PubMed Health⌕ Search

Biomedical subjects

P Ohlmann

Publications and source records attributed to P Ohlmann.

At least 19 recordsLinked to original sources
PubMed2007

Role of pre-infarction angina and inflammatory status in the extent of microvascular obstruction detected by MRI in myocardial infarction patients treated by PCI.

BACKGROUND/OBJECTIVES: The extent of microvascular obstruction (MVO) during myocardial infarction referred to as the "no-reflow phenomenon", may determine myocardial damage. Our study aimed to investigate the incidence and the influencing factors of MVO in patients with ST-elevation myocardial infarction (STEMI) treated by primary percutaneous intervention (PCI). PATIENTS, METHODS: Using contrast-enhanced MRI, microvascular obstruction was defined as early hypoenhancement. Contrast defects were scored from 0 (no hypoenhancement) to 3 (strong hypoenhancement). 50 patients (56+/-11 years) with STEMI underwent PCI. Contrast-enhanced MRI (6+/-2 days after STEMI) and biochemical parameters were evaluated. RESULTS: Microvascular obstruction (score 1 to 3) was observed in 90% of the patients and major microvascular obstruction (score 2-3) in 54%. In univariate analysis, leukocytes and CRP levels were associated with MVO, whereas pre-infarction angina and prior medication by aspirin or calcium channel antagonist appeared protective. Microvascular obstruction intensity positively correlated with baseline inflammation status assessed by C-reactive protein and leukocytes (rho=0.43 and rho=0.44; p=0.003), the peak of CK (rho=0.56; p=0.01) or Troponin I (rho=0.59; p=0.01) and negatively correlated with LVEF (rho=-0.44; p=0.002). Multivariate analysis identified the absence of pre-infarction angina as the only independent predictor for microvascular obstruction (odds ratio, 8.35, 95% confidence interval 1.27-54.71; p=0.027). CONCLUSION: MRI-detected microvascular obstruction has a high incidence in patients with STEMI treated by primary PCI and determines post-MI LVEF even in patients with post PCI TIMI 3 flow score. Pre-infarction angina appears to be an independent determinant of the extent of MVO detected by MRI.

Adult↗
PubMed2006

Inhibition of adhesive and signaling functions of the platelet GPIb-V-IX complex by a cell penetrating GPIbalpha peptide.

BACKGROUND: Interaction between the platelet glycoprotein (GP)Ib-V-IX complex and von Willebrand factor (VWF) is critical for initiating platelet-vessel wall contacts, particularly under high shear conditions. This interaction also plays an important role in initiating platelet activation through the generation of intracellular signals resulting in platelet shape change and integrin alpha(IIb)beta3 activation. OBJECTIVE: A cell-penetrating peptide strategy was used to study the role of the intracellular domain of the GPIbalpha subunit in VWF/GPIb-V-IX-dependent adhesion and activation. METHODS: Peptides of 11-13 amino acids, covering the 557-610 region, were coupled to a nine-arginine permeating tag (R9) and the effects of their cell entry on VWF-dependent responses were analyzed. RESULTS: The R9alpha557 peptide corresponding to the 557-569 segment reduced platelet agglutination in response to VWF, while the other peptides had no effect. The decreased platelet agglutination appeared to be an indirect consequence of adenosine diphosphate release as a normal response was restored by apyrase or a P2Y1 receptor antagonist. A more direct effect of R9alpha557 on GPIb VWF-dependent functions was observed in adhesion studies on a VWF matrix, where it decreased platelet adhesion and profoundly inhibited filopodia formation. In addition, cell adhesion was reduced and shape change absent when Chinese hamster ovary cells expressing the GPIb-IX complex were incubated with R9alpha557. CONCLUSION: This study performed in intact platelets suggests a functional role of the 557-569 domain of GPIbalpha in controlling VWF-dependent adhesion and signaling.

Adenosine Diphosphate↗
PubMed2005

[Variable extent of platelet responsiveness to clopidogrel inhibition: "clopidogrel resistance"?].

