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Zusammenfassung Die pulmonale Hypertonie umfasst eine Gruppe von Erkrankungen heterogener Ätiologie, die mit einem Anstieg des hydrostatischen Druckes in der Lungenstrombahn einhergehen. Während sich die sekundäre pulmonale Hypertonie zumeist als direkte Folge eines akuten oder chronischen linksventrikulären Pumpversagens entwickelt, resultieren die primären Formen häufig aus charakteristischen Gendefekten oder typischen Auslösemechanismen. Trotz ihrer unterschiedlichen Pathogenese weisen jedoch die verschiedenen Formen der pulmonalen Hypertonie ähnliche pathophysiologische Veränderungen und zelluläre Reaktionsmuster in der pulmonalen Mikrozirkulation auf. Die Dysfunktion der pulmonalvaskulären Endothelzellen, die den hämodynamischen Veränderungen unmittelbar exponiert sind, ist die treibende Kraft des pathophysiologischen Geschehens. Die endotheliale Dysfunktion bewirkt durch eine verminderte Freisetzung vasodilatierender, anti-proliferativer Mediatoren bei gleichzeitig vermehrter Produktion vasokonstriktiver, proliferativer Substanzen nicht nur eine zunehmende pulmonale Vasokonstriktion, sondern unterstützt auch die pathologischen Umbauprozesse in Gefäßintima und -media. Darüber hinaus trägt das pulmonale Endothel durch die Rekrutierung von Thrombozyten und Leukozyten wesentlich zur Freisetzung zusätzlicher vasokonstriktiver, proliferativer Faktoren und zur Bildung charakteristischer Gefäßthromben bei. Diese endothelial initiierten Pathomechanismen verstärken sich zudem wechselseitig, führen zu einem weiteren Anstieg des pulmonalen Strömungswiderstandes und fixieren schließlich die pulmonale Hypertonie. Die pulmonale Hypertonie beschreibt folglich nicht nur eine Änderung der Lungenhämodynamik, sondern umfasst ein komplexes zelluläres Geschehen, an dem parenchymatöses Lungengewebe und korpuskuläre Blutbestandteile gleicherweise beteiligt sind. Bei der Entwicklung neuer Therapiekonzepte ist dieser multifaktorielle Charakter der Erkrankung zu berücksichtigen.

Vertigo of various and often unknown aetiologies has been associated with and attributed to impaired microvascular perfusion in the inner ear or the vertebrobasilar system. Vertigoheel is a low-dose combination preparation of proven value in the symptomatic treatment of vertigo. In the present study we tested the hypothesis that Vertigoheel's anti-vertiginous properties may in part be due to a vasodilatory effect exerted via stimulation of the adenylate and/or guanylate cyclase pathways. Thus, the influence of Vertigoheel or its single constituents on synthesis and degradation of cyclic nucleotides was measured. Furthermore, vessel myography was used to observe the effect of Vertigoheel on the vasoreactivity of rat carotid arteries. Vertigoheel and one of its constituents, Anamirta cocculus, stimulated adenylate cyclase activity, while another constituent, Conium maculatum, inhibited phosphodiesterase 5, suggesting that the individual constituents of Vertigoheel contribute differentially to a synergistic stimulation of cyclic nucleotide signalling pathways. In rat carotid artery rings, Vertigoheel counteracted phenylephrine-induced tonic vasoconstriction. The present data demonstrate a vasorelaxant effect of Vertigoheel that goes along with a synergistic stimulation of cyclic nucleotide pathways and may provide a mechanistic basis for the documented anti-vertiginous effects of this combination preparation.

