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Biomedical subjects

J L Gordon

Publications and source records attributed to J L Gordon.

At least 19 recordsLinked to original sources
PubMed1990

The effects of radiographic contrast media on myocardial contractility and coronary resistance: osmolality, ionic concentration, and viscosity.

With the ongoing development of new contrast agents, questions develop concerning the cardiac effects of these drugs. We used the perfused rat heart model to investigate the effects on cardiac and coronary function of hypertonic ionic (sodium chloride) and nonionic (glucose) solutions and conventional and low osmolality radiographic contrast media (RCM). We also evaluated the concurrent effects of RCM on prostacyclin and adenine nucleotide/nucleoside release. Hypertonic solutions of glucose had little effect on myocardial contraction (increase up to 7.7 +/- 0.9%), while NaCl solutions of similar osmolality were negatively inotropic (contractile force decreased up to 76.1 +/- 9.2%). Conventional RCM were negatively inotropic (decrease of 59.6 +/- 5.6% with Conray (Mallinckrodt Pharmaceuticals, St. Louis, MO), 32.2 +/- 3.2% with Angiovist 282 (Berlex Laboratories, Cedar Knolls, NJ]; two nonionic RCM, Iopamidol and Iotrol had little effect on myocardial contraction (reduction of 6.9 +/- 1.4% and increase of 12.0 +/- 2.9%, respectively). Hypertonic solutions of glucose and NaCl reduced coronary resistance in direct relationship to hyperosmolality. Conventional RCM also reduced coronary resistance, while the nonionic media caused minor alteration. None of the solutions tested altered prostacyclin or adenine nucleotide/nucleoside efflux from the heart. A solution of Ficoll 70 with a viscosity similar to that of RCM increased myocardial contraction by 9.6 +/- 3.6% and had no effect on coronary resistance, indicating that viscosity per se did not contribute to the negative inotropic effects or the reduction in coronary resistance. Hypertonic solutions, including conventional RCM, reduce coronary resistance as a result of their hyperosmolality Negative inotropic effects, however, are more related to high ionic concentration than to osmolality.

Adenine Nucleotides↗
PubMed1989

Lysosomal hydrolases of human vascular cells: response to agonists of endothelial function.

Endothelial injury has been proposed as a feature of a wide variety of vascular diseases, and release of endothelial lysosomal hydrolases could contribute to the pathological changes seen. We have determined the relative activities of 14 glycosidases, two esterases and four peptide hydrolases in human umbilical vein endothelial cells and investigated whether known agonists of endothelial function, or materials known to modulate hydrolase secretion in other phagocytic cells, influenced the activity or secretion of these enzymes by human umbilical vein endothelial cells. Hexosaminidase, beta-galactosidase, beta-glucuronidase and alpha-iduronidase accounted for most of the measured glycosidase activity. Acid phosphatase activity greatly exceeded arylsulphatase activity, and most of the measured peptidase activity was due to acid peptidases. Optimum pH and apparent Km values were determined for the most abundant hydrolases. Exposure of human umbilical vein endothelial cells to bradykinin, thrombin or interleukin-1 resulted in negligible release of either hexosaminidase or lactate dehydrogenase (LDH), in contrast to phorbol myristate acetate, which caused a parallel, dose-dependent release of both enzymes. Treatment of these cells with calcium ionophore A23187, trypsin or platelet-activating factor, caused less than 10% release of either hexosaminidase or LDH. Agents known to modulate lysosomal enzyme secretion by other phagocytic cells failed to induce selective secretion of lysosomal enzymes by human umbilical vein endothelial cells.

Bradykinin↗
PubMed1989

Kinetics of adenine nucleotide catabolism in coronary circulation of rats.

