scholarly journals Targeting Metabolic Enzyme Pyruvate Kinase M2: A Novel Strategy to Inhibit Platelet Function and Arterial Thrombosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1056-1056
Author(s):  
Manasa K Nayak ◽  
Madankumar Ghatge ◽  
Nirav Dhanesha ◽  
Gagan D Flora ◽  
Manish Jain ◽  
...  
Keyword(s):  
Platelet Function ◽  
Arterial Thrombosis ◽  
Aerobic Glycolysis ◽  
Flow Chamber ◽  
Dense Granule ◽  
Metabolic Enzyme ◽  
Clot Retraction ◽  
Atp Production ◽  
Novel Strategy

Background: The cellular responses initiated upon platelet activation are energy consuming. Activated platelets, in comparison to their resting state, exhibit a high level of aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen) relative to oxidative phosphorylation (OXPHOS), suggesting that metabolic plasticity exists in platelets. Although aerobic glycolysis yields less total ATP when compared to OXPHOS, the rate of ATP generation is faster in aerobic glycolysis compared to OXPHOS, which we hypothesize is well suited for high-energy requirement during platelet activation. The glycolytic enzyme pyruvate kinases (PKs) catalyzes the final step of glycolysis and contributes to net ATP production. Four PK isoforms (L, R, M1 and M2) exist in mammals: L and R isoforms are expressed in the liver and red blood cells; the M1 isoform is expressed in most adult tissues that have high catabolic demands including muscle and brain; M2 is expressed in cells including activated platelets and leukocytes. Unlike other isoforms of PK that function only as tetramers, PKM2 can exist in either a tetrameric state or a dimeric state. PKM2 is allosterically regulated by the upstream metabolite fructose-1, 6 biphosphate. While PKM1 and tetrameric PKM2 favor ATP production from OXPHOS through the TCA cycle, dimeric PKM2 drives aerobic glycolysis. The glycolytic and non-glycolytic functions of PKM2 in platelets have not investigated yet. Objective: We tested an innovative concept that whether targeting metabolic enzyme PKM2 will inhibit platelet function and arterial thrombosis. Methods: Using a specific inhibitor of PKM2 (that prevents PKM2 dimerization and stabilizes tetramers) and a range of standardized platelet in vitro assays, we determined the mechanistic role of PKM2 in modulating platelet function in human and mice. To provide definitive evidence, we generated a megakaryocyte or platelet-specific PKM2-/- mouse (PKM2fl/flPF4Cre). Susceptibility to thrombosis was evaluated in vitro (microfluidics flow chamber) and in vivo (FeCl3-induced carotid and laser-injury induced mesenteric artery thrombosis models) by utilizing intravital microscopy. Susceptibility to hemostasis was evaluated in tail bleeding assay. Results: Human and mouse platelets pretreated with PKM2 inhibitor significantly decreased platelet aggregation to sub-optimal doses of collagen, convulxin, thrombin, and ADP. Consistent with this, inhibiting PKM2 dimerization reduced αIIbβ3 activation, alpha and dense granule secretion, clot retraction that was concomitant with decreased glucose uptake. Furthermore, treatment with PKM2 inhibitor reduced Akt and GSK3β phosphorylation, that are predominantly involved in PI3K/Akt signaling, suggesting a non-glycolytic role of the PKM2 in regulating platelet function. In microfluidics flow chamber assay, human and whole mouse blood pretreated with PKM2 inhibitor formed small thrombi when perfused over collagen for 5 minutes at an arterial shear rate of 1500s-1 (P<0.05 vs. vehicle). In agreement with PKM2 inhibitor studies, platelets from PKM2fl/flPF4Cre mice exhibited decreased agonist-induced platelet aggregation, which was in agreement with decreased alpha and dense granule secretion, αIIbβ3 activation, clot retraction, lactate production, and Akt and GSK3β phosphorylation (P<0.05 vs. PKM2fl/fl littermate controls). Wild-type mice-treated with PKM2 inhibitor and/or PKM2fl/flPF4Cre were less susceptible to thrombosis in the FeCl3-induced carotid and laser injury-induced mesenteric artery thrombosis models. Lack of effect on tail bleeding time suggested normal hemostasis in PKM2fl/flPF4Cre mice and PKM2 inhibitor-treated wild-type mice. No sex-based differences were observed. Currently, we are performing platelet metabolomics to determine the effect of targeting PKM2 on metabolic pathways. Conclusions: Our results suggest that manipulating metabolic plasticity by targeting dimeric PKM2 may be explored as a novel strategy to inhibit platelet function and arterial thrombosis. Disclosures Lentz: Novo Nordisk Inc.: Consultancy, Honoraria, Research Funding.