During percutaneous coronary angioplasty, platelet inhibition by clopidogrel and aspirin has drastically decreased the risk of thrombotic occlusion of the stented vessels. However, despite the widespread use of these drugs, the incidence of acute or subacute stent thrombosis remains elevated, concerning 1 to 2% of the treated patients. Considerable differences in the responsiveness to clopidogrel could be observed, suggesting a possible underlying biological resistance. "Clopidogrel resistance" has recently been associated to an increased risk of thrombotic events following coronary angioplasty. Variations in enteric absorption, biotransformation in the liver by the CYP3A4, changes in the ADP receptor P2Y12, abnomalies of intraplatelet signal transduction, extent of platelet activation, class angina, diabetes mellitus may account for the considerable interindividual response variability widely reported. In this view, laboratory tests evaluating "clopidogrel resistance" might be useful tools for the identification and follow-up of patients at higher thrombotic risk. Indeed, in these patients, further platelet inhibition can be achieved by higher doses of clopidogrel.

Angioplasty, Balloon↗
PubMed2005

[Microparticles and cardiovascular disease].

Microparticles are membrane fragments liberated by activated or apoptopic cells. Thought for a long time to be cellular debris with no specific biologic function, in the vascular compartment they are a circulating reservoir of cellular effectors involved in thrombosis, inflammation, vascular remodelling and angiogenesis. High concentrations of circulating procoagulating microparticles found in many cardiovascular diseases indicate the importance of platelet, endothelial and monocytic activation and could contribute to the persistence of atherothrombotic disease. Pharmacological modulation of circulating microparticle concentrations could become a major therapeutic target in the future.

Blood Coagulation↗
PubMed2004

The P2Y1 receptor plays an essential role in the platelet shape change induced by collagen when TxA2 formation is prevented.

ADP and TxA2 are secondary agonists which play an important role as cofactors when platelets are activated by agonists such as collagen or thrombin. The aim of the present study was to characterize the role of the ADP receptor P2Y(1) in collagen-induced activation of washed platelets. Inhibition of P2Y(1) alone with the selective antagonist MRS2179 prolonged the lag phase preceding aggregation in response to low or high concentrations of fibrillar collagen, without affecting the maximum amplitude of aggregation or secretion. A combination of MRS2179 and aspirin resulted in complete inhibition of platelet shape change at low and high collagen concentrations, together with a profound decrease in aggregation and secretion. Scanning electron microscopy showed that these platelets had conserved the discoid morphology typical of the resting state. A lack of shape change was also observed in aspirin-treated P2Y(1)- and G(alphaq)-deficient mouse platelets and in delta-storage pool-deficient platelets from Fawn Hooded rats. In contrast, when the second ADP receptor P2Y(12) was inhibited with AR-C69931MX, aspirin-treated platelets were still able to change shape and displayed only a moderate decrease in aggregation and secretion. In conclusion, this study provides evidence that collagen requires not only the TxA2 receptor Tpalpha, but also P2Y(1), to induce platelet shape change.

Adenosine Diphosphate↗
PubMed2003

A PLC gamma 2-independent platelet collagen aggregation requiring functional association of GPVI and integrin alpha2beta1.

The role of the phospholipase C (PLC)gamma 2 isotype in platelet activation was evaluated by studying PLC gamma 2 -/- mice. These mice have a prolonged bleeding time but their platelets respond normally to non-collagenous agonists. PLC gamma 2-null platelets show residual aggregation response to collagen fibres (6% versus 74% for wild-type) with minimal granule secretion and no shape change. A delayed shape change is observed at later aggregation times. Specific activation by glycoprotein (GP)VI agonists (convulxin, collagen-related peptide and GPVI crosslinking) is, however, abolished. Antibodies against integrin alpha(2)beta(1) and GPVI each inhibit the residual collagen response, implying a role of alpha(2)beta(1) in platelet activation and a functional association with GPVI. These responses are also prevented by blocking integrin alpha(IIb)beta(3) and phosphoinositide 3-kinase, whereas aspirin treatment and ADP receptor blockade only inhibit shape change. These results provide evidence for a PLC gamma 2-independent collagen activation pathway requiring cooperation between GPVI and alpha(2)beta(1) leading to alpha(IIb)beta(3)-dependent aggregation and shape change by released ADP and thromboxane A(2).

Animals↗
PubMed2002

[Heart failure and vasopeptidase inhibitors].

