NO missing link

The report by Francis et al. in this issue of the Higgs, 1993). Potential physiological roles for NO in endothelial, neuronal and cardiac function have Journal of Molecular and Cellular Cardiology provides an opportunity to reflect on several important and been and are continuing to be described (Moncada and Higgs, 1993). Clearly defined beneficial roles recurrent themes in clinical investigation. The most obvious lesson is that cross-fertilization is essential for the much larger quantities of induced NO are less obvious. to provide fresh, new insights into disease pathogenesis. Francis et al. provide evidence that interAlmost concurrent with these advances in basic NO biology, clinical investigators were undergoing leukin-1 (IL-1) is a previously “missing link” between nitric oxide (NO), pro-inflammatory cytoa shift in their approach to sepsis, systemic inflammatory response syndrome (SIRS) and multiple kines, basic science and clinical medicine. Nitric oxide (NO) was initially recognized as a organ failure. The 1980s brought about the recognition that circulating inflammatory mediators microbial product and an environmental pollutant from automobile exhaust. The importance of NO could play an important role in end-organ damage induced by various serious illnesses, which include, in cellular signaling has been appreciated only recently. Furchgott sought to explain why aortic but are not limited to, septic shock, severe pancreatitis, major trauma, and thermal injury (Parillo, ring preparations sometimes dilated and other times constricted in response to acetylcholine. He dem1993). Circulating levels of the pro-inflammatory cytokines, tumor necrosis factor (TNF), interleukinonstrated that stripping off the inner lining (endothelium) of rabbit aortae consistently resulted in a 1 (IL-1) and interleukin-6 (IL-6) were each observed to be increased in clinical and experimental sepsis. constrictive response to acetylcholine. He deduced from this simple observation that vascular endoFurther insight was provided by studies that demonstrated reversal of myocardial depression in septic thelium possesses a relaxing factor that he called “endothelial derived relaxing factor” (EDRF) (Furchpatients with the use of anti-TNF antibodies (Vincent et al., 1992). The lessons learned were that gott and Zawadski, 1980). Subsequently, Moncada and Ignarro independently identified NO as Fursepsis-induced myocardial depression is reversible and that it is not merely the result of inadequate chgott’s EDRF (Moncada and Higgs, 1993). Nitric oxide, NO synthases and their genes were soon perfusion. These cytokines were subsequently shown to reversibly depress myocardial contractility identified in other cell types using the tools of molecular and cellular biology that proliferated in in an NO-dependent manner (Finkel et al., 1992). Eventually, these newly identified endogenous regthe 1980s. It became clear that endothelial cells, neurons and cardiac myocytes produce NO norulators of myocardial contractility were implicated in a variety of clinical conditions associated with mally under tight physiological control (constitutively). By contrast, macrophages, hepatocytes inflammation, reversible myocardial depression and b-adrenergic densitization (Finkel, 1996). The reand smooth muscle cells make NO only as part of an inflammatory response (induced) (Moncada and versible nature of these effects of cytokines and NO