We have used the rat isolated, perfused heart to study the metabolism of adenine nucleotides on a single passage through the coronary circulation. Low doses (3-30 nmol) of ATP, ADP, or AMP injected as a bolus were extensively catabolized by ectoenzymes. Increasing doses of each nucleotide demonstrated saturability of catabolism that occurred at significantly lower doses of AMP than of ADP or ATP. The patterns of catabolites formed in each case were consistent with the major pathway of metabolism being sequential dephosphorylation of ATP----ADP----AMP----adenosine, although from experiments in which [3H]ATP was co-injected with unlabeled ADP, it appears that some direct conversion of ATP----AMP can occur. Furthermore, particularly in the presence of excess unlabeled ATP, [3H]ADP was phosphorylated to [3H]ATP, indicating that ectoenzymes capable of interconverting nucleotides are present. By evaluating recovery and metabolism in serial samples collected rapidly after bolus injection, we were able to use the integrated form of the Michaelis-Menten equation as developed by Bronikowski et al. (Math. Biosci. 61: 237-266, 1982) to derive Michaelis constant (Km) and maximum velocity times capillary plasma volume (Amax) values for adenosinetriphosphatase, adenosine diphosphatase, and 5'-nucleotidase (450, 300, and 93 microM; and 5.3, 5.9, and 1.7 mumol/min, respectively). This analysis also indicated that there is a high degree of heterogeneity of path lengths within the coronary circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1989

Reflections and remembrances.

Two brief and very personal essays written by practicing nurses in the Rhode Island community. These commentaries reflect their remembrances of the human dimensions of dying and the role of hospice in easing the accompanying burdens of anguish and grief.

Family↗
PubMed1988

Desensitization of agonist-stimulated prostacyclin release in human umbilical vein endothelial cells.

Prostacyclin (PGI2) release was studied in perfused columns of human umbilical vein endothelial cells cultured on microcarrier beads. Substantial homologous desensitization of PGI2 release occurred when cells were exposed to agonist for 2 min after a previous exposure; the extent depended on the concentration and duration of the first challenge. Recovery from exposure to ATP or bradykinin was complete in less than 80 min; recovery from thrombin was incomplete after greater than 80 min, and this was apparently related to its proteolytic activity. Experiments with ibuprofen, a reversible inhibitor of cyclo-oxygenase, demonstrated that homologous desensitization did not involve inactivation of cyclo-oxygenase. ATP and bradykinin did not induce heterologous desensitization. Thrombin and trypsin induced cross-desensitization, but neither agonist significantly reduced responses to ATP or bradykinin, suggesting that a common proteolytic mechanism is responsible for their ability to induce PGI2 synthesis. We conclude that desensitization of PGI2 release in response to physiological agonists is generally agonist-specific and involves modulation of molecular events at or close to the receptors involved, rather than inactivation of prostanoid biosynthesis.

Adenosine Triphosphate↗
PubMed1988

ADP plays a key role in thrombogenesis in rats.

The relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR 4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1988

Endothelial functional responses and increased vascular permeability induced by polycations.

Polycations such as poly-L-lysine powerfully stimulated cultured endothelial cells from pig aorta to release prostacyclin and cytoplasmic purines in a dose (charge)-dependent and molecular weight (size) dependent manner. Neutral or anionic polymers were inactive. Qualitatively similar findings were made in vivo where poly-L-lysine induced charge and size-dependent local edema formation after intradermal injection in the rabbit. Pretreatment of cultured endothelium with heparin or trypsin (but not neuraminidase) effectively reduced the response of the cells to subsequent exposure to poly-L-lysine suggesting an interaction of polycations with integral membrane proteins. Edema responses to poly-L-lysine were reduced in the presence of indomethacin suggesting that generation of an endogenous vasodilator prostaglandin, perhaps endothelial cell-derived, was an important component of the response. Poly-L-lysine-induced edema formation was not dependent on endogenous histamine release but was reduced by locally administered trasylol while soybean trypsin inhibitor failed to inhibit the response. Our results indicate that polycations such as poly-L-lysine can induce responses of vascular endothelium in vitro and in vivo and that the effects are not only charge-related but are also dependent on the size of the polycation. We suggest that naturally occurring polycations such as those derived from leukocytes and platelets may play an important role in various pathologic processes and that this may be closely related to their size.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

Inhibition of vascular smooth muscle cell proliferation in culture by pentosan polysulphate and related compounds.