The morbidity and mortality of cardiac insufficiency remains such that it justifies the pursuit of finding new drugs and new sensitive techniques to slow or abolish its evolution. Bringing the vasopeptidases, such as omapatrilat, up to date results in a rational process aimed at simultaneously modulating certain interactive humoral systems. They represent drugs which simultaneously inhibit neutral endopeptidase and angiotensin converting enzyme with the effect of potentiating the natiuretic peptide system and bradykinin, and blocking the conversion of angiotensin I and angiotensin II. In the IMPRESS study, omapatrilat has been evaluated in patients with cardiac insufficiency versus lisinopril; there was no significant difference on the principal outcome measure which was exercise tolerance, however it was significantly more effective than lisinopril on the outcome measure combining death and hospital admission for deteriorating cardiac insufficiency. A wider study is underway, the OVERTURE study, which is evaluating omapatrilat versus enalapril on hospital admission and all-cause mortality. The Vanlev dossier has not yet been submitted to the regulatory authorities for obtaining its authorisation to be put on the market.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

The P2Y(12) receptor induces platelet aggregation through weak activation of the alpha(IIb)beta(3) integrin--a phosphoinositide 3-kinase-dependent mechanism.

High concentrations of adenosine-5'-diphosphate ADP are able to induce partial aggregation without shape change of P2Y(1) receptor-deficient mouse platelets through activation of the P2Y(12) receptor. In the present work we studied the transduction pathways selectively involved in this phenomenon. Flow cytometric analyses using R-phycoerythrin-conjugated JON/A antibody (JON/A-PE), an antibody which recognizes activated mouse alpha(IIb)beta(3) integrin, revealed a low level activation of alpha(IIb)beta(3) in P2Y(1) receptor-deficient platelets in response to 100 microM ADP or 1 microM 2MeS-ADP. Adrenaline induced no such activation but strongly potentiated the effect of ADP in a dose-dependent manner. Global phosphorylation of (32)P-labeled platelets showed that P2Y(12)-mediated aggregation was not accompanied by an increase in the phosphorylation of myosin light chain (P(20)) or pleckstrin (P(47)) and was not affected by the protein kinase C (PKC) inhibitor staurosporine. On the other hand, two unrelated phosphoinositide 3-kinase inhibitors, wortmannin and LY294002, inhibited this aggregation. Our results indicate that (i) the P2Y(12) receptor is able to trigger a P2Y(1) receptor-independent inside-out signal leading to alpha(IIb)beta(3) integrin activation and platelet aggregation, (ii) ADP and adrenaline use different signaling pathways which synergize to activate the alpha(IIb)beta(3) integrin, and (iii) the transduction pathway triggered by the P2Y(12) receptor is independent of PKC but dependent on phosphoinositide 3-kinase.

Androstadienes↗
PubMed2001

Evidence for cross-talk between glycoprotein VI and Gi-coupled receptors during collagen-induced platelet aggregation.

Collagen-induced platelet aggregation is a complex process and involves synergistic action of integrins, immunoglobulin (Ig)-like receptors, G-protein-coupled receptors and their ligands, most importantly collagen itself, thromboxane A(2) (TXA(2)), and adenosine diphosphate (ADP). The precise role of each of these receptor systems in the overall processes of activation and aggregation, however, is still poorly defined. Among the collagen receptors expressed on platelets, glycoprotein (GP) VI has been identified to play a crucial role in collagen-induced activation. GPVI is associated with the FcRgamma chain, which serves as the signal transducing unit of the receptor complex. It is well known that clustering of GPVI by highly specific agonists results in platelet activation and irreversible aggregation, but it is unclear whether collagen has the same effect on the receptor. This study shows that platelets from Galphaq-deficient mice, despite their severely impaired response to collagen, normally aggregate on clustering of GPVI, suggesting this not to be the principal mechanism by which collagen activates platelets. On the other hand, dimerization of GPVI by a monoclonal antibody (JAQ1), which by itself did not induce aggregation, provided a sufficient stimulus to potentiate platelet responses to Gi-coupled, but not Gq-coupled, agonists. The combination of JAQ1 and adrenaline or ADP, but not serotonin, resulted in alpha(IIb)beta(3)-dependent aggregation that occurred without intracellular calcium mobilization and shape change in the absence of Galphaq or the P2Y(1) receptor. Together, these results provide evidence for a cross-talk between (dimerized) GPVI and Gi-coupled receptors during collagen-induced platelet aggregation. (Blood. 2001;97:3829-3835)

Animals↗
PubMed2001

Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice.

