SUMMARY Reflex inputs to the circulatory and ventilator)' centers from dynamically contracting muscles and their interaction with extramuscular inputs were studied in anesthetized dogs. Dynamic work of hindlimb muscles was evoked by electrical stimulation of sciatic nerve branches (40 tetani/min with square wave pulses: 0.2-1.0 V, 0.3-0.7 msec, 30-100 Hz). These pulses activated group I and II nerve fibers and they affected heart rate (HR), minute ventilation (V E ), and mean arterial pressure (MAP) only to a small degree when neuromuscular transmission was blocked by cooling distally from the electrodes. Comparable small changes were obtained if these fibers were excited by their natural stimuli when moving and stretching the legs and muscles, respectively. But these responses disappeared when the legs were moved and the muscles stretched after the dogs had been immobilized with drugs, indicating that they were caused by increased muscle tension and not movement per se. If neuromuscular transmission was restored, muscular contractions were induced which caused great reflexogenifc increases of HR, V t , and MAP. Muscular reflex drives to the centers were then eliminated by cold blockade of nervous transmission in both sciatic nerves proximally from the stimulating electrodes while contractions were not interrupted. Blood metabolically enriched in this way entered the systemic circulation, thereby creating humoral extramuscular drives. Muscular reflex inputs accounted for the major and humoral drives for the minor portion of the total cardiovascular and respiratory responses during onset as well as during steady state of dynamic work, although humoral drives increased with time. The time courses of the reflexly induced changes tallied with those of muscular blood flow, indicating a relation with similar metabolic processes. The reflex drives were abolished if a blocking temperature typical for nonmyelinated or small myelinated group IV or III nerve fibers was reached. Similarly, the main responses were only obtained if electrical stimuli were raised to levels where they activated group III or IV afferents.NUMEROUS findings suggest that muscular drives, created by a variety of different stimuli, constitute an important factor in cardiovascular and respiratory regulation during exercise. 20 The significance of these drives during different stages and types of exercise, their adequate triggering mechanism, and their afferent fiber group seem not to be established adequately. This may be because only a few studies, interrupting the afferents from muscles during strenuous isometric and isotonic contractions, 1 ' 13 have established the reflex nature of these drives. However, the cardiovascular and ventilatory reactions following sustained isometric efforts seem to be somewhat different from those of dynamic work. 21 Moreover, since isometric contractions substantially enhance intramuscular pressure, 22 it seems conceivable that an increase in intramuscular pressure without contraction produces similar drives.9 ' "• 16...

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The new electrophysiological model earlier described as stereo-EEG is extended now to allow recording from the freely moving rat by means of a telemetric device. Chronic implantation of 4 electrodes into the brain allows simultaneous transmission of field potentials from frontal cortex, hippocampus, striatum and reticular formation. Frequency analysis of these potentials results in a drug-specific ‘fingerprint’ which cannot only be used to compare different chemicals with each other but also to detect onset and time dependence of drug actions. Application of the model to the question if fenetylline has its own intrinsic mode of action or merely develops its stimulatory effect after metabolic separation into its molecular moieties amphetamine and theophylline (prodrug hypothesis) revealed that fenetylline indeed displays its own stimulatory effect to the same extent and at a similar time course as amphetamine and theophylline. The ‘fingerprint’ as obtained by the analysis of the action of fenetylline in the rat resembles closely that obtained after the application of theophylline with respect to decreased alpha activity, but resembles amphetamine with respect to betai activity. Thus the applied method allows studying structure function relationships as the action of fenetylline seems to reflect both its molecular moieties.

To date, three isoforms of phospholipase A2 (PLA2) have been identified. Of these, the two Ca2+-dependent isoforms, secretory (sPLA2) and cytosolic phospholipase A2 (cPLA2), are targets for new anti-inflammatory drugs. The catalytic mechanisms and functions of the third isoform, Ca2+-independent cytosolic phospholipase A2 (iPLA2), are unknown at present. sPLA2 and cPLA2 are both implicated in the release of arachidonic acid and prophlogistic lipid mediators. However, recent findings provide evidence that cPLA2 is the dominant isoform in various kinds of inflammation, such as T-cell-mediated experimental arthritis. A triple function of PLA2-derived lipid mediators has been suggested: causing immediate inflammatory signs, involvement in secondary processes, e.g., superoxide free radical (O2) generation, apoptosis, or tumour necrosis factor-alpha (TNF-alpha)-cytotoxicity, and controlling the expression and activation of pivotal proteins implicated in inflammation and cell development, e.g., cytokines, adhesion proteins, proteinases, NF-kappaB, fos/jun/AP-1, c-Myc, or p21ras. In the past, research predominantly focused on the development of sPLA2 inhibitors; however, present techniques enable discrimination of cPLA2, sPLA2, and iPLA2, and specific inhibitors of each of the three isoforms are likely to appear soon. Over the last decade, between 40 and 50 sPLA2 inhibitors have been described; and the list is growing. However, of these, few have the potential for clinical success, and those that do are predominantly active site-directed inhibitors, e.g., BMS-181162, LY311727, ARL-67974, FPL67047, SB-203347, Ro-23-9358, YM-26734, and IS-741. At present, there are no likely clinical candidates emerging from the ranks of cPLA2 and iPLA2 inhibitors in development. Indications for which PLA2 inhibitors are being pursued include, sepsis, acute pancreatitis, inflammatory skin and bowel diseases, asthma, and rheumatoid arthritis. The three main obstacles to the successful development of PLA2 inhibitors include, insufficient oral bioavailability, low affinity for the enzyme corresponding to low in vivo efficacy and insufficient selectivity.