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Biomedical subjects

G M Vercellotti

Publications and source records attributed to G M Vercellotti.

At least 55 records · Page 3Linked to original sources
PubMed1993

Endothelial activation and the kidney: vasomediator modulation and antioxidant strategies.

We have come to appreciate that the endothelium plays a major role in regulation of renal hemodynamics and excretory function. In the normal state, the endothelium maintains an intricate balance of interacting relaxing and contracting factors that can influence vasomotor tone and renal sodium handling, but also plays a role in the control of the coagulation system and cellular proliferation. Studies of reactive oxygen species as mediators of endothelial injury have shown that the perturbed endothelium can respond to such a threat, calling on intrinsic protective mechanisms such as induction of heme oxygenase and ferritin synthesis. In vivo studies have demonstrated that these mechanisms may confer protection in experimental models of acute renal injury. However, when endothelial injury or dysfunction does occur, adverse renal hemodynamic consequences, systemic hypertension, enhanced platelet aggregation, and mesangial cell proliferation could all contribute to progressive renal dysfunction. The role of the endothelium in modulation of normal renal function and in the pathogenesis of renal diseases will be the focus of future research efforts.

Animals↗
PubMed1993

Vitamin E, LDL, and endothelium. Brief oral vitamin supplementation prevents oxidized LDL-mediated vascular injury in vitro.

In previously reported in vitro studies, we found that heme, a physiologically widespread hydrophobic iron compound, can rapidly generate oxidized low-density lipoprotein (LDL), which then becomes cytotoxic to cultured vascular endothelial cells; both LDL oxidation and endothelial cytotoxicity were inhibited by incubation with exogenous alpha-tocopherol (vitamin E) or ascorbic acid (vitamin C). Seeking relevance to in vivo conditions, we performed a study in which 10 human volunteers were given daily antioxidant supplements of 800 IU of DL-alpha-tocopherol acetate alone or in combination with 1000 mg of ascorbic acid for 2 weeks. LDL resistance to heme oxidation ex vivo, as measured by the lag time for conjugated-diene formation, increased by as much as threefold from a mean +/- SD of 58 +/- 11 to 104 +/- 18 minutes (P < .001); LDL alpha-tocopherol increased from 11 +/- 2 to 26 +/- 6 molecules per LDL particle (P < .001); and most impressively, cytotoxicity to porcine aortic endothelial cells incubated with LDL conditioned with heme plus H2O2 or with copper was completely prevented (cytotoxicity before supplementation was 42 +/- 12%, decreasing after supplementation to 3 +/- 2%, P < .001). These measurements reverted to their presupplement levels within 2 weeks after participants stopped taking antioxidant supplements and were reproduced in 4 subjects taking 800 IU of DL-alpha-tocopherol acetate supplements alone but not in the same subjects taking 1000 mg ascorbic acid supplements alone. In conclusion, oral vitamin E supplementation increases LDL alpha-tocopherol content, increases LDL resistance to oxidation, and decreases the cytotoxicity of oxidized LDL to cultured vascular endothelial cells.

Adult↗
PubMed1993

Eosinophil cationic granule proteins impair thrombomodulin function. A potential mechanism for thromboembolism in hypereosinophilic heart disease.

Thromboembolism is a prominent but poorly understood feature of eosinophilic, or Loeffler's endocarditis. Eosinophil (EO) specific granule proteins, in particular major basic protein (MBP), accumulate on endocardial surfaces in the course of this disease. We hypothesized that these unusually cationic proteins promote thrombosis by binding to the anionic endothelial protein thrombomodulin (TM) and impairing its anticoagulant activities. We find that MBP potently (IC50 of 1-2 microM) inhibits the capacity of endothelial cell surface TM to generate the natural anticoagulant activated protein C (APC). MBP also inhibits APC generation by purified soluble rabbit TM with an IC50 of 100 nM without altering its apparent Kd for thrombin or Km for protein C. This inhibition is reversed by polyanions such as chondroitin sulfate E and heparin. A TM polypeptide fragment comprising the extracellular domain that includes its naturally occurring anionic glycosaminoglycan (GAG) moiety (TMD-105) is strongly inhibited by MBP, whereas its counterpart lacking the GAG moiety (TMD-75) is not. MBP also curtails the capacity of TMD-105 but not TMD-75 to prolong the thrombin clotting time. Thus, EO cationic proteins potently inhibit anticoagulant activities of the glycosylated form of TM, thereby suggesting a potential mechanism for thromboembolism in hypereosinophilic heart disease.

