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Biomedical subjects

J B Smith

Publications and source records attributed to J B Smith.

At least 307 records · Page 17Linked to original sources
PubMed1984

Platelet-activating factor is a weak platelet agonist: evidence from normal human platelets and platelets with congenital secretion defects.

We have examined the effects of a novel platelet agonist, platelet activating factor (PAF), on human platelets. Irreversible aggregation and 14C-serotonin secretion in response to PAF (10(-5) M) was found to be dependent on both thromboxane production and secreted adenosine diphosphate (ADP). Liberation of arachidonic acid (AA) from membrane-bound phospholipids is a prerequisite step in platelet thromboxane production. Studies with 3H-AA-labeled platelets revealed that PAF (10(-5) M) was a weak stimulus for the mobilization of AA. In addition, PAF (10(-5) M) was found to be a weak inducer of thromboxane synthesis (mean = 6 pmol/10(8) platelets) as compared to thrombin 5 U/ml (mean = 177 pmol/10(8) platelets), measured using a radioimmunoassay for thromboxane B2. Formation of phosphatidic acid is an early step in stimulus-response coupling in platelets. Our studies indicate that PAF is a weak stimulus for phosphatidic acid formation as well. To obtain further insights into its action, we examined the effect of PAF on platelets from three groups of patients with congenital secretion defects: patients with the storage pool deficiency, those with impaired thromboxane synthesis due to impaired liberation of AA from phospholipids, and those with impaired secretion despite normal granule stores and thromboxane production. The response to PAF was impaired in all patients, providing further evidence that PAF-induced platelet activation is dependent on secreted ADP and thromboxane A2 synthesis, and occurs by mechanisms common to a number of agonists. Overall, these studies indicate that PAF is a weak platelet agonist.

Adenosine↗
PubMed1984

Genetic analysis of sodium-lithium countertransport in 10 hypertension-prone kindreds.

The rate of sodium-lithium countertransport (SLC flux) across red cell membranes has been reported to be elevated in hypertensive persons and their relatives as compared to normotensive individuals without family histories of hypertension. We have investigated the inheritance of this trait in 434 persons from 10 kindreds. Relatives show positive correlation of SLC flux values, but there is no spouse-spouse correlation. Pedigree analysis favors a model of polygenic inheritance over models of major-gene inheritance. Major-gene index statistics and offspring-between-parent statistics provide similar results. The proportion of total phenotypic variance that is attributable to polygenic differences between persons is estimated at 71%. The SLC flux values of hypertensive persons in this study population are lower than those reported from Boston, but are similar to those reported from Europe. We found a broad overlap of SLC flux values for hypertensive and normotensive persons. We conclude that SLC flux probably is not useful as a preclinical marker for essential hypertension.

Adolescent↗
PubMed1984

Aluminum ions stimulate DNA synthesis in quiescent cultures of Swiss 3T3 and 3T6 cells.

Micromolar concentrations of AI3+ are shown to be strongly mitogenic for quiescent cultures of Swiss 3T3 and 3T6 cells. AI3+ caused a striking shift in the dose-response curve for the effect of fetal bovine serum on 3H-thymidine incorporation. In the absence of serum the mitogenic effect of aluminum was greatly potentiated by insulin or cholera toxin, but not epidermal growth factor or 12-0-tetradecanoyl-phorbol-13-acetate. The stimulation of DNA synthesis was maximal by 15-20 microM AI3+ X AI3+ at 100 microM had no inhibitory effect on DNA synthesis. AI3+ had no significant effect on cellular cyclic adenosine monophosphate in the presence or absence of insulin or an inhibitor of cyclic nucleotide phosphodiesterases.

Aluminum↗
PubMed1984

Beta-adrenergic stimulation inhibits calcium efflux and alters the morphology of cultured arterial muscle cells.

