Tetanic contraction of hindlimb skeletal muscle, induced by electrical stimulation of either ventral roots or peripheral nerves, is well known to activate group III and IV afferents. Nevertheless, the effect of dynamic exercise on the discharge of these thin fiber afferents is unknown. To shed some light on this question, we recorded in decerebrate cats the discharge of 24 group III and 10 group IV afferents while the mesencephalic locomotor region (MLR) was stimulated electrically. Each of the 34 afferents had their receptive fields in the triceps surae muscles. Stimulation of the MLR for 1 min caused the triceps surae muscles to contract rhythmically, an effect induced by an alpha-motoneuron discharge pattern and recruitment order almost identical to that occurring during dynamic exercise. Eighteen of the 24 group III and 8 of the 10 group IV muscle afferents were stimulated by MLR stimulation. The oxygen consumption of the dynamically exercising triceps surae muscles was increased by 2.5-fold over their resting levels. We conclude that low levels of dynamic exercise stimulate group III and IV muscle afferents.

Our laboratory has shown previously that a low level of dynamic exercise induced by electrical stimulation of the mesencephalic locomotor region (MLR) stimulated group III and IV muscle afferents in decerebrate unanesthetized cats (C. M. Adreani, J. M. Hill, and M. P. Kaufman. J. Appl. Physiol. 83: 1811-1817, 1997). In the present study, we have extended these findings by examining the effect of occluding the arterial supply to the dynamically exercising muscles on the afferents' responses to MLR stimulation. In decerebrate cats, we found that arterial occlusion increased the responsiveness to a low level of dynamic exercise in 44% of the group III and 47% of the group IV afferents tested. Occlusion, compared with the freely perfused state, did not increase the concentrations of either hydrogen ion or lactate ion in the venous effluent from the exercising muscles. We conclude that arterial occlusion caused some unspecified substance to accumulate in the working muscles to increase the sensitivity of equal percentages of group III and IV afferents to dynamic exercise.

ABSTRACT:The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ϳ70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2-to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development.

Stimulation of group III and IV muscle afferents has been shown to have important reflex effects on both the somatic and autonomic nervous systems. These include an inhibitory effect on alpha motoneurones, an excitatory effect on gamma motoneurones and an excitatory effect on the sympathetic nervous system. The purpose of this review is to describe the mechanical and metabolic stimuli that discharge group III and IV muscle afferents. Particular attention will be paid to the responses of these afferents to dynamic exercise induced by electrical stimulation of the mesencephalic locomotor region.

Two neural mechanisms contribute to the cardiovascular responses to exercise. The first, central command, proposes a parallel activation of central locomotor and brain stem circuits controlling cardiovascular function. The second, the muscle reflex, proposes that contraction-activated group III and IV afferents increase cardiovascular function. In humans, whole nerve recordings of sympathetic discharge suggest that central command increases sympathetic outflow to skin but not to skeletal muscle and that the muscle reflex increases sympathetic outflow to skeletal muscle but not to skin. We therefore tested the hypothesis that the muscle reflex, but not central command, increases the discharge of single sympathetic postganglionic efferents innervating the triceps surae muscles of decerebrate unanesthetized cats. Central command was evoked by electrical stimulation of the mesencephalic locomotor region. The reflex was evoked by electrical stimulation of the tibial nerve, which in turn contracted the triceps surae muscles. Hexamethonium abolished spontaneous and evoked activity, verifying that the recordings were from sympathetic postganglionic fibers. The discharge of 13 efferents was increased by static contraction (from 0.6 +/- 0.2 to 1.0 +/- 0.3 imp/s; P < 0.05) but was not increased by central command (from 0.6 +/- 0.2 to 0.8 +/- 0.2 imp/s; P > 0.05). Nevertheless, the discharge of nine efferents, not increased by central command before alpha-adrenergic blockade (from 0.5 +/- 0.2 to 0.9 +/- 0.4 imp/s; P > 0.05), was increased after blockade (from 1.3 +/- 0.2 to 3.2 +/- 0.8 imp/s; P < 0.05). We conclude that the muscle reflex stimulates sympathetic postganglionic efferents innervating the vasculature of skeletal muscle. Furthermore, baroreceptors appear to buffer the central command-induced increases in the discharge of these efferents.