Personalized risk prediction of postoperative cognitive impairment - rationale for the EU-funded BioCog project.

Postoperative cognitive impairment is among the most common medical complications associated with surgical interventions - particularly in elderly patients. In our aging society, it is an urgent medical need to determine preoperative individual risk prediction to allow more accurate cost-benefit decisions prior to elective surgeries. So far, risk prediction is mainly based on clinical parameters. However, these parameters only give a rough estimate of the individual risk. At present, there are no molecular or neuroimaging biomarkers available to improve risk prediction and little is known about the etiology and pathophysiology of this clinical condition. In this short review, we summarize the current state of knowledge and briefly present the recently started BioCog project (Biomarker Development for Postoperative Cognitive Impairment in the Elderly), which is funded by the European Union. It is the goal of this research and development (R&D) project, which involves academic and industry partners throughout Europe, to deliver a multivariate algorithm based on clinical assessments as well as molecular and neuroimaging biomarkers to overcome the currently unsatisfying situation.

[Analysis of cardiovascular diseases after the upload phase with intravitreal ranibizumab and bevacizumab in patients with exudative age-related macular degeneration]. / Analyse kardiovaskulärer Erkrankungen nach der Upload-Phase mit intravitrealem Ranibizumab oder Bevacizumab bei Patienten mit exsudativer altersbedingter Makuladegeneration.

BACKGROUND: The intravitreal administration of vascular endothelial growth factor (VEGF) inhibitors is the gold standard in the treatment of exudative age-related macular degeneration (AMD) but the possible risks of systemic, particularly cardiovascular side effects are still discussed. PATIENTS AND METHODS: We prospectively followed 111 patients at the University Hospital in Göttingen with exudative AMD and intravitreal ocular treatment with bevacizumab and ranibizumab during the upload phase of 3 months using a questionnaire for documentation of possible cardiovascular events. RESULTS: In 5 out of 111 patients angina pectoris was observed and in 6 patients the antihypertensive medication had to be increased. No differences were found between bevacizumab and ranibizumab. A patient with pre-existing cardiovascular diseases suffered a stroke in the upload phase but no thromboembolic events were observed in the other patients. CONCLUSION: In this small but prospective clinical study no increased risk for cardiovascular events during the upload phase of the VEGF inhibitors ranibizumab and bevacizumab could be detected when taking the age and pre-existing cardiovascular diseases into consideration.

Relaxin: a pregnancy hormone as central player of body fluid and circulation homeostasis.

The peptide relaxin has long been regarded as an important hormone of pregnancy, contributing to changes in connective tissue composition as well as to regulation of implantation, myometrial activity and labor. On the other hand, the astonishing pleiotropy of this hormone escaped scientific awareness. This review focuses on new facets of relaxin, including its antifibrotic effects, its role in the control of pituitary hormone release, its vasodilator and pro-angiogenic properties and its versatile myocardial actions. Recent progress in understanding relaxin's receptor and signaling mechanisms is also highlighted. The peptide will be characterized as potential regulator of body fluid and circulation homeostasis.

Cessation of pulmonary and coronary secretion of adrenomedullin peptides in the progression of human heart failure.

In human heart failure (CHF), adrenomedullin (AM) counteracts vasoconstriction and sodium retention. We investigated circulating levels of proadrenomedullin N-20 peptide (PAMP) and AM, and left ventricular expression of preproAM and calcitonin receptor-like receptor (CRLR) mRNA. Peptide levels were determined from the left ventricle, pulmonary artery, coronary sinus, and antecubital vein in patients demonstrating severe CHF (n = 12; mean +/- SEM cardiac index, 1.9 +/- 0.2 l/min/m(2); pulmonary wedge pressure, 32 +/- 1 mmHg), moderate CHF (n = 11; cardiac index, 2.9 +/- 0.2; pulmonary wedge pressure, 14 +/- 2), and in controls (n = 11). Left ventricular mRNA was quantified using RT-PCR and Southern blot hybridization. Depending on sites of measurement, PAMP and AM in severe CHF were 1.3 - 2.0 and 1.2 - 1.9 times as high as in moderate CHF, and 3.8 - 4.6 and 2.3 - 2.8 times as high as in controls. Only patients with moderate CHF demonstrated pulmonary and coronary net release of both peptides, that is, significant step-ups in concentrations between the pulmonary artery, left ventricle, and coronary sinus. In failing ventricles, preproAM mRNA increased 2.9 times above control, but CRLR mRNA was unchanged. Altogether, the heart and the lungs release AM peptides in moderate CHF. This secretion breaks down in severe CHF: a process that may contribute to and indicate decompensation. Unlike AM, the CRLR is not transcriptionally upregulated in severe CHF.

