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B F Becker

Publications and source records attributed to B F Becker.

At least 73 records · Page 4Linked to original sources
PubMed1994

CEO summit. The new delivery & financing realities. Part III of III.

In cooperation with McManis Associates Inc., Washington, Hospitals & Health Networks recently convened a summit on the integration of financing and delivery in health care. This installment is the third of a three-part series on lessons learned by those on the front lines of integration activity. The session was designed and facilitated by senior associates at McManis. Among the issues summit participants discussed in the second segment: What level of understanding do purchasers have of the factors that differentiate quality in health care services? Can provider-driven integrated delivery systems compete with insurer-driven ones? And what happens when a large integrated delivery system merges with a dominant insurer, as happened in the Philadelphia market? Can that model be successfully replicated in other markets? In this final segment, participants talk about whether providers' deep connections to their communities will add value in a reformed delivery system; how incentives might be aligned among all the players in integrated networks and organizations; how the concept of community focus might be redefined under systems integration; and the process involved in preparing for constant, accelerated change. The second segment concluded with comments about the assets providers and insurers bring to integrated health systems, and whether the merger experience of Graduate Health System and QCC/Independence Blue Cross could be replicated in other markets or not.

Community-Institutional Relations↗
PubMed1994

CEO summit. The new delivery & financing realities. Part II of III.

In cooperation with McManis Associates Inc., Hospitals & Health Networks recently convened a summit on the integration of financing and delivery in health care. This is the second of a three-part series on lessons learned by those on the front lines of integration activity. The session was designed and facilitated by senior associates at McManis. Among the issues discussed in this second segment. What level of understanding do purchasers have of quality differentiators in health care services? Can provider-driven integrated delivery systems compete with insurer-driven ones? And what happens when, as in the Philadelphia market, a large integrated delivery system merges with a dominant insurer? Can that model be replicated in other markets?

Comprehensive Health Care↗
PubMed1994

CEO summit. The new delivery & financing realities. Part I of III.

In cooperation with McManis Associates Inc., Hospitals & Health Networks recently convened a summit on the integration of financing and delivery of health care. This report is the first of a three-part series on lessons learned by those on the front lines of integration activity. The session was designed and facilitated by senior associates at McManis. Among the issues discussed in this first segment: Is integration necessary to satisfy the demands of health care payers? Is integration the way to cost-containment? How can costs be squeezed out of the system? What relationship will physicians have to hospitals and insurers in integrated systems?

Chief Executive Officers, Hospital↗
PubMed1994

Correlation between vascular and cellular responses to atrial natriuretic peptide and to sodium nitroprusside.

Atrial natriuretic peptide (ANP) and sodium nitroprusside (SNP) increase cGMP in vascular smooth muscle cells and act as vasodilators in some, but not all, blood vessels. In this present study, we attempted to correlate the ability of these two agents to dilate blood vessels with the ability to increase cGMP in cultured vascular smooth muscle cells. In the isolated guinea pig heart, SNP dose-dependently increased coronary flow while ANP was ineffective. In smooth muscle cells cultured from the coronary system, SNP increased intracellular cGMP in a dose-dependent manner while ANP had no effect on cGMP in these cells. In isolated guinea-pig thoracic aorta, precontracted with K+, both ANP and SNP produced relaxation and ANP was the more potent. In smooth muscle cells cultured from the aorta, ANP and SNP increased cGMP and the potency relationship was similar to the intact vessel. These results support the view that phenotypic properties of vascular smooth muscle cells can account for differences in the response of blood vessels to vasodilators.

Analysis of Variance↗
PubMed1994

Stimulation of endothelial adenosine A1 receptors enhances adhesion of neutrophils in the intact guinea pig coronary system.