Detection and visualization of lung tissue structures is impaired by predominance of air. However, by using synchrotron x-rays, refraction of x-rays at the interface of tissue and air can be utilized to generate contrast which may in turn enable quantification of lung optical properties. We utilized multiple image radiography, a variant of diffraction enhanced imaging, at the Canadian light source to quantify changes in unique x-ray optical properties of lungs, namely attenuation, refraction and ultra small-angle scatter (USAXS or width) contrast ratios as a function of lung orientation in free-breathing or respiratory-gated mice before and after intra-nasal bacterial endotoxin (lipopolysaccharide) instillation. The lung ultra small-angle scatter and attenuation contrast ratios were significantly higher 9 h post lipopolysaccharide instillation compared to saline treatment whereas the refraction contrast decreased in magnitude. In ventilated mice, end-expiratory pressures result in an increase in ultra small-angle scatter contrast ratio when compared to end-inspiratory pressures. There were no detectable changes in lung attenuation or refraction contrast ratio with change in lung pressure alone. In effect, multiple image radiography can be applied towards following optical properties of lung air-tissue barrier over time during pathologies such as acute lung injury.

In recent decades, it has become evident that the endothelium is by no means a passive inner lining of blood vessels. This 'organ' with a large surface (approximately 350 m2) and a comparatively small total mass (approximately 110 g) is actively involved in vital functions of the cardiovascular system, including regulation of perfusion, fluid and solute exchange, haemostasis and coagulation, inflammatory responses, vasculogenesis and angiogenesis. The present chapter focusses on two central aspects of endothelial structure and function: (1) the heterogeneity in endothelial properties between species, organs, vessel classes and even within individual vessels and (2) the composition and role of the molecular layer on the luminal surface of endothelial cells. The endothelial lining of blood vessels in different organs differs with respect to morphology and permeability and is classified as 'continuous', 'fenestrated' or 'discontinuous'. Furthermore, the mediator release, antigen presentation or stress responses of endothelial cells vary between species, different organs and vessel classes. Finally there are relevant differences even between adjacent endothelial cells, with some cells exhibiting specific functional properties, e.g. as pacemaker cells for intercellular calcium signals. Organ-specific structural and functional properties of the endothelium are marked in the vascular beds of the lung and the brain. Pulmonary endothelium exhibits a high constitutive expression of adhesion molecules which may contribute to the margination of the large intravascular pool of leucocytes in the lung. Furthermore, the pulmonary microcirculation is less permeable to protein and water flux as compared to large pulmonary vessels. Endothelial cells of the blood-brain barrier exhibit a specialised phenotype with no fenestrations, extensive tight junctions and sparse pinocytotic vesicular transport. This barrier allows a strict control of exchange of solutes and circulating cells between the plasma and the interstitial space. It was observed that average haematocrit levels in muscle capillaries are much lower as compared to systemic haematocrit, and that flow resistance of microvascular beds is higher than expected from in vitro studies of blood rheology. This evidence stimulated the concept of a substantial layer on the luminal endothelial surface (endothelial surface layer, ESL) with a thickness in the range of 0.5-1 microm. In comparison, the typical thickness of the glycocalyx directly anchored in the endothelial plasma membrane, as seen in electron micrographs, amounts to only about 50-100 microm. Therefore it is assumed that additional components, e.g. adsorbed plasma proteins or hyaluronan, are essential in constituting the ESL. Functional consequences of the ESL presence are not yet sufficiently understood and acknowledged. However, it is evident that the thick endothelial surface layer significantly impacts haemodynamic conditions, mechanical stresses acting on red cells in microvessels, oxygen transport, vascular control, coagulation, inflammation and atherosclerosis.

The left ventricular isovolumic pressure decay, obtained by cardiac catheterization, is widely characterized by the time constant tau of the exponential regression p(t)=Pomega+(P0-Pomega)exp(-t/tau). However, several authors prefer to prefix Pomega=0 instead of coestimating the pressure asymptote empirically; others present tau values estimated by both methods that often lead to discordant results and interpretation of lusitropic changes. The present study aims to clarify the relations between the tau estimates from both methods and to decide for the more reliable estimate. The effect of presetting a zero asymptote on the tau estimate was investigated mathematically and empirically, based on left ventricular pressure decay data from isolated ejecting rat and guinea pig hearts at different preload and during spontaneous decrease of cardiac function. Estimating tau with preset Pomega=0 always yields smaller values than the regression with empirically estimated asymptote if the latter is negative and vice versa. The sequences of tau estimates from both methods can therefore proceed in reverse direction if tau and Pomega change in opposite directions between the measurements. This is exemplified by data obtained during an increasing preload in spontaneously depressed isolated hearts. The estimation of the time constant of isovolumic pressure fall with a preset zero asymptote is heavily biased and cannot be used for comparing the lusitropic state of the heart in hemodynamic conditions with considerably altered pressure asymptotes.