scholarly journals Manipulating Metabolic Plasticity By Targeting Pyruvate Kinase M2 in Platelets Inhibits Arterial Thrombosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 868-868
Author(s):  
Manasa Nayak ◽  
Nirav Dhanesha ◽  
Manish Jain ◽  
Anil Chauhan
Keyword(s):  
Platelet Function ◽  
Arterial Thrombosis ◽  
Aerobic Glycolysis ◽  
Flow Chamber ◽  
Metabolic Plasticity ◽  
Laser Injury ◽  
Artery Thrombosis ◽  
Activated Platelets

Abstract Background: Most of the cellular responses initiated upon platelet activation are energy consuming. Like normal cells, resting platelets rely primarily on oxidative phosphorylation (OXPHOS) to generate ATP, whereas activated platelets exhibit a high level of aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen, a phenomenon referred to as the Warburg effect in tumor cells) suggesting that metabolic plasticity exists in activated platelets. Although aerobic glycolysis yields less total ATP when compared to OXPHOS, the rate of ATP generation is faster in aerobic glycolysis compared to OXPHOS, which is well suited for high-energy demands during platelet activation. Pyruvate kinases (PKs) catalyzes the final step of glycolysis, the formation of pyruvate and ATP from phosphoenolpyruvate and ADP. Four PK isoforms exist in mammals: L and R isoforms are expressed in the liver and red blood cells; the M1 isoform is expressed in most adult tissues that have high catabolic demands including muscle and brain; M2 is expressed in cells including activated platelets and leukocytes. While PKM1 and tetrameric PKM2 favor ATP production from OXPHOS through the TCA cycle, dimeric PKM2 drives aerobic glycolysis. Objective: We tested an innovative concept that by manipulating the energy demand of activated platelets (metabolic plasticity), by targeting PKM2, will inhibit platelet function and thrombosis. Methods: Using a specific inhibitor of PKM2 (inhibits PKM2 dimerization and stabilizes tetramers) and standardized platelet in vitro assays, we determined the mechanistic role of PKM2 in modulating platelet function in human and mice. To provide definitive evidence, we generated a megakaryocyte or platelet-specific PKM2-/- mouse (PKM2fl/flPF4Cre). Lactate assay was performed in WT and PKM2 null platelets. Susceptibility to thrombosis was evaluated in vitro (microfluidics flow chamber) and in vivo (FeCl3-induced carotid artery thrombosis and laser injury models) by utilizing intravital microscopy. Results: We found that PKM2 is relatively highly expressed compared to PKM1 in human and murine platelets. Transmission electron microscopy (immunogold staining) revealed that PKM2 is found in the cytoplasm and a- granule in resting platelets, whereas most of PKM2 translocated to cytoplasm upon activation. Human and mouse platelets pretreated with PKM2 inhibitor exhibited decreased platelet aggregation to sub-optimal doses of collagen and convulxin but not to thrombin. In microfluidics flow chamber assay, human and whole mouse blood pretreated with PKM2 inhibitor formed small thrombi when perfused over collagen for 5 min at an arterial shear rate of 1500s-1 (P<0.05 vs. vehicle control). Platelets from PKM2fl/flPF4Cre mice exhibited decreased platelet aggregation to sub-optimal doses of collagen and convulxin, but not to thrombin, compared to PKM2fl/fl mice concomitant with decrease lactate production. In microfluidics flow chamber assay, whole blood from PKM2fl/flPF4Cre mice formed smaller thrombi when perfused over collagen for 5 min at an arterial shear rate of 1500s-1, compared to PKM2fl/fl mice. PKM2fl/flPF4Cre mice were less susceptible to thrombosis in the FeCl3-induced carotid and laser injury-induced mesenteric artery thrombosis models (P<0.05 vs. vehicle control, N=10 mice/group), without altering hemostasis. PKM2 regulates the phosphorylation signal transducer and activator of transcription 3 (STAT3) and p-STAT3 act as a protein scaffold that facilitates the catalytic process of activating PLCg by kinase Syk in response to low-doses of collagen and CRP, but not TRAP or ADP in human and murine platelets. Interestingly, we found that PKM2 and STAT3 colocalized in the convulixn- stimulated control platelets and less phosphorylation of STAT-3 was observed in activated PKM2 null platelets (P<0.05 vs. WT), suggesting a non-glycolytic role of the PKM2 in regulating collagen signaling. Conclusions: Our results suggest that dimeric PKM2 regulates platelet function and arterial thrombosis most likely via GPVI signaling pathway. We suggest that manipulating metabolic plasticity by targeting dimeric PKM2 may be explored as a novel strategy to inhibit platelet function and arterial thrombosis. Disclosures No relevant conflicts of interest to declare.