OBJECTIVE: The primary aim was to determine the action of pathophysiologically relevant adenosine concentrations (0.1-1 microM) on adhesion of neutrophils to coronary endothelium. Further aims were to evaluate the nature and localisation of the adenosine receptor involved, and to assess the effect of endogenous adenosine. METHODS: Adhesion was studied in isolated perfused guinea pig hearts by determining the number of cells emerging in the coronary effluent after intracoronary bolus injections of 600,000 neutrophils prepared from guinea pig or human blood. The system was characterised by the use of the proadhesive stimulus thrombin. RESULTS: A 5 min infusion of adenosine (0.1-0.3 microM) or the A1 receptor agonist N6-cyclopentyladenosine (CPA, 0.01 microM) significantly increased adhesion from about 20% (control) to 30%. This effect was prevented by the A1 receptor antagonist dipropyl-8-cyclopentylxanthine (DPCPX, 0.1 microM). It was not diminished by cessation of adenosine infusion 90 s prior to neutrophil injection. At a higher concentration of adenosine (1 microM), adhesion did not seem to be enhanced. However, coinfusion of the A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX, 0.1 microM) with 1 microM adenosine unmasked the A1 action, adhesion rising to 39%. Adenosine had a quantitatively identical effect on adhesion of human neutrophils. Total ischaemia of 15 min duration raised adhesion of subsequently applied neutrophils to 35%. This effect was completely blocked by DPCPX, as well as by ischaemic preconditioning (3 x 3 min). Preconditioning raised initial postischaemic coronary effluent adenosine from about 0.8 microM to 1.5 microM. CONCLUSIONS: The findings suggest a bimodal participation of adenosine in the development of postischaemic dysfunction by an endothelium dependent modulation of neutrophil adhesion. Stimulation occurs via endothelial A1 receptors at submicromolar adenosine levels, whereas cardioprotection by adenosine may in part relate to the use of pharmacologically high concentrations of adenosine or enhanced endogenous production after preconditioning.

Adenosine↗
PubMed1994

Bradykinin accounts for improved postischemic function and decreased glutathione release of guinea pig heart treated with the angiotensin-converting enzyme inhibitor ramiprilat.

We investigated the role of bradykinin (BK) in cardioprotection elicited by angiotensin-converting enzyme (ACE) inhibition is isolated guinea pig heart performing pressure-volume work. Cardiac output (CO), coronary blood flow (CBF), and external heart work (EHW) were determined before and after ischemia and reperfusion (15 min each). Furthermore, the glutathione (GSH) content of hearts and the release of glutathione in coronary venous effluent were measured, as was lactate production. Addition of the ACE-inhibitor ramiprilat (RT) to the perfusate throughout the experiment improved postischemic function significantly (55% recovery of EHW for 25 microM RT vs. 30% for controls). RT was cardioprotective even if only given at onset of reperfusion (50% recovery). BK (0.1 and 1 nM) was similarly beneficial (55 and 76% recovery of EHW, respectively). The BK2-receptor antagonist HOE 140 (10 nM) inhibited the RT effect and attenuated the effect of 1 nM BK. Total CBF during reperfusion, lactate production, intracellular levels of GSH, and release of oxidized GSH (GSSG) did not differ among the groups. In contrast, release of reduced GSH during the first 5 min of reperfusion was considerably influenced by pharmacologic intervention, correlating inversely with postischemic heart function. Coapplication of Hoe 140 prevented the changes in GSH release. Our results demonstrate that BK, formed endogenously in the heart, is responsible for cardioprotection by the ACE inhibitor RT in isolated guinea pig heart and decreases GSH release during reperfusion. The exact mechanisms leading to hemodynamic improvement and metabolic changes by BK remain unclear.

Adenosine Diphosphate↗
PubMed1993

Adenosine contributes to neutrophil-mediated loss of myocardial function in post-ischemic guinea-pig hearts.

