Uwe Schwanke

Myocardial Dysfunction With Coronary Microembolization: Signal Transduction Through a Sequence of Nitric Oxide, Tumor Necrosis Factor-α, and Sphingosine

Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-&agr; (TNF-&agr;). TNF-&agr; uses a signal transduction involving nitric oxide (NO) and/or sphingosine. Therefore, we induced coronary microembolization in anesthetized dogs and studied the role and sequence of NO, TNF-&agr;, and sphingosine for the evolving contractile dysfunction. Four sham-operated dogs served as controls (group 1). Eleven dogs received placebo (group 2), 6 dogs received the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME, group 3), and 6 dogs received the ceramidase inhibitor N-oleoylethanolamine (NOE, group 4) before microembolization was induced by infusion of 3000 microspheres (42-&mgr;m diameter) per milliliter inflow into the left circumflex coronary artery. Posterior systolic wall thickening (PWT) remained unchanged in group 1 but decreased progressively in group 2 from 20.6±4.9% (mean±SD) at baseline to 4.1±3.7% at 8 hours after microembolization. Leukocyte count, TNF-&agr;, and sphingosine contents were increased in the microembolized posterior myocardium. In group 3, PWT remained unchanged (20.3±2.6% at baseline) with intracoronary administration of L-NAME (20.8±3.4%) and 17.7±2.3% at 8 hours after microembolization; TNF-&agr; and sphingosine contents were not increased. In group 4, PWT also remained unchanged (20.7±4.6% at baseline) with intravenous administration of NOE (19.5±5.7%) and 16.4±6.3% at 8 hours after microembolization; TNF-&agr;, but not sphingosine content, was increased. In all groups, systemic hemodynamics, anterior systolic wall thickening, and regional myocardial blood flow remained unchanged throughout the protocols. A signal transduction cascade of NO, TNF-&agr;, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.

Das isolierte Kaninchenherz: ein Vergleich zwischen fünf Varianten

Hintergrund: Das isolierte Herz ist seit mehr als 100 Jahren als experimentelles Modell fest etabliert.nMaterial und Methodik: In der vorliegenden Studie werden fünf verschiedene Varianten dises Modells miteinander verglichen: 1. modifizierte Langendorff-Anlage (LA) mit modifizierter Krebs-Henseleit-(KH-)Lösung a) ohne (n = 13) und b) mit (n = 16) Rinderalbumin, 2. LA mit KH-Lösung mit Albumin und Rindererythrozyten (n = 14), 3. LA mit Supportkaninchen (n = 6) und 4. “Working-Heart”-Präparation mit KH-Lösung. Albumin und Rindererythrozyten (n = 16). Im Gegensatz zu den ersten vier Varianten befand sich bei der letzten kein Latexballon im linken Ventrikel, d. h., systemischer und koronarer Kreislauf waren nicht voneinander getrennt.Nach dem Ende der Präparation und einer 20-minütigen Stabilisierungszeit wurden hämodynamische und metabolische Größen für auswerfende Bedingungen erhoben. Anschließend wurden Untersuchungen mit verschiedenen Fragestellungen durchgeführt, sodass anhand der gesamten Versuchsprotokolle auch Angaben über die Stabilität der Herzen vorliegen.nErgebnisse: Die Resultate legen nahe, dass mit KH-Lösung perfundierte Herzen für kürzere Versuche gut geeignet sind. Für länger dauernde Versuche und für Untersuchungen der Koronardurchblutung werden die mit höherem Zeit- und Materialaufwand verbundenen erythrozytenhaltigen Perfusate empfohlen.nSchlussfolgerungen: Die Working-Heart-Variante hat bei relativ geringem experimentellem Aufwand die beste Funktion und Stabilität, eignet sich aber nicht für Untersuchungen, bei denen der Perfusionsdruck unabhängig vom arteriellen Druck verändert werden soll. Alle untersuchten Varianten hatten eine Ventrikelfunktion, die deutlich unter In-vivo-Werten lag.Background: The isolated heart as an experimental model has been firmly established for more than 100 years.nMaterial and Methods: In this study, five modifications are compared: 1. modified Langendorff apparatus (LA) with modified Krebs-Henseleit (KH) solution a) not containing bovine serum albumin (BSA; n = 13) and b) containing BSA (n = 16), 2. LA with KH solution containing BSH and bovine erythrocytes (n = 14), 3. LA with support rabbit (n = 6), and 4. “working heart” preparation with KH solution, BSA and bovine erythrocytes (n = 16). In the latter modification, no balloon was inserted into the left ventricular cavity, i. e., systemic and coronary circuits were not separated from each other.After completion of the preparation and 20-min stabilization, hemodynamic and metabolic data were assessed while the hearts were contracting in the ejecting mode. Thereafter, protocols for different studies were performed that are not presented here. However, the stability of the modifications within their individual protocols is reported.nResults: The results suggest that hearts perfused with KH solution are well suited for short protocols. In spite of the additonal costs and time, blood perfusion is required for long-lasting protocols or if changes in coronary flow are to be investigated.nConclusions: The working heart exhibits both the best function and stability at a relatively low experimental expenditure. Yet, it is not suited for studies where perfusion pressure needs to be changed independent of arterial pressure.

Correlation between heterogeneous myocardial flow and oxidative metabolism in normoxic and stunned myocardium

Abstract Myocardial blood flow exhibits considerable heterogeneity. Consequently, oxygen supply to the myocardium is also heterogeneous, as is myocardial metabolism. Many lines of evidence show a close correlation between local flow and local metabolism in the normoxic myocardium. So far, myocardial metabolism has pre-dominantly been assessed indirectly by using labeled substrates. We used the 18O isotope, permitting analytical separation of H218O from the 18O isotope, as well as quantification of regional oxidative metabolism by measuring the tissue residue of oxidation water in the rabbit myocardium. Correlation of local flow with oxidative metabolism was significant in the normoxic myocardium. This correlation was lost in the postischemic/reperfused myocardium. Apart from the established mechanisms underlying myocardial stunning, a mismatch between local flow and oxidative metabolism might thus also contribute to the postischemic dysfunction.In the normoxic myocardium, function should correlate with metabolism and blood flow. For technical reasons, function has not been assessed on a very local scale. Nevertheless, some considerations are presented on the heterogeneity of function as well as on the scale on which heterogeneity should be investigated to convey physiologically meaningful information on regulatory cardiac mechanisms.