Flow-induced pressure differentially regulates endothelin-1, urotensin II, adrenomedullin, and relaxin in pulmonary vascular endothelium.

We hypothesized that increased pulmonary vascular pressure--one of the characteristics of congestive heart failure--directly regulates pulmonary endothelial vasoconstrictors (endothelin-1, urotensin II) and vasodilators (adrenomedullin, relaxin). To this end, we subjected pulmonary artery endothelial cells in a novel flow-chamber model to different shear stresses (17, 29, and 46 dyn/cm(2)) at low and elevated levels of downstream pressure (10 and 30 mm Hg). Application of elevated pressure over 16 h increased gene expression and peptide secretion of endothelin-1 at all shear levels, whereas secretion of adrenomedullin rose via decreased expression of its clearance receptor. In contrast, preprourotensin II mRNA and urotensin II peptide decreased in response to elevated pressure, and relaxin remained unaffected. This is the first study to identify pressure as key regulator of mediator synthesis by pulmonary vascular endothelium. Pressure-induced mediator regulation may represent an early event in the development of secondary pulmonary hypertension.

The pregnancy hormone relaxin is a player in human heart failure.

Human congestive heart failure is characterized by complex neurohumoral activation associated with the up-regulation of vasoconstricting and salt-retaining mediators and the compensatory rise of counter-regulatory hormones. In the present study, we provide the first evidence that relaxin (RLX), known as a pregnancy hormone, represents a potential compensatory mediator in human heart failure: plasma concentrations of RLX and myocardial expression of the two RLX genes (H1 and H2) correlate with the severity of disease and RLX responds to therapy. The failing human heart is a relevant source of circulating RLX peptides, and myocytes as well as interstitial cells produce RLX. Elevation of ventricular filling pressure up-regulates RLX expression and the hormone acts as a potent inhibitor of endothelin 1, the most powerful vasoconstrictor in heart failure. Furthermore, RLX modulates effects of angiotensin II, another crucial mediator. Our data identify RLX as a new player in human heart failure with potential diagnostic and therapeutic relevance.

Dexamethasone inhibits stimulation of pulmonary endothelins by proinflammatory cytokines: possible involvement of a nuclear factor kappa B dependent mechanism.

OBJECTIVES: Recent studies have indicated effectiveness of glucocorticoid (GC) treatment in late, fibroproliferative adult respiratory distress syndrome. There is furthermore growing evidence for a role of endothelin-1 (ET-1) in lung fibroproliferation, but the impact of GC on stimulated pulmonary ET-1 is not well defined. DESIGN AND SETTING: Prospective study in an experimental laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Isolated lungs were perfused over 120 min in recirculatory mode in presence of vehicle, interleukin-1 beta (IL-1 beta; 5 ng/ml) plus tumor necrosis factor-alpha (TNF-alpha; 5 ng/ml), dexamethasone (Dx; 1 nmol/l), Dx (10 nmol/l), IL-1 beta plus TNF alpha plus Dx 1, or IL-1 beta plus TNF alpha plus Dx 10 (n = 6 each). Pulmonary artery endothelial cells were stimulated over 30 min using a similar protocol. MEASUREMENTS AND RESULTS: Control lungs released 15.2 +/- 0.6 pg/ml big ET-1 and 0.46 +/- 0.06 pg/ml ET-1, and contained 0.73 +/- 0.05 ng/g wet weight (ww) big ET-1 and 3.06 +/- 0.22 ng/g ww ET-1. IL-1 beta plus TNF-alpha increased release of big ET-1 and ET-1, to 220% and 217%, and lung content of peptides, to 236% and 230%. Dx dose-dependently inhibited the cytokine-induced rise in peptide release and lung content and completely suppressed these effects at 10 nmol/l. Electrophoretic mobility shift assays with nuclear extracts of pulmonary artery endothelial cells demonstrated nuclear binding of the transcription factor nuclear factor kappa B in response to IL-1 beta plus TNF-alpha, which was decreased in presence of Dx 1 and Dx 10. CONCLUSIONS: GC inhibit the cytokine-induced upregulation of pulmonary vascular and tissue endothelins, possibly via nuclear factor kappa B dependent mechanisms. This finding may reinforce the therapeutic employment of GC in late ARDS.