Tissue injury associated with myocardial ischemia is assumed to largely result from the toxic effects of active oxygen species generated by accumulated polymorphonuclear leukocytes (PMNs). Recent reports have indicated that adenosine can interfere with the PMN function in vitro. The potential of adenosine to influence PMN-mediated myocardial tissue injury was assessed using a model of ischemia-reperfusion injury developed in the isolated working guinea-pig heart perfused with homologous PMNs. After an initial work phase, hearts were subjected to 30 min low-flow ischemia (1 ml/min) in the absence and presence of PMNs. Work was resumed after 15 min reperfusion in a non-working mode (Langendorff). Adenosine in the coronary effluent reached a maximum of 0.2 microM during low-flow ischemia. Recoveries of external heart work and cardiac output were reduced from about 80% to about 40% by PMNs. Infusion of adenosine deaminase (ADA, 5 U/ml), theophylline (50 microM) or the selective A1-antagonist dipropyl-8-cyclopentylxanthine (0.1 microM) prevented this effect. Furthermore, application of adenosine (0.1 microM) in combination with PMNs also resulted in a loss of pump function, even in the absence of a direct ischemic stimulus. The data indicate that adenosine contributes to post-ischemic, PMN-mediated damage in the isolated working guinea-pig heart model by a receptor-mediated action.

Adenosine↗
PubMed1993

Towards the physiological function of uric acid.

Uric acid, or more correctly (at physiological pH values), its monoanion urate, is traditionally considered to be a metabolically inert end-product of purine metabolism in man, without any physiological value. However, this ubiquitous compound has proven to be a selective antioxidant, capable especially of reaction with hydroxyl radicals and hypochlorous acid, itself being converted to innocuous products (allantoin, allantoate, glyoxylate, urea, oxalate). There is now evidence for such processes not only in vitro and in isolated organs, but also in the human lung in vivo. Urate may also serve as an oxidisable cosubstrate for the enzyme cyclooxygenase. As shown for the coronary system, a major site of production of urate is the microvascular endothelium, and there is generally a net release of urate from the human myocardium in vivo. In isolated organ preparations, urate protects against reperfusion damage induced by activated granulocytes, cells known to produce a variety of radicals and oxidants. Intriguingly, urate prevents oxidative inactivation of endothelial enzymes (cyclooxygenase, angiotensin converting enzyme) and preserves the ability of the endothelium to mediate vascular dilatation in the face of oxidative stress, suggesting a particular relationship between the site of urate formation and the need for a biologically potent radical scavenger and antioxidant.

Animals↗
PubMed1993

[Interaction of blood and the vascular wall: hemostatic aspects].

The coagulation enzyme thrombin, a serine protease like all other coagulation factors, plays a central role in the hemostatic processes engaged after injurious events. It induces, with particular efficacy, the aggregation of blood platelets (primary hemostasis) and accounts, via splitting of fibrinogen to fibrin, for the event actually responsible for the coagulation of blood (secondary hemostasis). As is well-known, thrombin itself is generated by a cascade of activation events involving various coagulation factors (F). In this respect the "tissue factor" (TF, formerly known as thromboplastin), in combination with F VIIa, attains decisive significance, not only in the extrinsic pathway of coagulation (activation of F X-->Xa), but also in the intrinsic pathway (activation of F IX-->IXa). Under physiological circumstances, platelet aggregation and coagulation are restricted to the area of the vascular lesion, since the surrounding intact endothelium inhibits an intraluminal spreading of both processes. These "antithrombotic" features of the endothelium encompass antiaggregatory mechanisms (formation and release of prostacyclin [PGI2], adenosine, EDRF [NO], degradation of ADP and other nucleotides mediated by ecto-nucleotidases) as well as anti-coagulatory properties (formation and release of "tissue factor pathway inhibitor" [TFPI], which blocks the coagulation cascade by joining F Xa, TF and F VIIa into an inactive complex, thrombomodulin--thrombin induced activation of protein C, which, together with protein S, inactivates F Va and F VIIIa, thereby attenuating further generation of thrombin, and the heparan sulfate-enhanced activation of antithrombin III and heparin-cofactor II).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

[Possible significance of free oxygen radicals for reperfusion injury].