Coronary artery thrombosis is often initiated by abrupt disruption of the atherosclerotic plaque and activation of platelets on the subendothelial layers in the disrupted plaque. The extracellular matrix protein collagen is the most thrombogenic constituent of the subendothelial layer; therefore, a selective inhibition of the collagen activation pathway in platelets may provide strong antithrombotic protection while preserving other platelet functions. Here we demonstrate that treatment of mice with a monoclonal antibody against the activating platelet collagen receptor glycoprotein VI (GPVI; JAQ1) results in specific depletion of the receptor from circulating platelets and abolished responses of these cells to collagen and collagen-related peptides (CRPs). JAQ1-treated mice were completely protected for at least 2 wk against lethal thromboembolism induced by infusion of a mixture of collagen (0.8 mg/kg) and epinephrine (60 microg/ml). The tail bleeding times in JAQ1-treated mice were only moderately increased compared with control mice probably because the treatment did not affect platelet activation by other agonists such as adenosine diphosphate or phorbol myristate acetate. These results suggest that GPVI might become a target for long-term prophylaxis of ischemic cardiovascular diseases and provide the first evidence that it is possible to specifically deplete an activating glycoprotein receptor from circulating platelets in vivo.

Animals↗
PubMed2001

Peripheral microcirculation during pregnancy and in women with pregnancy induced hypertension.

During pregnancy the cardiovascular system undergoes several changes so as to adapt the maternal organism to the strains of pregnancy. These adaptations can assume a pathological development in persons with a previous history of cardiovascular problems. On the other hand the absence of these adaptations may lead to a pathological course of pregnancy. Pregnancy induced hypertension (PIH) may be such a pathological development due to maladaptation. The causes are for the most part unknown. For some time it has been assumed that it is due to microcirculatory disorders. Using periungual capillary microscopy the present study prospectively investigated the changes in peripheral microcirculation during pregnancy focussing on pregnancy induced hypertension. Sixty-seven women with a normal course of pregnancy and 28 women with pregnancy induced hypertension were evaluated. Throughout the prospective study 3 examinations were performed during pregnancy and one during childbed. The women who developed a PIH were registered during the third trimester. Erythrocyte velocity at rest and vascular reagibility of capillaries following a 3 minute ischaemia were evaluated. In the course of pregnancy a significant increase of approximately 30% in erythrocyte velocity could be observed. Interpolation to obtain the best strait line result demonstrates that it is a continuous increase. Erythrocyte velocity returns to normal in the course of 14 weeks post partum. Due to a physiological vasodilatation during pregnancy, vascular reaction to ischaemic stress significantly decreases. During childbed these changes return to normal. Examinations on women with pregnancy induced hypertension not only showed a significant reduction of microcirculation under resting conditions but also a different pattern of reaction to ischaemic stress. Erythrocyte velocity under resting conditions lies 36% below normal values. Furthermore the distinctly shortened hyperaemic period indicates a hightened sensitivity to vasoconstrictive substances in women with PIH. While taking into account the clinical data a positive correlation with the severity of the illness was able to be established.

Adult↗
PubMed2000

ADP induces partial platelet aggregation without shape change and potentiates collagen-induced aggregation in the absence of Galphaq.