Pulmonary adrenomedullin counteracts deterioration of coronary flow and myocardial performance evoked by pulmonary endothelins in experimental acute respiratory distress syndrome.

OBJECTIVES: We recently showed that pulmonary endothelins may affect coronary circulation under various experimental and clinical conditions. Here, we investigated the effect of pulmonary mediators on coronary tone in experimental acute respiratory distress syndrome. We focused particularly on pulmonary endothelin-1, a major vasoconstrictor in acute respiratory distress syndrome, and on adrenomedullin, a potent vasodilator that is up-regulated by inflammatory stimuli. DESIGN: Controlled experiment that used isolated organs. SETTING: Experimental laboratory. SUBJECTS: Wistar rats. INTERVENTIONS: The saline effluent from an isolated lung was used to serially perfuse the coronary vessels of an isolated heart. We compared serial perfusion after 2-hr pretreatment of lungs with vehicle or endotoxin (50 microg/mL), and we used the following drugs to elucidate the coronary response observed: the endothelin type A receptor antagonist BQ-123 (2 microM), the endothelin type B antagonist A-192621 (500 nM), the endothelin-converting enzyme inhibitor phosphoramidon (50 microM), the calcitonin gene-related peptide type-1 receptor antagonist hCGRP(8-37) (2 microM), and the adrenomedullin receptor antagonist hAM(22-52) (200 nM) (n = 6 each). MEASUREMENTS AND MAIN RESULTS: In controls, serial perfusion decreased coronary flow to 87 +/- 3% of baseline (p < .05). BQ-123 and phosphoramidon prevented this effect, whereas blockade of endothelin type B and adrenomedullin-binding receptors had no effect. After endotoxin challenge, coronary flow significantly increased to 110 +/- 2%. This response was augmented by BQ-123 (124 +/- 2%) and phosphoramidon (123 +/- 3%); A-192621 had no effect. Application of hCGRP(8-37) and hAM(22-52) significantly decreased coronary flow to 81 +/- 3% and 88 +/- 2%, respectively. Flow decrease after blockade of both adrenomedullin-binding receptors (73 +/- 2%) significantly deteriorated peak left ventricular pressure, to 82 +/- 6% of baseline; rate of pressure increase, to 81 +/- 5%; and rate of pressure decline, to 77 +/- 6%. Endotoxin pretreatment elevated pulmonary venous big endothelin-1 (three-fold), endothelin-1 (two-fold), and adrenomedullin (five-fold). CONCLUSION: In experimental acute respiratory distress syndrome, pulmonary adrenomedullin--via calcitonin gene-related peptide type-1 receptor and adrenomedullin receptor--outweighs the coronary vasoconstrictor impact of pulmonary big endothelin-1 exerted via endothelin type A receptors after conversion to mature endothelin-1. The consequence is prevention of flow-related deterioration of myocardial performance.

Hyperhomocysteinaemia and adverse events complicating coronary catheter interventions.