Aged↗
PubMed1993

Oxidized low-density lipoproteins and endothelium: oral vitamin E supplementation prevents oxidized low-density lipoprotein-mediated vascular injury.

Vitamin E supplements may decrease the incidence of myocardial infarction by inhibiting LDL oxidation to atherogenic moieties. We previously reported that hemin is a potent and relevant lipophilic source of iron that can rapidly intercalate into LDL, catalyzing its oxidation and promoting its cytolysis of endothelium. The effects of oral vitamin E on heme-catalyzed LDL oxidation and resulting endothelial damage were studied in 10 volunteers who received daily 800 I.U. of vitamin E with or without vitamin C (1000 mg) for 2 weeks. Prior, during, and 2 weeks after supplementation, plasma LDL was isolated and its number of alpha-tocopherol molecules, resistance to heme-catalyzed oxidation, and ability to damage porcine aortic endothelial cells were assayed. Vitamin E supplementation doubled the lag phase of LDL peroxidation as compared to control (104 +/- 18 vs. 58 +/- 11 min; p < 0.001) accompanied by an increase in alpha-tocopherol content of LDL particles (26 +/- 6 vs. 11 +/- 2 mol/mol; p < 0.001). Most intriguingly, LDL-mediated endothelial cell cytotoxicity was prevented (3 +/- 2% vs. 42 +/- 12%; p < 0.001). After a 2-week washout period, LDL alpha-tocopherol content, the lag time of LDL oxidation, and oxidized LDL-mediated cytolysis all returned to baseline levels. To determine whether supplements of vitamin E and vitamin C beneficially synergize in these effects, we monitored several volunteers on daily vitamin E alone or vitamin C alone. Vitamin E alone (at doses as low as 400 I.U./day) affected all measurements in a manner identical to that when it was taken with vitamin C. Vitamin C alone had no significant effect on these measurements. We conclude: dietary vitamin E supplementation provides cytoprotection against LDL oxidation-mediated endothelial cell injury, but this salutary effect is rapidly lost after supplementation is stopped.

Administration, Oral↗
PubMed1993

Herpes simplex virus and atherosclerosis.

This paper presents a brief overview of our current understanding of the relationship between herpes simplex virus (HSV) and atherogenesis. In the search for a viral trigger of atherosclerosis, several investigators reported the detection of herpes simplex virus in some, but not all atherosclerotic lesions. HSV infections are very common, not only in atherosclerotic patients but also in the general population, making epidemiological studies difficult to interpret. Different mechanisms by which HSV may contribute to atherogenesis have been described. In vascular cells, HSV infection leads to lipid accumulation. HSV infection of endothelial cells attracts leukocytes with subsequent inflammatory damage; it activates procoagulant changes on endothelium with increased thrombin generation and platelet adhesion, and changes its interaction with extracellular matrix proteins. Future studies should delineate whether these mechanisms are operative in the pathogenesis of atherosclerosis.

Arteriosclerosis↗
PubMed1993

Herpes simplex virus type I does not require productive infection to induce tissue factor in human umbilical vein endothelial cells.