The tetraspanin superfamily member CD151 regulates outside-in integrin αIIbβ3 signaling and platelet function

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2368-2375 ◽  
Author(s):  
Lai-Man Lau ◽  
Janet L. Wee ◽  
Mark D. Wright ◽  
Gregory W. Moseley ◽  
P. Mark Hogarth ◽  
...  
Keyword(s):  
Platelet Function ◽  
Fluorescein Isothiocyanate ◽  
Dense Granule ◽  
Free Calcium ◽  
Clot Retraction ◽  
Altered Expression ◽  
Integrin Αiibβ3 ◽  
Normal Platelet ◽  
Granule Secretion

Abstract The tetraspanin family member CD151 forms complexes with integrins and regulates cell adhesion and migration. While CD151 is highly expressed in megakaryocytes and to a lesser extent in platelets, its physiologic role in platelets is unclear. In this study, we investigate the physical and functional importance of CD151 in murine platelets. Immunoprecipitation/Western blot studies reveal a constitutive physical association of CD151 with integrin αIIbβ3 complex under strong detergent conditions. Using CD151-deficient mice, we show that the platelets have impaired “outside-in” integrin αIIbβ3 signaling with defective platelet aggregation responses to protease-activated receptor 4 (PAR-4) agonist peptide, collagen, and adenosine diphosphate (ADP); impaired platelet spreading on fibrinogen; and delayed kinetics of clot retraction in vitro. This functional integrin αIIbβ3 defect could not be attributed to altered expression of integrin αIIbβ3. CD151–/– platelets displayed normal platelet alpha granule secretion, dense granule secretion, and static platelet adhesion. In addition, CD151–/– platelets displayed normal “inside-out” integrin αIIbβ3 signaling properties as demonstrated by normal agonist-induced binding of soluble fluorescein isothiocyanate (FITC)–fibrinogen, JON/A antibody binding, and increases in cytosolic-free calcium and inositol 1,4,5 triphosphate (IP3) levels. This study provides the first direct evidence that CD151 is essential for normal platelet function and that disruption of CD151 induced a moderate outside-in integrin αIIbβ3 signaling defect.