BACKGROUND: Since hyperhomocysteinaemia is an independent risk factor for development of atherosclerosis as well as for arterial and venous thrombosis we investigated whether elevated homocysteine levels are associated with procedural excess risk which complicates coronary interventions including coronary angioplasty (PTCA), stenting, or directional coronary atherectomy (DCA). DESIGN: Consecutive cases receiving coronary catheter interventions. SETTING: Tertiary referral centre in Germany. METHODS: Fasting total plasma homocysteine levels (tHcy) were determined in 648 consecutive coronary artery disease patients who underwent catheter interventions (272 PTCA, 102 DCA, and 274 stenting). Hyperhomocysteinaemia was defined as tHcy >/=15 micromol/l. The patients were investigated for a 30-day composite endpoint, including need for target-vessel revascularization, myocardial infarction, and death. RESULTS: Among the 648 patients, 78 (12%) demonstrated elevated tHcy levels. The composite endpoint occurred in 41 patients (6.3%). For the entire intervention group there was no evidence that hyperhomocysteinaemia was associated with excess procedural risk (odds ratio [OR]: 1.27; 95% confidence interval [CI]=0.52 to -3.13; P=0.62). In further analyses according to device, hyperhomocysteinaemia also failed to predict complications in the device related subgroups. CONCLUSION: The results indicate that hyperhomocysteinaemia is not a major risk factor for 30-day adverse events complicating PTCA, DCA, or stenting.

Adrenomedullin and myocardial contractility in the rat.

The effects of adrenomedullin in the regulation of myocardial contractility were investigated in the rat. In papillary muscles (n=6), adrenomedullin (0.1 to 10 nM) failed to show contractile effects. NO (nitric oxide) synthase inhibition with N(G)-nitro-L-arginine (L-NOARG) did not unmask any inotropic effect of adrenomedullin. The positive inotropic effect of isoprenaline (0. 01 nM to 10 microM) was identical after adrenomedullin, after L-NOARG, and after L-NOARG plus adrenomedullin (n=6 each). In field-stimulated rat ventricular myocytes, adrenomedullin (1, 10, and 100 nM; n=4 each) had impact neither on cell shortening nor on Ca(2+) transients. In isolated constant-flow perfused hearts (7.3+/-0.3 ml/min), adrenomedullin (1 nM, n=9; 10 nM, n=7) induced significant coronary vasodilation (-28%, -50%). In conclusion, adrenomedullin is a potent coronary vasodilator, but has no significant effects on myocardial contractility in the rat.

Pulmonary release and coronary and peripheral consumption of big endothelin and endothelin-1 in severe heart failure: acute effects of vasodilator therapy.

BACKGROUND: We investigated plasma endothelin (ET) levels in patients with congestive heart failure (CHF) during treatment for acute decompensation; we also measured imbalances in ET peptides across the pulmonary, coronary, and peripheral circulation. Methods and Results-In patients with severe CHF (n=21; cardiac index [CI], 1.9+/-0.2 L. min(-1). m(-2); pulmonary capillary wedge pressure [PCWP], 31+/-1 mm Hg), vasodilation was achieved with the nitric oxide donor sodium nitroprusside (n=11) or with the alpha(1)-antagonist urapidil (nitric oxide-independent, n=10). ET concentrations were determined from arterial blood and blood from the pulmonary artery, coronary sinus, and antecubital vein. Depending on sites of measurement, baseline big ET and ET-1 levels were, respectively, 12 to 16 times and 5 to 11 times higher than in controls (n=11), and 4 to 6 times and 2 to 3 times higher than in patients with moderate CHF (n=10; CI, 2.7+/-0.3 L. min(-1). m(-2); PCWP, 14+/-2 mm Hg). Patients with severe CHF demonstrated pulmonary net release and coronary and peripheral net consumption of both peptides (ie, arterial levels [big ET, 7.3+/-1.3 pmol/L; ET-1, 1.8+/-0.1 pmol/L] were higher than levels in the pulmonary artery [6.7+/-1.2 pmol/L; 1. 3+/-0.1 pmol/L], coronary sinus [6.4+/-1.0 pmol/L; 1.4+/-0.1 pmol/L], and antecubital vein [6.6+/-1.1 pmol/L; 1.3+/-0.1 pmol/L]). In these patients, sodium nitroprusside (SNP) and urapidil resulted in comparable hemodynamic improvement after 6 hours (CI: SNP, 63+/-2%; urapidil, 72+/-3%; PCWP: SNP, -50+/-2%; urapidil, -47+/-2%) and a maximum decrease in ET peptides by >50%. After 3 hours, pulmonary net release and coronary and peripheral net consumption were no longer detectable. CONCLUSIONS: In patients with severe CHF, the lungs act as a producer and the heart and the periphery act as consumers of elevated circulating ETs. Short-term vasodilator therapy decreases ETs and restores their pulmonary, coronary, and peripheral balance.