Platelets from Galphaq knockout mice are unable to aggregate in response to physiological agonists like adenosine 5'-diphosphate (ADP), thromboxane A(2), thrombin, or collagen, although shape change still occurs in response to all of these agonists except ADP. ADP-induced platelet aggregation results from simultaneous activation of the purinergic P2Y(1) receptor coupled to calcium mobilization and shape change and of a distinct P2 receptor, P2cyc, coupled through Gi to adenylyl cyclase inhibition, which is responsible for completion and amplification of the response. P2cyc could be the molecular target of the antithrombotic drug clopidogrel and the adenosine triphosphate (ATP) analogs AR-C69931MX, AR-C67085, and AR-C66096. The aim of the present study was to determine whether externally added ADP could still act through the Gi pathway in Galphaq-deficient mouse platelets and thereby amplify the residual responses to agonists such as thrombin or collagen. It was found that (1) ADP and adrenaline still inhibited cyclic AMP accumulation in Galphaq-deficient platelets; (2) both agonists restored collagen- but not thrombin-induced aggregation in these platelets; (3) the effects of ADP were selectively inhibited in vitro by the ATP analog AR-C69931MX and ex vivo by clopidogrel and hence were apparently mediated by the P2cyc receptor; and (4) high concentrations of ADP (100 micromol/L) induced aggregation without shape change in Galphaq-deficient platelets through activation of P2cyc. Since adrenaline was not able to induce platelet aggregation even at high concentrations, we conclude that the effects of ADP mediated by P2cyc are not restricted to the inhibition of adenylyl cyclase through Gi(2).

Adenosine Diphosphate↗
PubMed2000

Lipid composition of erythrocytes and thrombocytes of a subantarctic seabird, the king penguin.

Phospholipid (PL) compositions and fatty acid (FA) patterns of PL were determined in the erythrocytes and blood thrombocytes of a seabird, the king penguin, living in the subantarctic area and feeding on prey rich in n-3 polyunsaturated FA. Results were compared between birds in three different physiological states (breeding and molting adults, chicks) to those reported for other birds. In erythrocytes, the ratios of cholesterol to PL and of sphingomyelin to phosphatidylcholine (PC) were lower than in other birds. The PL distribution was similar to those previously reported in the hen and pigeon. In contrast to other birds, cardiolipin levels were unexpectedly high (4%). Very long chain n-3 FA were abundant (13-27%) in phosphatidylethanolamine (PE), phosphatidylserine and PC, probably in relation to the natural diet of these birds. Among n-3 FA, 22:6n-3 was the most abundant in all PL (2-20%), whereas the highest levels of arachidonic acid were observed in PE (14%). In thrombocytes, the PL distribution and FA composition of the main PL (PC, PE) differed from those of erythrocytes, and in particular, levels of n-3 FA (9-12%) were 1.5-2 times lower. The highest levels of arachidonic acid were found in phosphatidylinositol (24%). The lipid profile of penguin erythrocytes could contribute to the efficiency of blood circulation and oxygen delivery in microvascular beds, thus favoring diving capacity of these animals. Our observations do not support the hypothesis of a common origin of avian thrombocytes and erythrocytes.

Animals↗
PubMed2000

Lipid composition of blood platelets and erythrocytes of southern elephant seal (Mirounga leonina) and antarctic fur seal (Arctocephalus gazella).

Erythrocyte and blood platelet phospholipid compositions were studied in three elephant seals and two fur seals, two species of marine mammals living in the Subantarctic region feeding on preys rich in (n-3) polyunsaturated fatty acids. Results were compared with those reported for related species and humans. In erythrocytes, the phospholipid (PL) and cholesterol (CHOL) contents were lower in pinnipeds than in humans. Phosphatidylcholine (PC) levels were higher in elephant seals than in fur seals, with a reverse trend for phosphatidylethanolamine (PE) and phosphatidylserine (PS). Both species had lower SM/PC ratios and PE plasmalogen concentrations than human. Erythrocytes were richer in (n-3) fatty acids (FA) in pinnipeds than in humans. In platelets, the PL content was lower and the CHOL content higher in elephant seals than in humans or in other phocid seal species studied to date. The SM/PC ratio was much higher than in other seal species or in man. In both species, the proportion of PE plasmalogens was higher in platelets than in erythrocytes. PL were more saturated in elephant seals than in fur seals. These results suggest that the erythrocytes and platelets of wild marine mammals may prove useful models to study the influence of dietary lipids on the structure and hemostatic function of these cells.

Animals↗
PubMed2000

Involvement of protein kinase C, tyrosine kinases, and Rho kinase in Ca(2+) handling of human small arteries.

