomethacin prevented irreversible platelet aggregation responses induced by 0.2 microM AGEPC but had no effect upon platelet secretion; prostacyclin inhibited AGEPC-induced aggregation and secretion. EDTA or EGTA inhibited AGEPC-induced aggregation but had no effect on platelet secretion.

Blood Coagulation Factors↗
PubMed1981

Activation of human neutrophils with 1-O-hexadecyl/octadecyl-2-acetyl-sn-glycerol-3-phosphorylcholine (platelet activating factor).

1-O-Hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC), the acetylated alkyl phosphoglyceride known as platelet-activating factor, stimulated human neutrophil (PMN) exocytosis, migration, superoxide production and aggregation over a concentration range of 10(-10) to 10(-5) M. AGEPC-induced PMN exocytosis of azurophilic (myeloperoxidase and beta-glucuronidase) and specific (lactoferrin and lysozyme) lysosomal granules was rapid (T 1/2 = 20 sec), dependent on the presence of cytochalasin B, but was not associated with release of cytoplasmic LDH. As seen with the complement-derived peptide stimulus, C5a, AGEPC-initiated PMN enzyme release was dependent on temperature and cellular glycolysis but not on the presence of extracellular Ca++. When analyzed by gradient analysis, PMN migration caused by AGEPC was primarily chemotactic in nature. An unusual feature for both enzyme secretion and migration was a decrease in response between 10(-6) M and 10(-5) M AGEPC. This decreased responsiveness could be explained by rapid PMN desensitization occurring at high AGEPC concentrations, limiting the overall cellular response. Rapid desensitization for exocytosis was demonstrated in PMN stimulated with AGEPC in the absence of cytochalasin B. When cytochalasin B was added subsequently and PMN challenged with AGEPC or C5a, stimulus-specific desensitization to AGEPC but not C5a-induced lysosomal enzyme release occurred. PMN desensitized to C5a responded normally to a subsequent AGEPC challenge. Stimulation of all the PMN functions examined was markedly attenuated with removal of the 2-acetyl group from AGEPC (lyso GEPC). These results suggest that AGEPC stimulates a wide variety of human PMN responses by a receptor-like mechanism, dependent on the short chain fatty acid ester in the 2-position of the alkyl phosphoglyceride.

Animals↗
PubMed1981

Acetyl glyceryl ether phosphorylcholine. Intravascular alterations following intravenous infusion into the baboon.

The intravenous infusion of 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC) in baboons (28 micrograms per kg.) induced acute, but reversible, thrombocytopenia and neutropenia and the intravascular release of platelet factor 4 and thromboxane B2. Maximal depression of circulating platelets and neutrophils occurred within 30 seconds after AGEPC infusion and was accompanied by significant elevations in plasma platelet factor 4 and thromboxane B2 levels (p less than 0.02). Hematocrit values increased after AGEPC infusion, but this increase was delayed relative to the other intravascular alterations, i.e., maximal hematocrit values occurred at 10 to 20 minutes after AGEPC infusion.. The thrombocytopenia induced by AGEPC was reversed within 2 to 3 minutes; in contrast, circulating neutrophils did not return to preinfusion levels until 30 minutes after AGEPC infusion. Plasma platelet factor 4 and thromboxane B2 elevations gradually decreased and returned to preinfusion levels within 30 to 60 minutes. The deacetylated derivative of AGEPC, lyso-glyceryl ether phosphorylcholine, had no effect when similarly infused into baboons. These studies demonstrate that the intravenous administration of AGEPC into baboons initiated significant but reversible intravascular alterations; thus, this unusual acetylated alkyl phosphoglyceride may be an important mediator of inflammation in primates, including man.

Animals↗
PubMed1980

Identification of platelet activating factor isolated from rabbit basophils as acetyl glyceryl ether phosphorylcholine.

Platelet activating factor obtained from antigen-stimulated rabbit buffy coat leukocytes containing 10% IgE-sensitized basophils was shown by gas-liquid chromatographic and mass spectrometric analysis of products after acetolysis and by base and acid hydrolysis to be acetyl-alkylglyceryl phosphorylcholine. The alkyl side chains were composed of octadecyl (greater than 90%) and hexadecyl (less than 10%) residues.