Beta-adrenoreceptor stimulation with isoproterenol (IP) rapidly and reversibly rounded and arborized smooth muscle cells (SMC) cultured from rat aorta. The arborized SMC remained firmly attached to the substratum via a network of long, dendritelike processes. Arborization of the SMC correlated closely with increases in cellular cAMP produced by IP and a variety of other compounds. The intracellular calcium antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) also rounded and arborized the SMC. Antitubulin compounds potently blocked arborized by IP, dibutyryl cAMP, and TMB-8. The release of cell-bound 45Ca2+ was followed in the presence and absence of IP. IP strikingly increased the amount of 45Ca2+ that remained cell bound between 20 and 120 min. Propranolol and colchicine prevented IP from inhibiting the release of cell-bound 45Ca2+. These results suggest that the modulation of Ca2+ transport is involved in the arborization of cultured SMC by cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Angiotensin receptors and the control of Na+ and K+ transport in cultured aortic smooth muscle and brain microvessel cells.

We examined the effect of angiotensin on Na+ and K+ transport by cultures of aortic smooth muscle and brain microvessel cells. Angiotensin II (AII) and angiotensin III (AIII) stimulated net Na+ uptake, which was assayed in the presence of ouabain to block Na+ efflux via the Na+-K+ pump. The combination of saturating concentrations of AII and AIII produced no greater stimulation of net Na+ uptake than either angiotensin by itself. AII also stimulated ouabain-sensitive 86Rb+ uptake by cultured aortic smooth muscle and brain microvessel cells. AII was not as effective as monensin, a Na+ ionophore, in stimulating the Na+-K+ pump. In the presence of monensin, AII had no effect on ouabain-sensitive 86Rb+ uptake. These data are consistent with previous observations suggesting that AII stimulates the Na+-K+ pump by supplying it with more of its rate-limiting substrate, Na+. 125I-AII bound tightly to cultured aortic muscle cells. Approximately 5 nM unlabelled AII half-maximally inhibited 125I-AII binding. Incubation of intact cultures with 1.0 microM AII produced a time-dependent decrease in specific 125I-AII binding. This slow loss of AII binding was prevented by methylamine, a known inhibitor of receptor clustering and internalization. We conclude (1) that angiotensin increases the Na+ permeability of smooth muscle cells in culture, thereby stimulating the Na+-K+ pump; (2) that AII binds to a specific receptor on the cell surface; and (3) that the AII-receptor complex may be internalized by a methylamine-inhibited pathway.

Angiotensin II↗
PubMed1984

Potentiation of leukotriene formation in pulmonary and vascular tissue.

Leukotriene (LT) release from vascular and pulmonary tissue was assessed by a radioimmunoassay for peptide leukotrienes (i.e., LTC4, LTD4 and LTE4). The calcium ionophore A-23187 at 1-3 micrograms/ml and platelet activating factor (PAF) at 10 micrograms/ml produced marked formation of peptide leukotrienes in minced cat pulmonary tissue. This was also confirmed by bioassay of the incubates in isolated perfused cat coronary arteries. Rat pulmonary tissue was comparable to cat with regard to LT production, but guinea-pig lung produced about 30-50% less on a weight basis. In addition, aortic and coronary artery vessel walls produced significant amounts of LTs. The time course for maximal leukotriene production occurred at 45-60 min of incubation at 37 degrees C in both the radioimmunoassay and the bioassay. Cat coronary artery constricted markedly to LTC4 or LTD4 (30-40 mm Hg) and to the lung or blood vessel incubate. This constriction was virtually totally blocked by the leukotriene antagonist FPL-55712, but not by the thromboxane receptor antagonist, pinane thromboxane A2, the alpha-adrenergic receptor antagonist, phenoxybenzamine, or the angiotensin receptor antagonist, saralasin. Thus, pulmonary and vascular tissue produce leukotrienes that appear to exert coronary constrictor effects on specific leukotriene receptors. These results indicate that the ischemia of shock and anaphylaxis may be accentuated by the release of peptide leukotrienes.

Animals↗
PubMed1984

Initiation of DNA synthesis in quiescent Swiss 3T3 and 3T6 cells by lanthanum.