Pentosan polysulphate (PPS; SP 54; Hemoclar), a highly sulphated semi-synthetic polysaccharide of MW 4.7 kD, was tested in vitro as an inhibitor of rabbit aortic smooth muscle cell (SMC) proliferation and its effects were compared with those of dextran sulphate, laminarin sulphate and heparin fractions. When added to the cell cultures simultaneously with foetal calf serum, all sulphated polysaccharides inhibited cell growth. PPS was five fold more active than heparin and its low molecular weight fractions. A high molecular weight fraction of PPS was the most active inhibitor (IC50: 2.7 micrograms/ml vs 45 micrograms/ml for PPS, and 241 micrograms/ml for heparin). When PPS and heparin were pre-incubated with the cells for three days, then removed before foetal calf serum was added to stimulate growth, their inhibitory effects were comparable with those seen when the compounds were present throughout the growth phase, suggesting that they exert their effect by binding to the cell surface, and not by interacting with the growth factors in serum.

Animals↗
PubMed1985

Specificity of P2-purinoceptor that mediates endothelium-dependent relaxation of the pig aorta.

ATP (EC50 5 microM) induced endothelium-dependent relaxation of the isolated aorta of the newborn pig, but the other naturally occurring nucleotides CTP, GTP, ITP and UTP were more than 100 times less potent. 2-Methylthio-ATP (EC50 0.1 microM) was 50 times more potent than ATP, but the unnatural enantiomers L-ATP and 2-methylthio-L-ATP were virtually inactive. beta,gamma-Imido-ATP and beta,gamma-methylene-ATP, both of which are resistant to degradation by ectonucleotidases on cultured pig endothelial cells, were much less potent than ATP. ADP beta S, which is also resistant to degradation, was equipotent with ATP at low concentrations but achieved a maximal relaxation of only 50% that of ATP. The Rp and Sp diastereoisomers of ATP beta S were both equipotent with ATP at low concentrations and both achieved approximately 60% of the maximal relaxation of ATP. The Rp and Sp diastereoisomers of ADP alpha S were both less potent than ATP and achieved only approximately 25% of the maximal relaxation of ATP. These results demonstrate that the P2-purinoceptor mediating endothelium-dependent relaxation of the pig aorta exhibits a high degree of specificity for the adenine base, is stereospecific for the D-ribofuranosyl moiety, requires a phosphate chain of 2 or 3 units but is not stereoselective toward this phosphate chain. These structural requirements have some features in common with the P2-purinoceptors on smooth muscle and on platelets, and are quite different from those of the ectonucleotidases present on pig endothelial cells in culture.

Adenosine Triphosphate↗
PubMed1979

Vascular endothelial and smooth muscle cells in culture selectively release adenine nucleotides.

Endothelial cells in culture can modulate platelet aggregation and vascular tone, in part by producing prostacyclin (PGI2), a powerful vasodilator and inhibitor of platelet aggregation, but also by their ecto-ADPase activity, which initiates the conversion of pro-aggregating ADP to adenosine, a potent vasodilator and platelet inhibitor. We have now demonstrated that cultured aortic endothelial cells exposed to trypsin, thrombin or other stimuli can liberate a high proportion of their adenine nucleotides without substantial loss of lactate dehydrogenase. ADP rapidly accumulates extracellularly, reaching biologically active concentrations before there is further breakdown to adenosine. Whether this selective release of nucleotides is a response to damage, or whether it represents a specific secretory mechanism remains to be resolved. Cultured aortic smooth muscle cells can secrete adenine nucleotides in a similar manner, but extracellular conversion to adenosine occurs much faster.

Adenine Nucleotides↗