Human Platelet Acetylcholinesterase: The Effects of Anticholinesterases on Platelet Function

1979 ◽  
Vol 42 (05) ◽  
pp. 1615-1619 ◽  
Author(s):  
Martin J Smith ◽  
Boyd Braem ◽  
Kent D Davis
Keyword(s):  
Platelet Function ◽  
Ache Activity ◽  
Room Temperature ◽  
Platelet Rich Plasma ◽  
Complete Inhibition ◽  
Clot Retraction ◽  
Plasma Clot ◽  
Normal Platelet ◽  
Aggregation Factor

SummaryPlatelet acetylcholinesterase (AChE) activity was measured in gel-filtered platelet preparations. Three different anticholinesteratic agents (eserine, neostigmine, and diiso- propylphosphorofluoridate) at final concentrations of 10 μM caused complete inhibition of AChE activity after 30 min incubation at room temperature with either platelet-rich plasma or gel-filtered platelets. Complete inhibition of platelet AChE had no effect on platelet aggregation, factor-3 availability, and plasma clot retraction. We conclude that platelet membrane AChE activity is not required for normal platelet function as measured by these in vitro parameters.

Abstract 13598: The G-protein BetaGamma Subunits Regulate Platelet Function

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ahmed Alarabi ◽  
Zubair Karim ◽  
Victoria Hinojos ◽  
Patricia A Lozano ◽  
Keziah Hernandez ◽  
...  
Keyword(s):  
G Protein ◽  
Platelet Function ◽  
Thrombus Formation ◽  
Human Platelets ◽  
Inhibitory Effects ◽  
Clot Retraction ◽  
Betagamma Subunits

Platelet activation involves tightly regulated processes to ensure a proper hemostasis response, but when unbalanced, can lead to pathological consequences such as thrombus formation. G-protein coupled receptors (GPCRs) regulate platelet function by interacting with and mediating the response to various physiological agonists. To this end, an essential mediator of GPCR signaling is the G protein Gαβγ heterotrimers, in which the βγ subunits are central players in downstream signaling pathways. While much is known regarding the role of the Gα subunit in platelet function, that of the βγ remains poorly understood. Therefore, we investigated the role of Gβγ subunits in platelet function using a Gβγ (small molecule) inhibitor, namely gallein. We observed that gallein inhibits platelet aggregation and secretion in response to agonist stimulation, in both mouse and human platelets. Furthermore, gallein also exerted inhibitory effects on integrin αIIbβ3 activation and clot retraction. Finally, gallein’s inhibitory effects manifested in vivo , as documented by its ability to modulate physiological hemostasis and delay thrombus formation. Taken together, our findings demonstrate, for the first time, that Gβγ directly regulates GPCR-dependent platelet function, in vitro and in vivo . Moreover, these data highlight Gβγ as a novel therapeutic target for managing thrombotic disorders.

scholarly journals Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Simeng Zhang ◽  
Zhongyan Hua ◽  
Gen Ba ◽  
Ning Xu ◽  
Jianing Miao ◽  
...  
Keyword(s):  
Cell Death ◽  
Synergistic Effects ◽  
Aerobic Glycolysis ◽  
Single Agent ◽  
Molecular Compound ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Atp Production

Abstract Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

Polyvalent immunoglobulin preparations inhibit pneumolysin-induced platelet destruction

2021 ◽  
Author(s):  
Friederike Wiebe ◽  
Stefan Handtke ◽  
Jan Wesche ◽  
Annabel Schnarre ◽  
Raghavendra Palankar ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Platelet Function ◽  
Calcium Release ◽  
Intravenous Immunoglobulins ◽  
Flow Chamber ◽  
Platelet Destruction ◽  
Immunoglobulin Preparations ◽  
Immunoglobulin Preparation ◽  
Polyvalent Immunoglobulin