Stimulation of pulmonary big endothelin-1 and endothelin-1 by antithrombin III: a rationale for combined application of antithrombin III and endothelin antagonists in sepsis-related acute respiratory distress syndrome?

OBJECTIVES: Antithrombin (AT) III reduces lung damage in animal models of septic acute respiratory distress syndrome (ARDS), which is generally attributed to stimulation of endothelial prostacyclin synthesis. However, clinical studies have failed so far to demonstrate mortality reduction by application of AT III. We investigated whether AT III stimulates pulmonary prostacyclin release. In addition, we hypothesized that it may promote pulmonary endothelins, thereby mitigating its own protective effect in the course of ARDS. DESIGN: Controlled experiment using isolated organs. SETTING: Experimental laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Isolated lungs were perfused over 120 mins in recirculatory mode in the presence of 50 microg/mL endotoxin (n = 11), 2U/mL AT III (n = 10), 5 U/mL AT III (n = 13), endotoxin plus 2 U/mL AT III (n = 5), or vehicle alone (controls, n = 13), respectively. MEASUREMENTS AND MAIN RESULTS: We determined the effects of AT III on vascular release of thromboxane B2, 6-keto-prostaglandin-F1alpha, big endothelin-1, and endothelin-1. Control lungs released 59+/-23 pg/mL thromboxane B2, 1,480+/-364 pg/mL 6-keto-prostaglandin-F1alpha, 15.2+/-4.5 pg/mL big endothelin-1, and 0.46+/-0.13 pg/mL endothelin-1. Exposure to endotoxin increased thromboxane B2 release 2.9-fold, 6-keto-prostaglandin-F1alpha release 1.6-fold, and endothelin-1 1.6-fold (p < .05 each); levels of big endothelin-1 were unchanged. AT III at 2 U/mL elevated production of big endothelin-1 (1.7-fold) and endothelin-1 (1.2-fold) (p < .05 for both). AT III at 5 U/mL enhanced levels of big endothelin-1 (1.6-fold) and endothelin-1 (1.3-fold) (p < .05 for both). Neither dose of AT III affected thromboxane B2 or 6-keto-prostaglandin-F1alpha concentrations. Application of 2 U/mL AT III plus endotoxin stimulated big endothelin-1 production (2.6-fold) compared with endotoxin or AT III alone (p < .05 for both), but did not further elevate endothelin-1 release. CONCLUSIONS: AT III does not stimulate pulmonary prostacyclin, but promotes pulmonary release of big endothelin-1 and endothelin-1 under basal and, particularly, under septic conditions, which may blunt the AT III-induced lung protection during ARDS. Therefore, we suggest combined application of AT III and endothelin antagonists in animal models of septic ARDS.

Antithrombin increases pulmonary endothelins: inhibition by heparin and Ca2+ channel antagonism.

We investigated the mechanism of antithrombin III-induced vascular release of endothelins in rat isolated lung. The antithrombin III-stimulated release of big endothelin-1 and endothelin-1 (1.7-fold and 1.3-fold over baseline) was abolished by nicardipine (L-type Ca2+ channel blocker), heparin, and N-acetyl heparin (a derivative devoid of antithrombin affinity), whereas staurosporine and genistein (inhibitors of protein kinase C and tyrosine kinase, respectively) were ineffective. Thus, (i) the antithrombin III-induced release of endothelins requires extracellular Ca2+, but not protein kinase C or tyrosine kinase activation, and (ii) heparin binding to antithrombin III is not necessary for its inhibitory effect.

