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Biomedical subjects

P C Isakson

Publications and source records attributed to P C Isakson.

At least 91 records · Page 5Linked to original sources
PubMed1981

Increased susceptibility to lethal effects of bacterial lipopolysaccharide in mice with B-cell leukemia.

Susceptibility to the lethal effects of bacterial lipopolysaccharide (LPS) increased more than one hundredfold in BALB/c mice given syngeneic B-cell tumor transplants. The increased susceptibility to LPS that developed during the following weeks paralleled tumor growth in the liver and spleen. The tumor-bearing animals also developed an enhanced capacity to clear colloidal carbon from the blood, consistent with increased activity of the reticuloendothelial system. Although hypersusceptibility to LPS has been reported to a number of animal models, our experiment was th first demonstration in a tumor model that susceptibility correlates with tumor burden.

Animals↗
PubMed1981

BCL1, a murine model of prolymphocytic leukemia. I. Effect of splenectomy on growth kinetics and organ distribution.

BCL1 is a transplantable murine B-cell leukemia that closely resembles human prolymphocytic leukemia (PLL). Syngeneic mice injected with BCL1 cells develop massively enlarged spleens followed by leukemia. Splenectomy performed either prior to BCL1 transplantation or prior to the leukemic phase of transplanted BCL1 results in a markedly altered clinical syndrome: the onset of leukemia is delayed by about 2 months; the leukemia is low-grade; and the lymph nodes, which are not prominently involved in leukemic animals with intact spleens, are massively infiltrated in the splenectomized transplant recipient. The immunologic phenotype of the BCL1 cell is not altered by splenectomy and thus does not appear to account for the altered tissue distribution of BCL1 in the splenectomized host. However, the results indicate a striking dependence of BCL1 on microenvironmental influences of the host lymphoid tissues.

Animals↗
PubMed1980

Acquisition of cell surface IgD after in vitro culture of neoplastic B cells from the murine tumor BCL1.

Murine BCL1 tumor cells bear large amounts of surface IgM and trace amounts of surface IgD. In the present studies we have shown that cultivation of these cells, in the absence of lipopolysaccharide, results in the acquisition of IgD by virtually all the cells. These results suggest that BCL1 cells can differentiate in vitro into more mature B cells and offer an attractive model for analyzing the factors controlling appearance of IgD on a monoclonal cell line.

Animals↗
PubMed1980

The effect of anti-immunoglobulin antibodies on the in vitro proliferation and differentiation of normal and neoplastic murineB cells.

In these studies, we have compared the effects of anti-mu and anti-delta antibodies on normal and neoplastic murine B cells. Spleen cells from normal BALB/c mice or from mice carrying the BCL1 tumor were treated with F(ab')2 fragments of affinity purified anti-mu or anti-delta antibodies and the effec of the antibodies on cell proliferation was assessed. F(ab)'2 fragments of both antibodies induced proliferation of normal adult B cells but inhibited (anti-mu) or had no effect (anti-delta) on proliferation of BCL1 cells. In addition, both antibodies further enhanced the LPS-induced proliferative response of cells from adult mice. In contrast, the LPS responses of neonatal cells and BCL1 cells were inhibited by F(ab')2 anti-mu antibodies. These data indicate that interaction of antibody with surface IgD as well as surface IgM can activate adult B cells. In addition, the results provide further evidence that BCL1 cells are neoplastic analogs of immature B cells since the tumor cells, like neonatal cells, are not activated after treatment with anti-Ig antibodies.

Animals↗
PubMed1979

Preparation of stable erythrocyte target cells suitable for detection of the antibody response to the haptens azobenzenearsonate, azophenyltrimethylammonium and azophenylphosphorylcholine by plaque-forming cell assay.

The preparation of sheep red blood cells (SRBC) which have been sensitized with the haptens azobenzenearsonate, phosphorylcholine and azophenyltrimethylammonium, and are suitable for use in a plaque-forming cell assay, is described. Each hapten is first coupled to a phenolic imidoester (methyl-p-hydroxybenzimidate) and the substituted imidoesters are employed to prepare target SRBC. Details are presented concerning synthesis and purification of the imidoesters, as well as conditions for coupling to SRBC. The hapten-SRBC prepared by this method are very stable and offer significant advantages over other procedures for coupling these haptens to red blood cells.

Animals↗
PubMed1979

Murine B cell leukemia (BCL1): organ distribution and kinetics of growth as determined by fluorescence analysis with an anti-idiotypic antibody.