Enhanced formation of radicals during post-ischemic reperfusion, foremost of superoxide (O2-) and hydroxyl (OH) radicals, has been directly and indirectly demonstrated in a number of tissues. However, the close chemical interrelationship of O2- and OH with other non-radical oxidants, such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), makes it prudent to speak of reactive oxygen metabolites in conjunction with cell and organ dysfunction incurred by reperfusion. In the case of the heart, evidence for the causal involvement of such reactive molecular species includes (1) the increased formation of lipid peroxides, (2) the ability to mimic all facets of reperfusion injury (arrhythmias, contractile and vascular dysfunction, infarct extension) by exogenously applying reactive oxygen species, and (3) the propensity of a great variety of antioxidative and radical scavenging measures to afford cardioprotection during reperfusion. Potential sources of reactive oxygen metabolites in the reperfused heart are the mitochondrial redox-chain, endothelial enzymes such as cyclooxygenase, monoaminooxidase, NO-synthase and xanthine oxidase, and formed blood constituents (platelets, monocytes, granulocytes). According to our own results, adenosine, endogenously formed in the heart during ischemia, rapidly enhances adhesion of granulocytes introduced into the coronary system at reperfusion. Furthermore, small numbers of these cells suffice to induce contractile dysfunction in an isolated guinea pig heart model of ischemia-reperfusion injury, the major mediator of damage being HOCl. The striking disparity between the enormous volume of experimental data supporting involvement of reactive oxygen metabolites in reperfusion damage and the virtual lack of clinical-therapeutic regimens employing anti-oxidative measures is largely due to a still rudimentary knowledge of the homeostatic control of formation and removal of radicals and oxidants. In particular, the inability to correctly assess the individual time-course and extent of oxidative stress seems to be a major problem. Also, confounding issues such as compartmentation of radical formation as opposed to radical scavenging and the unwitting down-regulation of endogenous protective systems (e.g., of uric acid in the course of inhibiting xanthine oxidase) need to be resolved. On the other hand, we have been able to demonstrate protection by ACE inhibitors elicited via endothelially produced nitric oxide (a scavenger of O2- and OH) in the isolated heart. Thus, enhancement of endogenous protection may offer a perspective for mitigating against reperfusion damage.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Different endothelial mechanisms involved in coronary responses to known vasodilators.

The role of the endothelium in mediating flow responses to acetylcholine (ACh), bradykinin (BK), adenosine (Ado), and the poorly hydrolyzable ATP-derivative beta,gamma-methylene-ATP (MeATP) was evaluated in the intact coronary system of the isolated perfused guinea pig heart. In the presence of superoxide anions, known to inactivate the endothelium-derived relaxing factor nitric oxide (NO), only steady-state dilatation induced by ACh (1 microM) was fully inhibited and that of BK (0.1 nM) attenuated. Similar effects were obtained with methylene blue and N omega-nitro-L-arginine; however, the latter also reduced the actions of Ado (0.1 microM) and MeATP (0.5 microM). Conversely, perfusion with the NO precursor L-arginine (10 microM) resulted in a potentiated relaxation by ACh, whereas steady-state responses to BK and Ado remained unchanged. Pretreatment of hearts with hydroxyl radicals (.OH) elevated vascular permeability. Under this condition, flow increases induced by ACh, BK, and Ado were enhanced by 130, 89, and 47%, respectively, whereas the effect of MeATP (0.5 microM) was reduced by 45%. Preexposure of hearts to the oxidant hypochlorous acid (HOCl) prevented dilatations by ACh, BK, MeATP and Ado (0.1 microM), and the response to Ado (5 microM) was reduced by 68%; postischemic hyperemia was attenuated. Glyburide, an inhibitor of ATP-sensitive K+ channels, halved the flow response to infused Ado (0.1 and 5 microM), inhibited MeATP, and abolished reactive hyperemia. We conclude that in the guinea pig coronary system ACh, BK, MeATP, and Ado (0.1 microM) induce endothelium-dependent vasodilatation, some step(s) of the signal transmission being vulnerable to oxidative attack by HOCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Difference in effect of atrial natriuretic peptide on cGMP in aortic and coronary smooth muscle cells.

