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Die akute Entzundung als physiologische Antwort auf schadigende Reize ist u. a. durch komplex regulierte Wirkungen pro- und antiinflammatorischer Mediatoren charakterisiert. Die Forschung der letzten Jahrzehnte hat die Wechselwirkungen dieser Mediatoren weitgehend aufgeklart und zur Entwicklung antiinflammatorisch wirksamer Medikamente gefuhrt. Allerdings wurde die endgultige Abheilung der akuten Entzundung bis vor wenigen Jahren als passiver Prozess angesehen. Es ist daher nicht verwunderlich, dass die Mechanismen weitgehend unbekannt waren, die entweder zur vollstandigen Abheilung mit Wiederherstellung der normalen Funktion oder zur chronischen Entzundung mit Gewebeschadigung und eingeschrankter Funktion fuhren. Vor allem im letzten Jahrzehnt wurden die sogenannten entzundungsauflosenden Lipidmediatoren (ELM) identifiziert, die in verschiedenen Zellen aus essenziellen Fettsauren gebildet werden. Diese Mediatoren – Lipoxine, Resolvine, Protektine und Maresine – beenden die akute Entzundungsantwort und stimulieren deren vollstandige Abheilung. ELM wirken somit sowohl antiinflammatorisch als auch entzundungsauflosend, indem sie die proinflammatorischen Zytokine hemmen, die Gewebseinwanderung der Neutrophilen eindammen, die Aufnahme der Makrophagen im entzundeten Gewebe fordern, eine nonphlogistische Aktivierung der Makrophagen bewirken und schlieslich die Beseitigung apoptotischer Neutrophilen und mikrobieller Partikel stimulieren. Es konnte in verschiedenen Tiermodellen der humanen chronischen Entzundung nachgewiesen werden, dass z. B. die Atherosklerose, der Diabetes und die chronisch-entzundlichen Darmerkrankungen durch erniedrigte Spiegel der entzundungsauflosenden Lipidmediatoren gekennzeichnet waren und dass deren Substitution zu einer Regression der Krankheitserscheinungen fuhrte. Zukunftige Studien sollen untersuchen, ob die bei den Tiermodellen gewonnenen Erkenntnisse auch auf Entzundungsprozesse des Menschen ubertragbar sind und ob die ELM und deren stabile Analoga therapeutisch zur Behandlung akuter und chronischer Entzundungen und deren Komplikationen eingesetzt werden konnen.

Acute myocardial ischemia provokes sensitization of the adenylyl cyclase system. This sensitization can be differentiated in a receptor-specific and an enzyme-specific sensitization. The receptor-linked sensitization is characterized by an increase of β-adrenergic receptors in the plasma membranes after 15 mins of global ischemia (49.8 ± 3.6 to 67 ± 6 fmol/mg protein) followed by a further increase (89 ± 4 fmol/mg protein) after 50 min of ischemia in isolated perfused hearts. Concomitantly functionally coupled receptors which are able to bind the β-agonist with high affinity, increased by 32% after 15 min and by 57% after 50 min of ischemia. The affinities of the receptors for their agonists or their antagonists remain unchanged. Maximally isoproterenol-stimulated adenylyl cyclase activity rose from 66 ± 7 to 101 ± 10 pmol cAMP/min/mg protein after 15 min of global ischemia indicating the β-receptor-specific sensitization of the β-adrenergic system. This sensitization was followed by a gradual decline of the adenylyl cyclase activity after 30 and 50 min of global ischemia. Additionally, 15 min of myocardial ischemia induced an enzyme-linked sesitization of the adenylyl cyclase activity as indicated by an increase of the forskolin-stimulated activity by about 25% (300 ± 20 vs 378 ± 25 pmol cAMP/min/mg protein). In contrast after 50 min of ischemia the total adenylyl cyclase activity declined (232 ± 24 pmol cAMP/min/mg protein) despite the persistent increase of β-adrenergic receptors in the plasma membranes. These data demonstrate that the enzyme-specific sensitization is only transient. The early sensitization and late inactivation of the adenylyl cyclase activity occurred independently of receptor activation and could not be prevented by β-blockade (10−6 m alprenolol). Cyanide perfusion (1 m m), used to block energy metabolism, lead to energy depletion similar to acute myocardial ischemia. This resulted in an increase of functionally coupled receptors with a time course comparable to that of global ischemia. Additional perfusion with desensitizing concentrations of the β-agonist isoproterenol did not induce uncoupling or internalization of β-adrenergic receptors in cyanide treated hearts, suggesting that the rise in functionally coupled receptors is due to a redistribution in part caused by the abolition of continuous receptor internalization. In contrast, the enzyme-linked sensitization is independent of cellular localization of the β-adrenergic receptors. The increased activity was carried by the enzyme even after partial purification with solubilization and wheat germ affinity chromatography. These data suggest an ischemia-induced, covalent modification of the adenylyl cyclase. This enzyme-specific sensitization or its late inactivation of the enzyme does not occur after cyanide perfusion demonstrating that energy depletion is not solely responsible for this sensitization process. The characterization of these distinct pathomechanisms and time courses of the ischemia-induced activation of the β-adrenergic system allowed to differentiate a receptor- versus an enzyme-specific sensitization of the adenylyl cyclase system in acute myocardial ischemia. Such dual sensitization of the β-adrenergic system may contribute to the increased sensitivity of the infarcted heart to catecholamines.

The activity of the adrenergic system plays an important role in the genesis of malignant arrhythmias and the spreading of the infarcted zone in acute myocardial ischemia. Acute myocardial ischemia induces an increased activity of adenylyl cyclase. This sensitization at the enzyme level as shown in the isolated perfused rat heart occurs rapidly after the onset of ischemia (5-15 minutes) and is rapidly reversible on reperfusion. With prolonged ischemia, it is only transient and is followed by a gradual loss of the adenylyl cyclase activity. The increased activity of adenylyl cyclase is even retained after partial purification, suggesting a covalent modification of the enzyme. Blockade of alpha 1-adrenergic receptors does not prevent this sensitization, demonstrating that it occurs independently of alpha 1-adrenergic receptor activation. Only blockade of protein kinase C by various inhibitors, such as polymyxin B or staurosporine, is able to completely prevent this sensitization process. Moreover, in acute myocardial ischemia an activation of protein kinase C could be identified using its translocation from the cytosol to the particulate fraction as an indicator. Blockade of alpha 1-adrenergic receptors using prazosin fails to prevent the activation of protein kinase C and consequently the sensitization of the adenylyl cyclase system, indicating that the ischemia-induced translocation of protein kinase C occurs independently of alpha 1-adrenergic receptors. These data characterize for the first time an important interaction of two effector enzymes of two distinct signal transduction pathways, i.e., the adenylyl cyclase system and the protein kinase C system in acute myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)