Bacterial pneumonias evoke an inflammatory response characterized by neutrophil influx into the alveolar space. Depending on the initial pathogen, neutrophil emigration in the lung occurs via two distinct adhesion cascades: Escherichia coli (E. coli)-induced emigration is dependent on CD18-positive β2-integrins, whereas neutrophil recruitment by Streptococcus pneumoniae (S. pneumoniae) is CD18-independent [1, 2]. The differential stimulation of these two emigration pathways may be controled by different signal transduction pathways. We have recently identified a TNF-α-inducible paracrine signaling mechanism between alveolar epithelium and capillary endothelium [3]: A TNF-receptor-1 (TNFR1)-mediated, calcium-dependent activation of the epithelial cytosolic phospholipase A2 (cPLA2) generates arachidonic acid, which acts as a paracrine mediator and induces a calcium influx into juxtaposed endothelial cells. Here, we investigated the relevance of this signaling pathway for the inflammatory response to alveolar E. coli and S. pneumoniae. In isolated blood-perfused rat lungs, the cytosolic calcium concentration ([Ca2+]i) was quantified in alveolar epithelial and capillary endothelial cells in situ using our recently described fura-2 ratio technique [4]. Intra-alveolar infusion of E. coli (108 CFU/ml), but not of S. pneumoniae (109 CFU/ml), induced a rapid ( 20 min) increase of [Ca2+]i both in alveolar epithelial and capillary endothelial cells (n=4 each). Hence, the epithelial response varies depending on the infused microorganism. The E. coli-induced signal transduction, quantified as an endothelial [Ca2+]i response to the alveolar stimulus, was completely blocked by pretreatment of the alveolar epithelium with: [1] the intracellular Ca2+-chelator BAPTA (40 µM), or [2] the cPLA2-inhibitor AACOCF3 (1 µM) 10 min prior to E. coli infusion (n=4 each). Thus, the signal pathways induced by E. coli and TNF-α are similar. However, epithelial pretreatment with the blocking anti-TNFR1-antibody E-20 (10 µg/ml) had no effect on the endothelial [Ca2+]i response to E. coli. Hence, the epithelial [Ca2+]i response is TNFR1-independent. E. coli, but not S. pneumoniae, induces an endothelial [Ca2+]i response through an alveolocapillary signaling mechanism similar to that recently described for TNF-α. This signal pathway may play a crucial role in the CD18-dependent inflammatory reaction to E. coli. The induction of epithelial [Ca2+]i transients may be an essential trigger mechanism for the differential regulation between CD18-dependent and -independent emigration pathways.

An experimental model has been developed for morphometric and microhemodynamic analysis of discrete arteriolar networks in the ventilated lung. We implanted a transparent window into the right thoracic wall of anesthetized rabbits. Autologous red blood cells were labeled with FITC in vitro. Using a fluorescence video microscopic technique the vessels of superficial arteriolar networks were mapped and classified hierarchically. Networks were investigated under zone 2 conditions (alveolarleft atrial pressure) during continuous monitoring of macrohemodynamics. We comprehensively measured segment length, diameter (D) and branching pattern in the whole network. Microhemodynamic parameters (red blood cell flux (Frbc), red blood cell velocity (Vrbc) and microhematocrit (H mu) were determined in terminal branches. As a result of network analysis the branching rules were found to be similar to those found by cast techniques in human and cat lungs. In terminal arterioles D (21 +/- 4 microns), Frbc (1472 +/- 662 cells/s), Vrbc (863 +/- 250 microns/s) and H mu (0.28 +/- 0.067) were heterogeneously distributed. Geometric, as well as microhemodynamic parameters fitted best to a lognormal distribution. This study represents an example of in vivo analysis of discrete microvascular networks. The measurements in hierarchically equivalent segments of pulmonary arteriolar vessel trees have been shown to be appropriate for estimation of topological, geometrical and microhemodynamic heterogeneity in pulmonary arteriolar networks.