Platelets play an important role in the development and progression of respiratory distress. Functional platelets are known to seal inflammatory endothelial gaps and loss of platelet function has been shown to result in loss of integrity of pulmonary vessels. This leads to fluid accumulation in the pulmonary interstitium, eventually resulting in respiratory distress. Streptococcus pneumoniae is one of the major pathogens causing community-acquired pneumonia. Previously, we have shown that its major toxin pneumolysin forms pores in platelet membranes and renders them non-functional. In vitro, this process was inhibited by polyvalent intravenous immunoglobulins (IVIG). In this study, we compared the efficacy of a standard intravenous immunoglobulin preparation (IVIG, 98% IgG; Privigen, CSL Behring, USA) and an IgM/IgA-enriched immunoglobulin preparation (21% IgA, 23% IgM, 56% IgG; trimodulin, Biotest AG, Germany) to inhibit pneumolysin-induced platelet destruction. Platelet destruction and functionality were assessed by flow cytometry, intracellular calcium release, aggregometry, platelet viability, transwell, and flow chamber assays. Overall, both immunoglobulin preparations efficiently inhibited pneumolysin-induced platelet destruction. The capacity to antagonize pneumolysin mainly depended on the final IgG content. As both polyvalent immunoglobulin preparations efficiently prevent pneumolysin-induced platelet destruction and maintain platelet function in vitro, they represent promising candidates for clinical studies on supportive treatment of pneumococcal pneumonia to reduce progression of respiratory distress.

Effect of Lidoflazine (R 7904) on Human Platelet Function in Vitro

1972 ◽  
Vol 28 (02) ◽  
pp. 228-236 ◽  
Author(s):  
F De Clerck
Keyword(s):  
Platelet Function ◽  
Mode Of Action ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Serotonin Release ◽  
Clot Retraction ◽  
Plasma Coagulation ◽  
Release Reaction ◽  
Platelet Release

SummaryThe effect of lidoflazine and of cinnarizine on human platelet function in vitro was compared to that of dipyridamole.Pre-incubation for 30 min at 37° C of platelet rich plasma with lidoflazine or with dipyridamole 5 ×10–4 M resulted in an appreciable inhibition of collagen aggregation in particular and to a lesser extent of ADP aggregation; cinnarizine was marginally active only.Clot retraction was inhibited by lidoflazine and by dipyridamole. Experiments on biphasic ADP aggregation and C14-serotonin release during aggregation show that lidoflazine reduces the platelet release reaction.The possible mode of action of the compound is discussed.Plasma coagulation and PF – 3 availability were not affected.

scholarly journals Point-of-care platelet function tests: relevance to arterial thrombosis and opportunities for improvement

2020 ◽  
Author(s):  
Diana A. Gorog ◽  
Richard C. Becker
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Arterial Thrombosis ◽  
Point Of Care ◽  
Laboratory Research ◽  
Platelet Function Tests ◽  
Function Tests ◽  
Antiplatelet Medication ◽  
Platelet Aggregometry

Abstract Studies using whole blood platelet aggregometry as a laboratory research tool, provided important insights into the mechanism and modulators of platelet aggregation. Subsequently, a number of point-of-care (POC) platelet function tests (PFTs) were developed for clinical use, based on the concept that an individual’s thrombotic profile could be assessed in vitro by assessing the response to stimulation of platelet aggregation by specific, usually solo agonists such as adenosine diphosphate (ADP), collagen and thrombin. However, adjusting antiplatelet medication in order to improve the results of such POC PFTs has not translated into a meaningful reduction in cardiovascular events, which may be attributable to important differences between the POC PFT techniques and in vivo conditions, including patient-to-patient variability. Important limitations of most tests include the use of citrate-anticoagulated blood. Citrate directly and irreversibly diminishes platelet function and even after recalcification, it may result in altered platelet aggregation in response to ADP, epinephrine or collagen, and interfere with thrombin generation from activated platelets. Furthermore, most tests do not employ flowing blood and therefore do not assess the effect of high shear forces on platelets that initiate, propagate and stabilize arterial thrombi. Finally, the effect of endogenous thrombolysis, due to fibrinolysis and dislodgement, which ultimately determines the outcome of a thrombotic stimulus, is mostly not assessed. In order to accurately reflect an individual’s predisposition to arterial thrombosis, future tests of thrombotic status which overcome these limitations should be used, to improve cardiovascular risk prediction and to guide pharmacotherapy.