The mechanisms of Ca(2+) handling and sensitization were investigated in human small omental arteries exposed to norepinephrine (NE) and to the thromboxane A(2) analog U-46619. Contractions elicited by NE and U-46619 were associated with an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), an increase in Ca(2+)-independent signaling pathways, or an enhancement of the sensitivity of the myofilaments to Ca(2+). The two latter pathways were abolished by protein kinase C (PKC), tyrosine kinase (TK), and Rho-associated protein kinase (ROK) inhibitors. In Ca(2+)-free medium, both NE and U-46619 elicited an increase in tension that was greatly reduced by PKC inhibitors and abolished by caffeine or ryanodine. After depletion of Ca(2+) stores with NE and U-46619 in Ca(2+)-free medium, addition of CaCl(2) in the continuous presence of the agonists produced increases in [Ca(2+)](i) and contractions that were inhibited by nitrendipine and TK inhibitors but not affected by PKC inhibitors. NE and U-46619 induced tyrosine phosphorylation of a 42- or a 58-kDa protein, respectively. These results indicate that the mechanisms leading to contraction elicited by NE and U-46619 in human small omental arteries are composed of Ca(2+) release from ryanodine-sensitive stores, Ca(2+) influx through nitrendipine-sensitive channels, and Ca(2+) sensitization and/or Ca(2+)-independent pathways. They also show that the TK pathway is involved in the tonic contraction associated with Ca(2+) entry, whereas TK, PKC, and ROK mechanisms regulate Ca(2+)-independent signaling pathways or Ca(2+) sensitization.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Induction of nitric oxide synthase and dual effects of nitric oxide and cyclooxygenase products in regulation of arterial contraction in human septic shock.

BACKGROUND: The role of endogenous nitric oxide (NO) and cyclooxygenase metabolites was investigated in contractile responses of small omental arteries from patients with hyperdynamic septic shock. METHODS AND RESULTS: Expression of inducible NO synthase (immunostaining) and a high but variable level of NO production (NO spin trapping) was detected in arteries from patients with septic shock. In these vessels, ex vivo contractile responses to the thromboxane A2 analogue U46619 and to low concentrations of norepinephrine (NE) (up to 10 micromol/L) were not significantly different from controls. However, higher concentrations of NE caused pronounced fading of contraction in septic but not in nonseptic arteries. Exposure to either the NO synthase inhibitor NG-nitro-L-arginine methyl ester or the cyclooxygenase inhibitor indomethacin had no effect in control vessels. However, both inhibitors increased the response to the contractile effects of the 2 agonists only in patients with septic shock. In contrast to NG-nitro-L-arginine methyl ester, which decreased the threshold concentration of the fading effect of NE, indomethacin abolished this effect in arteries from septic patients. CONCLUSIONS: These results provide direct evidence for the induction of NO synthase in small arteries from patients with septic shock. They suggest that in these arteries, increased production of NO, in conjunction with vasodilatory cyclooxygenase metabolites, contributes to counteract hyperreactivity to agonists and decreases the cyclooxygenase product-mediated pronounced fading of contraction caused by a high concentration of NE.

Adult↗
PubMed1999

The kinetics of translocation and cellular quantity of protein kinase C in human leukocytes are modified during spaceflight.

Protein kinase C (PKC) is a family of serine/threonine kinases that play an important role in mediating intracellular signal transduction in eukaryotes. U937 cells were exposed to microgravity during a space shuttle flight and stimulated with a radiolabeled phorbol ester ([3H]PDBu) to both specifically label and activate translocation of PKC from the cytosol to the particulate fraction of the cell. Although significant translocation of PKC occurred at all g levels, the kinetics of translocation in flight were significantly different from those on the ground. In addition, the total quantity of [3H]PDBu binding PKC was increased in flight compared to cells at 1 g on the ground, whereas the quantity in hypergravity (1.4 g) was decreased with respect to 1 g. Similarly, in purified human peripheral blood T cells the quantity of PKCdelta varied in inverse proportion to the g level for some experimental treatments. In addition to these novel findings, the results confirm earlier studies which showed that PKC is sensitive to changes in gravitational acceleration. The mechanisms of cellular gravisensitivity are poorly understood but the demonstrated sensitivity of PKC to this stimulus provides us with a useful means of measuring the effect of altered gravity levels on early cell activation events.

Biological Transport↗