Blood vessels show a heterogeneous response to the atrial natriuretic peptide (ANP). In our experiments thoracic aorta from the guinea pig relaxed in response to atriopeptin III (AP; rat ANP-103-126) and to sodium nitroprusside (SNP). In contrast, in perfused guinea pig hearts, AP III produced no change in coronary flow, while SNP increased flow. In smooth muscle cells cultured from the coronary system (CASM) and from the thoracic aorta (TASM), we compared receptor binding and the effects on guanosine 3',5'-cyclic monophosphate (cGMP) production of AP III. AP III bound specifically with equal affinity and with equivalent numbers of binding sites in both cell types. AP III produced a dose-dependent increase in cGMP in TASM (50% effective concentration approximately 3 nM) with a maximum 11-fold increase over basal at 1 microM AP III. In contrast, in CASM, AP III failed to increase cGMP. Nitroprusside increased cGMP in both cell types. Autoradiograms of 125I-labeled AP III linked to cell membranes showed bands at 70 kDa (ANP-C receptor) in both cell types. A second band at 140 kDa (ANP-B receptor) was only seen in TASM. These results suggest that smooth muscle cells of coronary resistance vessels of the guinea pig do not express the particulate guanylyl cyclase that is activated by ANP.

Animals↗
PubMed1991

[Are the radical scavenging properties of ACE inhibitors with sulfhydryl groups in therapeutically effective concentrations of quantitative significance?].

The chemiluminescence reaction elicited from luminol in the presence of hydroxyl radicals was concentration-dependently suppressed by captopril, indicating efficacious radical scavenging. As to be expected, ACE inhibitors lacking free sulfhydryl groups (ramipril, enalapril) were inactive. However, the endogenous scavenger and anti-oxidant uric acid proved to be far superior to captopril, when concentrations of both were compared that are realized in vivo. A substantial augmentation of endogenous scavenging ability during therapy with captopril thus seems unlikely. In a model of standardized myocardial hypoxia (isolated working heart of the guinea pig with 30 min low flow perfusion) captopril, ramiprilat and uric acid equally improved post-hypoxic heart function. There was no cardioprotective action of captopril in excess of that accountable for by inhibition of ACE. It seems possible that ACE (kininase II) inhibitors exert cardioprotection via elevated tissue levels of kinins: bradykinin also improved heart performance after low flow perfusion and bradykinin-induced coronary dilatation was markedly enhanced in the presence of ramiprilate, reflecting attenuated degradation by endothelial kininase II.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Antibodies to ADP-ATP carrier--an autoantigen in myocarditis and dilated cardiomyopathy--impair cardiac function.

The adenosine diphosphate (ADP)-adenosine triphosphate (ATP) carrier of the inner mitochondrial membrane is identified as an autoantigen in myocarditis and dilated cardiomyopathy. Sera of patients with these diseases contain autoantibodies to the ADP-ATP carrier capable of inhibiting nucleotide transport in vitro. Recently, an antibody-related infringement of energy metabolism was shown in intact perfused hearts isolated from guinea pigs immunized with the ADP-ATP carrier. A decreased cytosolic-mitochondrial difference of the phosphorylation potential of ATP was measured that originated from a reduction in mitochondrial-cytosolic nucleotide transport. Nonimmunized animals did not show these changes in energy metabolism, despite being in a comparable metabolic state and performing equal external heart work. To establish whether antibodies to the ADP-ATP carrier can also alter cardiac function, hemodynamic parameters of isolated hearts of guinea pigs that were preimmunized with the carrier protein were measured. Cardiac metabolism was stimulated by exposing the hearts to a high calcium concentration in conjunction with a maximum elevation of the afterload. Mean aortic pressure, stroke volume, stroke work, and external heart work were found to be lowered significantly (p less than 0.005). The external heart work of the immunized hearts reached only about 20% of the level performed by control hearts. Myocardial oxygen consumption was lowered 2.5-fold, whereas the extent of lactate production was found to be more than doubled. These results show a diminished cardiac performance of hearts from animals immunized with the ADP-ATP carrier. Our findings demonstrate that autoimmunity to the ADP-ATP carrier may contribute to the pathophysiology of dilated cardiomyopathy as a subsequent stage of myocarditis by causing an autoantibody-mediated reduction in cardiac function on the basis of an imbalance between energy delivery and demand.