The life history of a transplantable B cell leukemia (BCL1) that arose spontaneously in a BALB/c mouse is described. Animals bearing this tumor live from 2 to 4 months in apparently good health despite massive splenomegaly and leukemia. Antibody to the idiotype or gamma light chain of the tumor IgM was used in conjunction with the fluorescence-activated cell sorter to identify tumor cells in the BCL1-bearing mice. The results suggest that these cells multiply and differentiate in the spleen and subsequently emigrate to the blood. Tumor cells do not recirculate as evidenced by their failure to enter the thoracic duct or to infiltrate lymph nodes to a significant extent. During tumor growth, a population of T cell blasts appears that may be involved with an immune response against the tumor.

Animals↗
PubMed1977

Characterization of a novel metabolic pathway of arachidonate in coronary arteries which generates a potent endogenous coronary vasodilator.

Bovine coronary artery strips were incubated with [1-14C]arachidonic acid and the chemical properties of the various prostaglandins (PG) formed were studied. Arachidonate was converted to two major prostaglandin products, PGE2 and a novel prostaglandin having chemical (i.e. base hydrolysis and borohydride reduction) and chromatographic properties identical with 6-keto-PGF1alpha. This final compound was inactive on coronary artery strips. The endoperoxide intermediates, PGG2 or PGH2, previously shown to induce coronary relaxation, were not released into the medium from isolated bovine coronaries. The arachidonic acid-induced dilation may have been due to an intracellular action of PGH2 (or PGG2) or to the action of another, yet unidentified, labile intermediate formed in the enzymatic conversion of endoperoxides to 6-keto PGF1alpha. When PGH2 was incubated with bovine coronary microsomes, the PGH2 was completely metabolized (i.e. loss of rabbit aorta contraction) but a compound was generated which was a much more potent coronary relaxant. We suggest that this major novel metabolic pathway of arachidonate generates a substance, intermediate between PGH2 and the final 6-keto PGF1alpha-like product, which is a potent coronary vasodilator.

Animals↗
PubMed1977

Hormone selective lipase activation in the isolated rabbit heart.

The synthesis and release of PGs by the isolated perfused rabbit heart upon bradykinin stimulation results from lipase stimulation which liberates arachidonic acid for PG biosynthesis. The [14C]-labelled fatty acids, arachidonate, linoleate, and oleate, when infused into the heart preparation, were efficiently incorporated into the phospholipid pool in the heart mostly in the 2-position of phosphatidylcholine. On the other hand, [14C]-palmitate was esterified into both the 1- and the 2-position. Bradykinin released bioassayable PG when injected into the rabbit hearts, regardless of which fatty acid label was incorporated into the phospholipid pool. However, only [14C]-arachidonic acid (but not [14C]-linoleate, oleate or palmitate) was liberated from the variously labelled hearts upon hormone stimulation. This selective bradykinin effect on fatty acid release suggests that hormone stimulation either activates a specific lipase that distinguishes different fatty acids in the 2-position or activates lipase which is selectively compartmented with arachidonate-containing phospholipids. Ischemia, on the other hand, appeared to non-specifically stimulate tissue lipases, resulting in a non-selective release of oleic as well as arachidonic acid. A disproportionally large release of arachidonic acid was observed accompanying a relatively small PG (10:1 arachidonate: PG ratio) production during ischemia, as compared to bradykinin (3:1 ratio), suggesting distinct mechanisms for PG biosynthesis induced by bradykinin and ischemia.

Animals↗
PubMed1977

Hormonal stimulation of arachidonate release from isolated perfused organs. Relationship to prostaglandin biosynthesis.

The lipids of isolated Krebs perfused rabbit kidneys and hearts were labelled with [14C]arachidonic acid. Subsequent hormonal stimulation (e.g. bradykinin, ATP) of the pre-labelled tissue resulted in dose-dependent release of [14C]prostaglandins; little or no release of the precursor [14C]arachidonic acid was observed. When fatty acid-free bovine serum albumin was added to the perfusion medium as a trap for fatty acids substantial release of [14C]arachidonic acid was detected following hormonal stimulation. The release of [14C]arachidonic acid was dose-dependent and greater than 3 fold that of [14C]prostaglandin release. Indomethacin by inhibiting the cyclo-oxygenase, completely inhibited release of [14C]prostaglandins and only slightly inhibited release of [14C]arachidonic acid. These results demonstrate that in both rabbit kidney and heart much more substrate is released by hormonal stimulation than is converted to prostaglandins. This suggests that either the deacylation reaction is not tightly coupled to the prostaglandin synthetase system or that there are two deacylation mechanisms, one which is coupled to prostaglandin synthesis while the other is non-specific. It has previously been shown that prostaglandin release due to hormones such as bradykinin is transient despite continued presence of the hormone (tachyphylaxis). By utilizing albumin to trap released fatty acid, it was found that hormone-stimulated release of arachidonic acid is also transient. This directly demonstrates that tachyphylaxis occurs at a step prior to the cyclo-oxygenase.