BACKGROUND: Herpes simplex virus (HSV)-infected endothelium is a model for vascular injury and possibly the development of atherosclerosis. In vitro infection of human umbilical vein endothelial cells (HUVEC) by HSV-1 results in a number of changes including the expression of a procoagulant activity (PCA) compatible with that due to tissue factor (TF) synthesis. In this study, we have further characterized this PCA using more stringent assays for TF, and examined whether virus rendered incapable of replication retains the ability to stimulate TF synthesis in HUVEC. EXPERIMENTAL DESIGN: Confluent monolayers of HUVEC were exposed to intact or ultraviolet/heat-inactivated HSV-1. At appropriate time intervals, TF PCA was assessed by clotting assays, and TF antigen by an enzyme-linked immunosorbent assay specific for TF. The appearance of mRNA specific for TF was performed by Northern blotting. RESULTS: TF activity was demonstrated by both 1-stage and 2-stage clotting assays; the dependence of the latter on factor VIIa, and the inhibition by specific blocking antibodies to human TF support the notion that the PCA is indeed due to TF. Furthermore, cellular TF antigen levels were found to parallel TF activity, and there was a transient de novo expression of TF mRNA. Tissue factor PCA in HSV-infected HUVEC remained "encrypted"; that is, full clotting activity was not expressed in the absence of cellular disruption in a situation analogous to that seen in all normal cells thus far examined that express TF PCA. However, this response did not appear to be dependent upon replicative infection of HSV-1 within the endothelial cell since a similar (although lesser) induction of TF PCA was present in cells that had been exposed to virus previously rendered incapable of replication. CONCLUSIONS: HSV-1 induces PCA in HUVEC which is clearly TF-dependent; this response does not require viral replication. These data indicate increased complexity in HSV interactions with vascular endothelium and imply induction of some procoagulant functions by nonproductive infection.

Blood Coagulation Factors↗
PubMed1992

Ferritin: a cytoprotective antioxidant strategem of endothelium.

Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome. We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H2O2). In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin. After 16 h heme oxygenase and ferritin have increased approximately 50-fold and 10-fold, respectively. Differential induction of these proteins determined that ferritin is probably the ultimate cytoprotectant. Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration. Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis. Conversely, a site-directed mutant of ferritin (heavy chain Glu62----Lys; His65----Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant. We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin.

Animals↗
PubMed1992

Prothrombotic phenotype diversity of human aortic endothelial cells in culture.

We have previously demonstrated that human aortic endothelium exhibits morphologic heterogeneity in situ, and this heterogeneity can be reproduced in culture. In this study, we have compared prothrombotic properties of cultured endothelial cells (EC) from areas of human aorta at high risk for atherosclerosis (HP-EC) with EC from areas at low risk (LP-EC). Using paired cultures from the same donors, we have found that the expression of cell surface thrombomodulin (TM)--as measured by the ability to generate activated protein C (APC) from protein C in the presence of thrombin--is relatively reduced on HP-EC compared to LP-EC (respectively, 4.98 +/- 4.43 vs. 5.83 +/- 4.37 pM APC/min/cm2; p = .03, n = 12). Furthermore, HP-EC more efficiently assemble the prothrombinase complex on their cellular surface, resulting in an increased rate of thrombin generation from prothrombin (9.81 +/- 3.10 (HP-EC) vs. 7.96 +/- 3.20 nM thrombin/min/cm2 (LP-EC); p less than .03, n = 7). The combination of reduced TM expression and increased prothrombinase complex assembly on HP-EC suggests a prothrombotic phenotype in these cells. These findings may be important in the pathogenesis of thrombosis associated with atherosclerotic plaques.

Aorta↗
PubMed1992

Characterization of multiple quinine-dependent antibodies in a patient with episodic hemolytic uremic syndrome and immune agranulocytosis.