Arrhythmogenic effects induced by coronary conversion of pulmonary big endothelin to endothelin: aggravation of this phenomenon in heritable hyperlipidemia.

OBJECTIVES: We investigated whether endogenous pulmonary big endothelin has arrhythmogenic properties under normal conditions and in heritable hyperlipidemia. BACKGROUND: Endothelin (ET), one of the most potent vasoconstrictors, is known to induce ventricular arrhythmias. It is unclear, however, whether its precursor, big endothelin, released from the lung, contributes to arrhythmogenesis. METHODS: In a lung-heart model in which a Langendorff heart is serially perfused with the effluent from the isolated lung of the same animal, we evaluated arrhythmias in control and in Watanabe heritable hyperlipidemic (WHHL) rabbits. RESULTS: In both controls (n=12) and WHHL (n=8), serial perfusion evoked a decrease in coronary flow (controls, -11+/-3%; WHHL, -25+/-6%) and a fourfold increase of ventricular extrasystoles (VES) (controls, 40.7+/-8; WHHL, 40.2+/-5 VES/40 min, p < 0.05). However, WHHL developed more and longer nonsustained ventricular tachycardias (VT) compared with controls (incidence, 1.38+/-1.1 vs. 0.33+/-0.5 VT/40 min, p < 0.05; length, 14.36+/-3.1 vs. 7.25+/-1.5 beats/VT, p < 0.05). Arrhythmias were not ischemia-induced because corresponding mechanical flow reduction had no arrhythmogenic effect (n=6 in controls and WHHL). Although vasoconstriction disappeared entirely, arrhythmias were only partly suppressed by ET(A) antagonists (BQ-123, 2 micromol/liter; A-127722, 20 micromol/liter). The ET-converting enzyme inhibitor phosphoramidon (50 micromol/liter) completely suppressed arrhythmias and vasoconstriction. The ET(B) antagonists (IRL-1038, 4 micromol/liter; IRL-1025, 5 micromol/liter) had no effect (n=6). CONCLUSIONS: Endogenous pulmonary big ET produces arrhythmogenic effects that are aggravated in heritable hyperlipidemia. These effects, requiring coronary conversion of big ET into ET, are partly ET(A)-mediated and ET(B)-independent.

Coronary constriction and consequent cardiodepression in pulmonary embolism are mediated by pulmonary big endothelin and enhanced in early endothelial dysfunction.

OBJECTIVES: Myocardial ischemia plays a central role in the development of right ventricular failure after acute pulmonary embolism. This study investigates whether pulmonary mediators act specifically on coronary tone and cardiac contractile function in acute pulmonary microembolization and whether such effects are altered in the case of early systemic atherosclerosis. We employ a novel model of serial perfusion in which an isolated rabbit heart is perfused with the effluent of the same animal's isolated lung. DESIGN: Controlled experiment using isolated organs. SETTING: Experimental laboratory. SUBJECTS: Male New Zealand White rabbits (controls). Age-matched, male Watanabe rabbits (hypercholesterolemic, development of accelerated atherosclerosis). INTERVENTIONS: Seven isolated control and seven isolated Watanabe hearts were perfused with the saline effluent of the same animal's isolated lung. After the assessment of the baseline data, the lungs were gradually embolized with glass beads measuring 100 microm in diameter to induce an increase in mean pulmonary arterial pressure from 6 to 8 mm Hg, at baseline, up to 25 mm Hg. MEASUREMENTS AND MAIN RESULTS: Pulmonary embolization to 25 mm Hg evoked a coronary constriction, measured as coronary flow decrease to 89 +/- 7% of the baseline value in controls. In the Watanabe group, coronary constriction was significantly enhanced, compared with controls, with coronary flow decreasing to 76 +/- 6% of the baseline value. In both groups, coronary constriction was followed by a deterioration in cardiac contractile performance. This cardiodepression was significantly deeper in Watanabe hearts with respect to both maximum ventricular pressures and maximum rates of pressure development and decline. Coronary constriction and cardiodepression were prevented by coronary infusion of the nonselective endothelin antagonist PD-145065, the endothelinA antagonists A-127722 and BQ-123, and the endothelin-converting enzyme inhibitor phosphoramidon. Concentration of big endothelin in pulmonary effluent increased from 5.6 +/- 0.3 pmol/L in controls and 5.6 +/- 0.2 pmol/L in the Watanabe group, at baseline, to 8.8 +/- 0.4 pmol/L in controls and 8.9 +/- 0.4 pmol/L in the Watanabe group, at 25 mm Hg pulmonary arterial pressure. Endothelin was not detectable at any time during the experiment in pulmonary effluent. The coronary gradient, calculated as a difference in concentration between coronary and pulmonary effluent, was negative for big endothelin and positive for endothelin in both groups. CONCLUSIONS: We have demonstrated that an increase in pulmonary release of big endothelin occurs during lung embolism, which, in turn, results in coronary constriction and consequent cardiodepression. This action of big endothelin is based on its local coronary conversion into endothelin. In addition, coronary endothelial dysfunction, attributed to early systemic atherosclerosis, was shown to represent a specific risk factor in these events.