scholarly journals MicroRNA-16-1-3p Represses Breast Tumor Growth and Metastasis by Inhibiting PGK1-Mediated Warburg Effect

2020 ◽  
Vol 8 ◽  
Author(s):  
Tianxin Ye ◽  
Yingchun Liang ◽  
Deyu Zhang ◽  
Xuewu Zhang
Keyword(s):  
Breast Cancer ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Phosphoglycerate Kinase ◽  
Glycolytic Enzyme ◽  
Breast Cancer Patients ◽  
Atp Production ◽  
Glycolysis Pathway

The Warburg effect (aerobic glycolysis) is a hallmark of cancer and is becoming a promising target for diagnosis and therapy. Phosphoglycerate kinase 1 (PGK1) is the first adenosine triphosphate (ATP)-generating glycolytic enzyme in the aerobic glycolysis pathway and plays an important role in cancer development and progression. However, how microRNAs (miRNAs) regulate PGK1-mediated aerobic glycolysis remains unknown. Here, we show that miR-16-1-3p inhibits PGK1 expression by directly targeting its 3′-untranslated region. Through inhibition of PGK1, miR-16-1-3p suppressed aerobic glycolysis by decreasing glucose uptake, lactate and ATP production, and extracellular acidification rate, and increasing oxygen consumption rate in breast cancer cells. Aerobic glycolysis regulated by the miR-16-1-3p/PGK1 axis is critical for modulating breast cancer cell proliferation, migration, invasion and metastasis in vitro and in vivo. In breast cancer patients, miR-16-1-3p expression is negatively correlated with PGK1 expression and breast cancer lung metastasis. Our findings provide clues regarding the role of miR-16-1-3p as a tumor suppressor in breast cancer through PGK1 suppression. Targeting PGK1 through miR-16-1-3p could be a promising strategy for breast cancer therapy.

scholarly journals Effect of propranolol on platelet function

Blood ◽  
1977 ◽  
Vol 49 (2) ◽  
pp. 185-196 ◽  
Author(s):  
BB Weksler ◽  
M Gillick ◽  
J Pink
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Direct Action ◽  
Blood Platelets ◽  
Adenosine Diphosphate ◽  
Ionophore A23187 ◽  
Atherosclerotic Vascular Disease ◽  
Clot Retraction

Abstract Excessive reactivity of blood platelets may contribute to atherosclerotic vascular disease. Hence drugs which alter platelet function may be protective. Prompted by findings that propranolol therapy normalized hyperactive platelet aggregation in patients with coronary artery disease, we studied propranolol in vitro to assess its action on platelets. At concentrations similar to those achieved in vivo (0.1–1 muM), propranolol raised the thresholds for aggregation of some normal paltelets by adenosine diphosphate (ADP). At higher concentrations (10-50 muM), propranolol abolished the second wave of platelet aggregation induced by ADP and epinephrine, and inhibited aggregation induced by collagen, thrombin, and the ionophore A23187. Propanolol blocked the release of 14C-serotonin from platelets, inhibited platelet adhesion to collagen, and interfered with clot retraction. Propranolol blocked ionophore-induced uptake of 45Ca by platelets. Inhibition appeared unrelated to beta-adrenergic blockage, as d(+) propranolol (which lacks beta-blocking activity) was equipotent with 1(-) propranolol. Moreover, practolol, a beta-blockading drug which is nonlipophilic, did not inhibit platelet function. These studies suggested that propranolol, like local anesthetics, decreased platelet responsiveness by a direct action on the platelet membrane, possibly by interfering with calcium availability. Modulation of platelet function by propranolol may occur at concentrations achieved at usual clinical doses of the drug.

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