A 23-year-old woman experienced six distinct episodes of severe combined neutropenia and thrombocytopenia. At least one of the episodes was accompanied by hemodialysis-requiring acute renal failure and fragmentation hemolysis (hemolytic uremic syndrome [HUS]). In retrospect, all episodes were probably associated with the ingestion of quinine. Quinine-dependent antibodies to platelets, neutrophils, T lymphocytes, and red blood cells (RBCs) were detected in the patient's serum. By a monoclonal antibody antigen capture assay, the patient's serum contained IgG antibodies, which in the presence, but not absence, of quinine reacted with platelet glycoprotein (GP) complexes Ib/IX and IIb/IIIa, but not Ia/IIa. By immunoprecipitation assay, the serum, after addition of quinine, reacted strongly with an 85-Kd neutrophil membrane protein and weakly with 130- and 60-Kd moieties. Serum adsorbed with RBCs in the presence of quinine continued to react with platelets and neutrophils, and serum that was absorbed with platelets continued to react with neutrophils and RBCs, indicating that the antigenic targets were different on platelets, neutrophils, and RBCs. Since platelets and endothelial cells share some antigens, we tested patient serum for antibodies to human umbilical vein endothelial cells (HUVEC); no quinine-dependent antibodies to HUVEC were detected. However, her quinine-dependent antibodies not only bound to platelets and neutrophils, but also activated neutrophils. Thus, the patient's serum with quinine aggregated neutrophils, but neither agent alone caused activation. Moreover, the patient's serum with quinine (but not without) augmented the adherence of neutrophils to HUVEC. Treatment of the patient's serum with staphylococcal protein A removed the quinine neutrophil aggregation cofactor, suggesting it was due to IgG. In both neutrophil aggregation and adherence assays, decomplementation of the patient's serum markedly blunted its effect. Furthermore, the patient's serum failed to aggregate formalin-inactivated neutrophils, suggesting neutrophil activation, probably by activated complement, was necessary for aggregation and adhesivity to endothelium. We conclude that our patient's neutropenia, thrombocytopenia, lymphopenia, and anemia were due to quinine-dependent antibodies, and that these antibodies recognized epitopes that were different in the three target cell populations. We further suggest that HUS was likely secondary to the activation and adhesion of neutrophils to endothelium.

Adult↗
PubMed1992

Vascular endothelial cell proteoglycans are susceptible to cleavage by neutrophils.

Heparan sulfate proteoglycan associated with vascular endothelial cells in vivo plays an important role in a number of endothelial functions, including the inhibition of intravascular coagulation and extravasation of plasma proteins and blood cells. In this report, we demonstrate that polymorphonuclear neutrophils, as well as cell-free neutrophil supernatants, lead to a rapid and dramatic loss of proteoglycan from endothelial cells in the absence of evidence of cell lysis. This cleavage appears to be relatively (although not absolutely) selective for heparan sulfate and is mediated by neutrophil-derived serine proteases. Inhibitors of neutrophil elastase appear to be the most effective inhibitors of proteoglycan release. Furthermore, purified human neutrophil elastase also leads to cleavage of cellular proteoglycans, although not to the same extent as neutrophils or neutrophil supernatants. Proteoglycans compared with all other protein-containing macromolecules appear to be especially vulnerable to neutrophil-mediated cleavage. The results of this study may be germane to the interaction of neutrophils with endothelium during the inflammatory process, during which the loss of endothelial heparan sulfate proteoglycan may play a critical role in the vascular injury that often accompanies inflammation.

Cells, Cultured↗
PubMed1992

Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat.

Heme proteins such as myoglobin or hemoglobin, when released into the extracellular space, can instigate tissue toxicity. Myoglobin is directly implicated in the pathogenesis of renal failure in rhabdomyolysis. In the glycerol model of this syndrome, we demonstrate that the kidney responds to such inordinate amounts of heme proteins by inducing the heme-degradative enzyme, heme oxygenase, as well as increasing the synthesis of ferritin, the major cellular repository for iron. Prior recruitment of this response with a single preinfusion of hemoglobin prevents kidney failure and drastically reduces mortality (from 100% to 14%). Conversely, ablating this response with a competitive inhibitor of heme oxygenase exacerbates kidney dysfunction. We provide the first in vivo evidence that induction of heme oxygenase coupled to ferritin synthesis is a rapid, protective antioxidant response. Our findings suggest a therapeutic strategy for populations at a high risk for rhabdomyolysis.

Animals↗
PubMed1992

Endothelial cell heme oxygenase and ferritin induction by heme proteins: a possible mechanism limiting shock damage.

Acutely, hemin sensitizes endothelial cells to oxidants but chronically protects the endothelium through the induction of ferritin. By releasing its heme, methemoglobin can sensitize endothelial cells in a fashion similar to free hemin. Furthermore, prolonged incubation with the endothelium allows methemoglobin to induce heme oxygenase and ferritin and concomitantly to modulate oxidant-mediated cytotoxicity. Methemoglobin but not hemoglobin, metmyoglobin or cytochrome c induces heme oxygenase and ferritin. Heme needs to be released from methemoglobin, since sodium cyanide, haptoglobin, and hemopexin inhibit the induction of these proteins. Neutrophils can oxidize hemoglobin to methemoglobin, which can subsequently induce both heme oxygenase and ferritin. We speculate that in shock with disseminated intravascular coagulation, marginated PMNs oxidize hemoglobin to heme-releasing methemoglobin. If critical defenses such as haptoglobin and hemopexin are overwhelmed, heme enters the endothelin cells, sensitizing them to oxidant damage. Endothelial cell adaptation via heme-induced heme oxygenase and ferritin production might limit ultimate progression to pulmonary and other vascular leak syndromes.