Pulmonary big endothelin affects coronary tone and leads to enhanced, ET(A)-mediated coronary constriction in early endothelial dysfunction.

BACKGROUND: Lung tissue produces a variety of mediators; however, little is known regarding how these mediators affect coronary regulation and myocardial contractility. In a novel rabbit lung-heart model, we investigated the possible influence exerted by pulmonary mediators on coronary tone both under normal conditions and in early endothelial dysfunction. METHODS AND RESULTS: In our model, the effluent from the isolated lung is used to serially perfuse the coronary vessels of the isolated heart of the same animal. Compared with the hearts of control rabbits, isolated hearts of Watanabe rabbits revealed pharmacological evidence of endothelial dysfunction and a significant steeper decrease of coronary flow during serial perfusion of the coronary vessels with lung effluent (75+/-6% versus 89+/-3%). This decline in coronary flow was prevented by the nonselective endothelin (ET) antagonist PD-145065, the ET(A) antagonists BQ-123 and A-127722, and the endothelin-converting enzyme inhibitor phosphoramidon. The concentration of big ET in lung effluent ranged from 5.5 to 5.8 pmol/L in both control and Watanabe groups, with levels in corresponding coronary effluent falling to 0.9 to 1.1 pmol/L in controls and to 1.0 to 1.2 pmol/L in the Watanabe group. In either group, ET was not detected in lung effluent, but it rose significantly in coronary effluent during serial perfusion. CONCLUSIONS: Pulmonary big ET, locally converted into ET during coronary passage, causes an ET(A)-mediated elevation in coronary tone under basal conditions as well as an enhanced coronary constriction when early endothelial dysfunction is present.

[Sedimentation analyser--calibration and testing of a newly developed device for recording separation behavior of blood and other dispersed systems]. / Sedimentationsanalysator--Eichung und Testung eines neuentwickelten Gerätes zur Aufzeichnung des Entmischungsverhaltens von Blut und anderen dispersen Systemen.

A computer-aided sedimentation analyser is described, which can be used for the continuous monitoring of the separation of blood and other dispersed systems by recording the separation-dependent infrared transmission in the range between 100 xg to 700 xg. Up to eight samples can be measured simultaneously within a short period of time, and only a small amount of suspension is required (15 minutes, 350 microliters). For centrifugal acceleration more than 100 xg and a haematocrit range of between 0.2 and 0.7, the evolution of the height of the plasma column (HPC) over time is expressed in non-linear regression form by HPC(t) = HPC infinity*(1-e-kt) + c. The separation constant k is influenced by plasma viscosity, haematocrit, aggregability and erythrocyte deformability, is directly proportional to centrifugal acceleration, and declines in hyperbolic fashion with increasing haematocrit between 300 xg and 650 xg. The separation constant is closely related to the maximum velocity which, in fact, represents the sensitive parameter of separation. Thus, the sedimentation analyser can be applied as an alternative to the traditional measurement of erythrocyte sedimentation rate according to Westergren.