Adenosine Triphosphate↗
PubMed1977

A novel prostaglandin is the major product of arachidonic acid metabolism in rabbit heart.

The prostaglandins (PGs) released from the heart have generally been characterized as resembling PGE by bioassay techniques. The major PG formed from [14C]arachidonate (C20:4) by the isolated perfused rabbit heart has chromatographic mobility similar to that of PGE2 in most solvent systems. However, additional analysis of this radioactive "PGE" peak suggests that two substances are formed by the heart and migrate like PGE2: one has chemical properties similar to those of authentic PGE2 and the other is a novel PG. The unknown compound is the major PG formed by the heart from either exogenous arachidonate or hormonal stimulation of PG biosynthesis. The novel PG produced by the heart may be identical with either 6(9)-oxy-PGF or 6-keto-PGF1 alpha.

8,11,14-Eicosatrienoic Acid↗
PubMed1977

Prostaglandins and the renin-angiotensin system in canine endotoxemia.

Adminstration of endotoxin to dogs caused a rapid initial decline in blood pressure followed by a transient recovery preceding death. Plasma renin activity was elevated 5 minutes after endotoxin administration and continued to rise throughout the course of shock. Indomethacin given 60 minutes after endotoxin caused an elevation of blood pressure and a 50% decrease in plasma renin activity. Pretreatment with indomethacin markedly attenuated both the hemodynamic changes and the rise in plasma renin activity caused by endotoxin administration. Prostaglandin (PG) E-like material was observed in renal venous blood 30 minutes after endotoxin administration and was abolished by indomethacin. In addtion, a non-PG substance was found in dialysate from both arterial and renal venous blood within 5 minutes of endotoxin administration, Renal and mesenteric angiograms were taken at various stages of shock. Endotoxin administration caused a substantial increase in the diameter of intrarenal arterial branches which was temporally associated with the appearance of PGE-like material in the renal venous effluent. The mesenteric arteries were initially and transiently constricted by endotoxin and then were markedly and chronically dilated. Indomethacin simultaneously abolished renal PG and decreased renal and mesenteric arterial diameter.

Angiotensin II↗
PubMed1976

Selective incorporation of 14C-arachidonic acid into the phospholipids of intact tissues and subsequent metabolism to 14C-prostaglandins.

A method is described for the efficient incorporation of radioactive arachidonic acid into the lipids of rabbit hearts and kidneys. Infusion of 14C-arachidonate through perfused tissues resulted in the quantitative removel of label from the media. Analysis of the lipids from tissues labeled by this procedure revealed that the majority of the 14C-arachidonate was incorporated into phospholipids. Essentially all of the radioactivity in phosphatidylcholine was found in the 2-position. Subsequent to the 14C-arachidonate infusion, stimulation of prostaglandin biosynthesis (e.g. by bradykinin) resulted in the release of radioactive prostaglandins. This suggests that the 14C-arachidonate is incorporated in a manner such that it is available for hormone-stimulated prostaglandin biosynthesis. The method described allows both qualitative and quantitative analysis of arachidonate metabolism in intact tissues and offers significant advantages over other presently used methods.

Animals↗
PubMed1976

Angiotensin antogonists as pharmacological tools.

The availability of specific competitive antagonists stimulated investigation of the physiological and pathological role of angiotensin (A-II) and permitted the qualitative and quantitative characterization of numerous angiotensin receptor sites. The specific, competitive antogonists for A-II inhibit both the direct actions of A-II on isolated smooth muscle preparations and the stimulation of specific vascular receptor sites by which A-II evokes prostaglandin biosynthesis and release. Converting enzyme inhibitors a) block the action of exogenous A-I; b) lower blood pressure in conditions associated with high plasma renin levels (e.g., two-kidney renal hypertension, dehydrated diabetes insipidus rats, or in hemorrhagic shock); c) enhance responses to exogenous bradykinin (by inhibiting bradykininase); but d) do not block the effects of A-II at its receptor sites. A-II-receptor antagonists a) block the action of both A-I and A-II, b) lower blood pressure in high renin states, but c) have no effect on bradykinin degradation or action. Angiotensin receptor and synthesis antagonists have been shown to decrease the overall peripheral resistance and to reverse the renal cortical vasoconstriction during hemorrhagic shock and to prolong survival time in hemorrhaged dogs. It is our belief that angiotensin antogonists have therapeutic potential in hemorrhagic shock and would be expected (alone or in combination with alpha-andrenergic blockade) to overcome vascular shutdown and enhance organ perfusion (especially in the kidney).

Angiotensin II↗