Animals↗
PubMed1992

Herpes virus infection of endothelium: new insights into atherosclerosis.

Several pieces of evidence suggest that vascular endothelium may be a site of latent herpetic viral infection, and that activation of such infection might cause or aggravate atherosclerosis. The present studies which utilized HSV-1 infection of cultured endothelial monolayers, provide insights into two phenomena seemingly relevant in considerations of atherosclerosis. Thus, mechanisms are reported by which infected endothelium may be damaged by marginated inflammatory cells, and be transformed from an anticoagulant to a procoagulant tissue. First, granulocytes are attracted to, and avidly bind, endothelium infected for very brief periods. This interaction is associated with denudation of intact cells as well as actual cytolysis through release of PMN proteases and toxic oxygen species. Second, several potentially additive abnormalities of HSV-infected endothelium would seem to foster coagulation. These include: a) its loss of surface heparans and thrombomodulin; b) its inability to synthesize prostacyclin with associated incapacity to deter platelet adhesion; c) its disordered membrane lipid conformation which is likely associated with excessive surface thrombin generation; and d) its unique ability to generate and release tissue factor. We speculate that mechanical abrasion may reactivate latent herpes (HSV or CMV) infection in endothelial cells particularly those exposed to high shear forces--for instance, at vessel bifurcations. This may underlie the endothelial damage, clotting and atheroma formation commonly found at these sites.

Animals↗
PubMed1992

Relapse of acute leukemia presenting as acute cholecystitis following bone marrow transplantation.

Though included in the differential diagnosis of jaundice and abdominal pain, acute acalculous cholecystitis is an uncommon hepatobiliary complication of bone marrow transplantation. Leukemic infiltration of the gallbladder presenting as acute cholecystitis is rare. We describe two cases of acute cholecystitis following marrow transplantation that represented an unexpected relapse with leukemic infiltration of the gallbladder wall.

Acute Disease↗
PubMed1992

Mechanism of complement activation in the hyperacute rejection of porcine organs transplanted into primate recipients.

The authors investigated the importance of natural antibody and complement in the pathogenesis of hyperacute xenograft rejection using in vivo and in vitro pig to primate models. Studies were carried out in rhesus monkeys transplanted with a pig heart or kidney in which hyperacute rejection was observed within a few hours. The rejected organs showed deposits of IgM, C3, C4, C5, and C9 neoantigen along small blood vessels, but few deposits of factors B and P. Removal of anti-endothelial cell "natural" antibodies by plasmapheresis, immunoabsorption, and immunosuppression techniques resulted in marked prolongation of the survival of a subsequently transplanted heart, even when complement levels were within the normal range. Thus, complement, in the absence of natural antibodies, did not initiate hyperacute rejection in this species combination. The requirements for complement activation in human serum to cause cytotoxicity of porcine endothelial cells were then evaluated. Cytotoxicity was abrogated by depleting human serum of IgM, C2, or C5, but not of factor B. Restoration of the effect of serum on endothelial cells was achieved by reconstitution of the respective depleted sera with purified IgM or with the corresponding complement proteins, indicating that IgM and the classical, but not the alternative, pathway of complement, were involved. Identical conclusions were drawn from experiments to ascertain the requirements for complement activation in human serum to mediate binding of iC3b to porcine endothelial cells. The authors conclude that in a pig to primate xenograft complement does not directly initiate injury to the graft but rather requires activation by bound xenoreactive natural antibodies; IgM antibodies directed against endothelial cells activate the classical complement pathway, which then contributes to endothelial cell activation and subsequent events characteristic of hyperacute rejection.