La3+ stimulated quiescent Swiss 3T3 and 3T6 cells to enter the DNA-synthesizing S phase of the cell cycle. La3+ and insulin interacted synergistically to increase DNA synthesis. A brief exposure of the cells to soluble LaCl3 optimally stimulated entry into S. La3+ was similar to A13+ in its mitogenic properties (J. Cell. Physiol. 118, 298, 1984), but La3+ was 10 times more potent than A13+.

Aluminum↗
PubMed1984

Thromboxane A2 in acute myocardial infarction.

We evaluated the presence of thromboxane B2, the stable metabolite of thromboxane A2, early in the course of acute myocardial infarction (AMI) in both animal and patient studies. In an open-chest model, the left anterior descending artery (LAD) was isolated and the great cardiac vein was cannulated in nine dogs. Following occlusion of the LAD, there was an increase in thromboxane B2 concentration from 0.77 +/- 0.0093 to 1.79 +/- 0.46 pmol/ml (p less than 0.05) and 1.96 +/- 0.48 pmol/ml (p less than 0.05) at 1 and 5 minutes, respectively, following coronary occlusion. At 30 and 60 minutes after occlusion there was no significant increase compared to the baseline. In 17 patients with AMI the mean thromboxane B2 concentration was 0.96 +/- 0.13 pmol/ml at 4.88 +/- 0.40 hours after the onset of chest pain. In 12 patients with sequential samples before and after restoration of patency of the occluded vessel, the initial concentration was 0.71 +/- 0.058 pmol/ml. At 5 minutes after restoration of patency thromboxane B2 concentration was 1.1 +/- 0.17 pmol/ml (p = 0.05). One hour later a return to baseline was noted (0.82 +/- 0.75 pmol/ml). Two patients with the highest thromboxane B2 concentrations (2.0 and 2.6 pmol/ml) were unable to have successful recanalization. We conclude that generation of thromboxane A2 occurs during the early stages of AMI and may be an important pathophysiologic phenomenon in AMI.

Animals↗
PubMed1984

Helper cells in the autologous mixed lymphocyte reaction (AMLR). IV. H-2 restriction and specificity of cytotoxic cells induced by AMLR helper factor.

Supernatants from Day 3 cultures of T cells stimulated with syngeneic non-T cells in the autologous mixed lymphocyte reaction (AMLR) contained a T-cell factor distinct from interleukin 2 (IL-2). The AMLR factor could mediate the cytotoxic response of T cells to hapten-modified nonstimulatory syngeneic cells. The activity of this helper factor was H-2 unrestricted. However, the cytotoxic cells which developed in the presence of this factor were H-2 restricted and hapten specific.

Animals↗
PubMed1984

Leukotriene production in isolated tissues of diabetic rats.

We examined the ability of heart, aorta and lung obtained from alloxan diabetic rats as well as control rats to produce peptide leukotrienes (LT). The isolated perfused heart preparation as well as incubated minced tissue preparations were studied. Upon infusion of the Ca++ ionophore A23187, hearts from diabetic rats produced significantly less peptide LT when compared to control hearts. Lung tissue from diabetic animals incubated with A23187 also produced less immunoreactive peptide leukotrienes (iLT) when compared to the control group. In both preparations, incubation with the lipoxygenase inhibitor propyl gallate significantly inhibited the production of iLT in both the diabetic and control group. The observed differences in production of leukotrienes may alter vascular reactivity and thus play a role in the cardiovascular complications observed in diabetes.

Animals↗
PubMed1984

Specificity of anti-leukotriene actions of nicardipine.

The calcium channel blocker, nicardipine (100 ng/ml) markedly antagonized the coronary vasoconstrictor effect of the peptide leukotrienes LTC4 and LTD4 on the isolated perfused cat coronary artery. However, nicardipine even at 300 ng/ml failed to antagonize the leukotriene induced contraction of either tracheal or pulmonary parenchymal strips from guinea pigs. However, at higher concentrations (i.e., 10 micrograms/ml), nicardipine inhibited the production of peptide leukotrienes from minced cat lung incubated in the presence of A23187. Thus, nicardipine exerts some selectivity in its anti-leukotriene actions.

Animals↗
PubMed1984

Angiotensin II rapidly increases phosphatidate-phosphoinositide synthesis and phosphoinositide hydrolysis and mobilizes intracellular calcium in cultured arterial muscle cells.