Animals↗
PubMed1989

Uric acid as radical scavenger and antioxidant in the heart.

Uric acid (UA) is released from the heart of many species, including man, and its site of formation has been shown to be the microvascular endothelium. Since UA reacts with oxygen radicals in vitro, experiments were conducted on guinea pig hearts perfused with Krebs-Henseleit buffer (KHB) to evaluate whether the formation of UA could afford protection from damage by radicals and oxidants. The following results were obtained: (1) Upon addition of the hydroxyl radical scavenger DMSO to the perfusate, the coronary rate of release of endogenous uric acid was increased relative to the precursor purines. (2) UA was degraded during passage through the coronary system and also in KHB in vitro after addition of substances generating hydroxyl radicals or hypochlorite. Superoxide (O2-) radicals did not seem to react directly with UA, though UA concentration-dependently quenched the chemiluminescence generated from luminol in the presence of O2- and OH radicals. (3) Coronary dilation by acetylcholine (Ach) and sub-microM concentrations of adenosine, induced by both via endothelial mechanisms, was attenuated after prolonged inhibition of endothelial UA formation by allopurinol. Furthermore, the effect of Ach but not of adenosine proved acutely sensitive to methylene blue and O2-, substances known to inactivate EDRF. This finding suggests involvement of EDRF in Ach-mediated, but not in adenosine-induced dilatation of the intact coronary system. Exogenously applied UA prevented the impairment of vascular responses to Ach and adenosine caused by allopurinol, and to Ach upon generation of O2-. (4) Hearts performed more pressure-volume work and exhibited greater functional stability when perfused with KHB supplemented with UA in a physiological concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Effects of chronic treatment with adrenaline or propranolol on platelet function and c-AMP levels in the rat.

Most of our knowledge about the modulation of platelet function by catecholamines is based on observations of acute in vitro actions. Little is known about the effects of chronically elevated or reduced adrenergic stimulation of the platelets. We therefore treated rats for 8 weeks with either adrenaline or the beta-blocker propranolol. Adrenaline (0.5 mg.kg-1.d-1) continuously administered from subcutaneously implanted osmotic mini pumps caused an increase in the sensitivity of the platelets towards ADP as stimulating agent. In contrast, chronic application of propranolol (10 mg.kg-1.d-1) via the drinking water led to a reduction in platelet aggregability. For animals treated with adrenaline, in accordance with the results of the aggregation experiments, the levels of c-AMP found in platelet rich plasma were reduced, both basally (by 33%) and after stimulation of platelet adenylate cyclase with prostaglandin E1 (by 39%). For the propranolol treated animals, the basal c-AMP concentrations remained unchanged. The levels of c-AMP attained after stimulation with prostaglandin E1 were diminished to a similar extent as for the adrenaline treated animals (by 38%). Although the in vitro addition of adrenaline to platelet rich plasma causes a beta-adrenoceptor mediated inhibition of platelet aggregation in the rat, the simulation seen after chronic adrenaline exposure in vivo, which is associated with decreases in both basal and stimulated c-AMP levels, suggests a functional preponderance of alpha-adrenoceptors over beta-adrenoceptors on the rat platelets. Although intraplatelet metabolic changes (blockade of stimulated c-AMP formation) after chronic application of propranolol should have resulted in enhancement of platelet aggregability, an inhibition of aggregation was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