Animals↗
PubMed1991

Neutrophil adhesion to xenogeneic endothelium via iC3b.

Neutrophils are thought to play an important role in the pathogenesis of hyperacute rejection, a dramatic form of tissue injury caused by the reaction of antigraft antibodies with endothelial cells of an organ allograft or xenograft. We asked whether the interactions of human polymorphonuclear leucocytes (PMN) with xenogeneic endothelium might be promoted by the binding of natural anti-endothelial antibodies and complement by using porcine aortic endothelial cells (PAEC), human serum, and human PMN in an in vitro model of hyperacute rejection. Pretreatment of PAEC with 10% human serum followed by washing markedly increased PMN adhesion from 15.7 +/- 1.8% to 62.5 +/- 3.6% (p less than 0.001). Complement and anti-endothelial antibodies were necessary for the increase, because heat-inactivated serum or serum depleted of IgM did not significantly increase PMN adhesion to treated endothelium. The induction of increased PMN adhesion to PAEC by human serum was observed within 1 min. The essential role of complement was defined using complement-depleted serum. Ten percent C2-deficient serum did not increase PMN adhesion whereas 10% C5-depleted or 10% C8-depleted serum caused the same increase in PMN adhesion as observed with normal human serum. These results suggested that C3 might play a critical role in enhanced neutrophil adhesion. In fact, PAEC treated with 10% human serum for 15 min and incubated with an F(ab')2 antihuman C3 for 10 min completely abolished the enhanced adhesion. PAEC treated with 10% human serum or C5-depleted serum displayed fluorescence of iC3b whereas monolayers treated with heat-inactivated serum or C2-deficient serum were non-reactive. The enhanced PMN adhesion to serum-treated PAEC was mediated through neutrophil receptors binding iC3b because mAb directed against CD11b/CD18 inhibited the serum-enhanced adhesion of PMN. We conclude that PMN adhesion to endothelium can be significantly enhanced by the endothelial deposition of iC3b.

Animals↗
PubMed1991

Calcium channel blockade inhibits platelet activating factor production by human umbilical vein endothelial cells.

An increase in intracellular calcium level is an important signal in the regulation of cellular responses under normal and pathological conditions. Because two key enzymes in the synthetic pathway of platelet activating factor (PAF), phospholipase A2 and acetyltransferase, are calcium dependent, we hypothesized that calcium channel blockade may inhibit agonist-induced PAF synthesis. Primary cultures of human umbilical vein endothelial cells (EC), pre-incubated with [3H]acetate, were exposed to thrombin (5 U/mL) and PAF production was quantitated by incorporation of radiolabel into the EC lipid fraction co-migrating with exogenous PAF in thin-layer chromatography. The effect of pre-incubation with calcium channel blockers (verapamil, diltiazem, 10(-4) M) or buffer was determined. Results (triplicate experiments, * P less than 0.05 vs buffer, P less than 0.05 vs thrombin) demonstrate that pre-incubation with calcium channel blocker markedly inhibits thrombin-induced PAF production (verapamil:buffer 273 +/- 122, thrombin 10,735 +/- 1524*, thrombin + verapamil 178 +/- 91 cpm/plate; diltiazem:buffer 1097 +/- 581, thrombin 15,283 +/- 2661*, thrombin + diltiazem 280 +/- 56 cpm/plate). The effect of diltiazem was dose-dependent (% inhibition: 10(-7) M, 46%; 10(-5) M, 60%; 10(-4) M, 98%). Diltiazem also inhibited bradykinin (10(-8) M) induced PAF synthesis. In calcium-free medium or in the presence of LaCl3 (10(-3) M), the PAF response of EC to thrombin was blunted (buffer 582 +/- 360, thrombin 5394 +/- 1069, thrombin + calcium free medium 1055 +/- 571, thrombin + LaCl3 1271 +/- 58 cpm/plate). We conclude that calcium channel blockers prevent agonist-induced PAF synthesis, possibly by preventing cellular calcium influx and activation of PAF synthetic enzymes. We speculate that this mechanism may underlie, at least in part, the beneficial effect of calcium channel blockade under various pathological conditions.

Bradykinin↗