Smooth muscle cells were cultured from rat thoracic aorta and labeled to a stable specific activity with 45Ca2+, myo-[2-3H]inositol, or 32Pi. The efflux of 45Ca2+ was monitored over 10-sec intervals. Angiotensin II (AII) increased the amount of 45Ca2+ lost by 5-fold in the first 10-sec interval after the addition of AII and by 10-fold in the second 10-sec interval. AII-stimulated 45Ca2+ release was blocked by the angiotensin antagonist [1-sarcosine, 8-leucine]AII and by La3+. The removal of external Ca2+ had no effect on AII-stimulated 45Ca2+ release. Depolarization with high external K+ only slightly increased 45Ca2+ efflux and had no effect on AII-induced 45Ca2+ release. AII had no effect on the initial rate of 45Ca2+ influx. These results indicate that the rapid 45Ca2+ efflux evoked by AII is probably due to the release of 45Ca2+ sequestered intracellularly rather than to an increase in the Ca2+ permeability of the plasma membrane. AII provoked rapid increases in the levels of phosphatidic acid and phosphoinositides in the cells. These increases in phospholipids were associated with increases in phospholipase C-generated inositol phosphates (tri-, di-, and mono-). It appears that AII simultaneously increases phosphoinositide hydrolysis and synthesis in vascular smooth muscle, and both phospholipid effects may contribute to inositol triphosphate generation, which was sufficiently rapid to have a role in intracellular Ca2+ mobilization.

Angiotensin II↗
PubMed1984

Knee instability after fractures of the intercondylar eminence of the tibia.

Fifteen children with fracture of the intercondylar eminence of the tibia were reviewed. Three with type I or type II fractures had closed treatment. Twelve with type III fractures had open reduction and internal fixation. Follow-up examination included history and examination of the knee; nine had follow-up radiographs. The mean follow-up period was 7 years. Seven patients were free of symptoms; eight had varying degrees of pain, of which four had to avoid some athletic activities; and two described subluxation episodes. All had normal motion, four had atrophy, and all had some evidence of anterior cruciate ligament laxity. The anterior cruciate ligament probably stretches before its tibial attachment fractures. Even though the fracture heals in its normal position, mild degrees of anterior cruciate ligament laxity often will result.

Adolescent↗
PubMed1984

Pathophysiological mechanisms of sudden death induced by platelet activating factor.

Platelet activating factor (Paf) (15-40 micrograms-1) kills male rabbits within 3 to 5 min. Intravenous injection of Paf at a dose of 15 micrograms kg-1 is uniformly lethal, and the rabbits died within 4.5 +/- 0.4 min. The sudden death is characterized by cessation of respiration, a marked decrease in mean arterial blood pressure (M.A.B.P.), and 8 fold increases in plasma thromboxane B2 (TxB2) concentrations with only modest elevation in plasma 6 keto-prostaglandin F1 alpha (6-keto PGF1 alpha) concentrations. Pretreatment with the cyclo-oxygenase inhibitor, ibuprofen (6.25 mg kg-1), or with the thromboxane synthetase inhibitors dazoxiben (2.5 mg kg-1), CGS-13080, or OKY-046 1 mg kg-1) increased survival rates to 83-100%. Protected rabbits showed only modest changes in M.A.B.P. and no significant increase in plasma TxB2 concentrations. The protective drugs showed a dose-related action on M.A.B.P., plasma TxB2 concentration and mortality rate in Paf-induced sudden death. The mechanisms of the protection appeared to be prevention of platelet aggregation (leading to pulmonary thrombosis) and pulmonary and coronary vasoconstriction. However, Paf does not appear to exert direct vasoconstrictor effects in isolated coronary or pulmonary arteries. The effects of Paf in vivo appear to be mediated by TxA2 released by activated platelets in the absence of the protective effects of prostacyclin. Inhibition of thromboxane synthesis effectively prevents the Paf-induced sudden death.

Animals↗
PubMed1984

Effects of lipoxygenase inhibitors in arachidonate-induced sudden death.