Animals↗
PubMed1980

Physical and chemical properties of platelet-activating factor obtained from human neutrophils and monocytes and rabbit neutrophils and basophils.

Platelet-activating factor secreted by stimulated human neutrophils and monocytes and rabbit neutrophils and basophils was isolated, purified and chemically and physically characterized. All four preparations had identical thin layer chromatographic behavior in a variety of solvent systems, identical solubility behavior in various organic and aqueous solvents and responded comparably to a variety of chemical and physical agents designed to reveal the presence functional groups. These findings indicate that human neutrophil and monocyte, and rabbit neutrophil and basophil derived platelet-activating factor preparations are indistinguishable, and support the conclusion that platelet-activating factor is a neutral, polar lipid molecule whose functional activity is dependent upon the presence of a carboxylic acid ester.

Animals↗
PubMed1980

Respiratory and circulatory alterations induced by acetyl glyceryl ether phosphorylcholine, a mediator of IgE anaphylaxis in the rabbit.

We examined the physiologic alterations induced in the rabbit by an acetyl glyceryl ether phosphorylcholine (AGEPC), a synthetic compound identical to rabbit basophil-derived platelet-activating factor. Intravenous administration of AGEPC led to a brief period of rapid, shallow breathing, a transient apnea, a decrease in dynamic compliance, and an increase in total pulmonary resistance. Circulatory alterations included brief bradycardia, increase in right ventricular pressure, and systemic hypotension. At a dose of 0.6 microgram/kg, AGEPC produced physiologic alterations both qualitatively and quantitatively indistinguishable from those which characterize IgE anaphylaxis in the rabbit. Mortality was also similar. After recovery to prechallenge baseline values, subsequent doses of AGEPC resulted in attenuated responses with respect to many of the physiologic alterations. Thrombocytopenia, leukopenia, and platelet secretion (as assessed by release of platelet factor 4 into the plasma) were also part of the response to AGEPC, further extending the similarity of this response to IgE anaphylaxis. Because AGEPC has been shown previously to be released into the circulation during IgE anaphylaxis, our results provide strong evidence that AGEPC is an important mediator of this acute allergic reaction in the rabbit.

Anaphylaxis↗
PubMed1980

Complement localization and mediation of ischemic injury in baboon myocardium.

We sought to determine whether the third component of complement (C3) is localized in ischemic baboon myocardium after coronary artery ligation. Furthermore, we assessed the effects of prior C3 depletion on myocardial necrosis. We studied seven control baboons (group I) and seven C3-depleted (group II) baboons that were killed 24 h after ligation of the anterior descending coronary artery. Multiple tissue samples were obtained from infarct, intermediate, and normal myocardial sites as defined by serial unipolar epicardial ECG mapping. In group I baboons, myocardial creatine kinase content from infarct sites was reduced as compared with normal sites (12.6+/-0.92 [SE] vs. 24.4+/-0.75 IU/mg protein, P < 0.001). The intermediate sites from group I contained more creatine kinase (19.0+/-1.25 IU/mg protein) than infarct sites (P < 0.001), but less (P < 0.025) than normal sites. In group II, intermediate sites showed no significant reduction in creatine kinase from normal sites and there was significantly less creatine kinase depletion in infarct sites when compared with group I animals (33.7+/-4.6 and 51.4+/-1.8% depletion, respectively, P < 0.001). In all seven group I baboons, uniform C3 localization was observed in infarct sites by direct immunofluorescence but appeared in mosaic patterns in intermediate sites. C3 was not demonstrated in any normal sites, nor in any site from group II baboons. Additional studies on baboons killed at earlier times after ligation indicated that C3 was localized focally on swollen myocytes in infarct sites as early as 4 h after coronary ligation. These results strongly implicate the active participation of the complement system of inflammatory proteins in the pathogenesis of myocardial tissue injury following coronary occlusion.

Animals↗