Both BW 755c, a cyclo-oxygenase and lipoxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a selective lipoxygenase inhibitor, were tested for their protection against arachidonate-induced sudden death in rabbits. 100% survival was seen with BW 755c (1 mg kg-1), while NDGA showed 0 and 17% survival (2 mg kg-1 and 4 mg kg-1). BW 755c prevented 12-fold increase in plasma thromboxane B2 concentrations and the formation of pulmonary artery thrombi normally seen with arachidonate-induced sudden death, while NDGA showed no such protective effect. Radioimmunoassay of rabbit plasma for leukotrienes (LTC4, LTD4 and LTE4) indicated that they do not accumulate in blood in the model and BW 755c had no effect, suggesting that the deleterious effects seen are caused by cyclo-oxygenase pathway metabolites such as thromboxane A2, but not by lipoxygenase pathway products such as leukotrienes.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

The relationship of plasma ionized calcium to cardiovascular disease endpoint and family history of hypertension.

Plasma ionized calcium and total calcium were measured on 271 individuals from 34 Utah pedigrees divided into groups defined by the method of pedigree ascertainment: 1) hypertension clusters, 2) early stroke death clusters and 3) clusters of early heart attack deaths. Normotensive individuals were also categorized by family history of hypertension. Members of stroke cluster pedigrees had higher mean plasma ionized Ca2+ than either hypertension pedigrees (p less than 0.05) or coronary artery disease pedigrees which had the lowest concentrations (p less than 0.001). Within the normotensive group, those subjects with a positive family history of hypertension exhibited significantly higher plasma ionized Ca2+ (2.18 +/- 0.10 (S.D.) mEq/l) than individuals without a family history of hypertension (2.12 +/- 0.08 mEq/l, p less than 0.01). In medicated hypertensives, both ionized (p less than 0.05) and total (p less than 0.01) plasma calcium were higher than calcium levels in the normotensive negative family history subjects. Plasma ionized Ca2+ in the adult normotensives (N = 134) had significant age corrected positive correlations with plasma sodium (r = 0.25, p less than 0.01), potassium (r = 0.29, p less than 0.001) and erythrocyte sodium-lithium countertransport values (r = 0.20, p less than 0.05). These findings provide additional evidence that plasma ionized calcium concentrations may be important to help define the heterogeneity of hypertension in adult Americans.

Adult↗
PubMed1984

Platelet secretion defect associated with impaired liberation of arachidonic acid and normal myosin light chain phosphorylation.

We describe four patients with impaired platelet aggregation and 14C-serotonin secretion during stimulation with adenosine diphosphate (ADP), epinephrine, collagen, and platelet-activating factor. The response to arachidonic acid was normal in all patients with regard to aggregation and in three of the four with regard to 14C-serotonin secretion. The total platelet adenosine triphosphate (ATP) and ADP content and the ATP to ADP ratio was normal in all patients, thereby excluding storage pool deficiency as the cause of the secretion defect. Studies with 3H-arachidonic acid-labeled platelets revealed that the thrombin-induced liberation of arachidonic acid from membrane-bound phospholipids was impaired in these patients. Further, platelet thromboxane B2 production, measured using a radioimmunoassay, was diminished during stimulation with ADP and thrombin, but was normal with arachidonic acid, indicating that the oxygenation of arachidonic acid was normal and that the diminished thromboxane production was due to a defect in the liberation of arachidonic acid. Release of arachidonic acid is mediated by phospholipases that are Ca++ dependent. To examine whether these patients may have a defect in making intracellular Ca++ available, another Ca++-dependent process, myosin light chain phosphorylation, was studied during thrombin stimulation. Platelets from three of the patients were found to behave the same as normal ones, suggesting that the deficiency in phospholipase activity may not be due to impaired Ca++ mobilization. Our studies demonstrate a novel group of patients with platelet secretion defects associated with impaired liberation of arachidonic acid from phospholipids. These patients exemplify a congenital defect, other than deficiencies of cyclooxygenase and thromboxane synthetase, by which thromboxane production may be impaired in platelets.

Adenosine Diphosphate↗