The vascular endothelium is an important mediator of tissue vasodilatation, yet the role of the specific substances, nitric oxide (NO) and prostaglandins (PG), in mediating the large increases in muscle perfusion during exercise in humans is unclear. Quadriceps microvascular blood flow was quantified by near infrared spectroscopy and indocyanine green in six healthy humans during dynamic knee extension exercise with and without combined pharmacological inhibition of NO synthase (NOS) and PG by l‐NAME and indomethacin, respectively. Microdialysis was applied to determine interstitial release of PG. Compared to control, combined blockade resulted in a 5‐ to 10‐fold lower muscle interstitial PG level. During control incremental knee extension exercise, mean blood flow in the quadriceps muscles rose from 10 ± 0.8 ml (100 ml tissue)−1 min−1 at rest to 124 ± 19, 245 ± 24, 329 ± 24 and 312 ± 25 ml (100 ml tissue)−1 min−1 at 15, 30, 45 and 60 W, respectively. During inhibition of NOS and PG, blood flow was reduced to 8 ± 0.5 ml (100 ml tissue)−1 min−1 at rest, and 100 ± 13, 163 ± 21, 217 ± 23 and 256 ± 28 ml (100 ml tissue)−1 min−1 at 15, 30, 45 and 60 W, respectively (P < 0.05 vs. control). In conclusion, combined inhibition of NOS and PG reduced muscle blood flow during dynamic exercise in humans. These findings demonstrate an important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction.

Plasma interleukin‐6 (IL‐6) concentration has been shown to increase with exercise and various cell types and tissues have been suggested to be responsible for this increase. At present no studies have measured the interstitial concentration of IL‐6 in skeletal muscle and connective tissue. The present study represents the first attempt to simultaneously measure IL‐6 in plasma, skeletal muscle and peritendinous connective tissue in response to prolonged exercise. Six healthy well‐trained volunteers completed a 36 km run (flat, 12 km h−1). IL‐6 was measured before, 2 h post‐exercise and 24 h, 48 h, 72 h and 96 h post‐exercise in both the medial gastrocnemius muscle (not measured at rest due to risk of disabling the subsequent exercise, and 24 h and 72 h post‐exercise) and the peritendinous tissue around the Achilles tendon using microdialysis catheters with a high molecular mass cut‐off value (3000 kDa). The plasma concentration of IL‐6 was measured simultaneously, and in addition every hour during the exercise, by enzyme‐linked immunosorbent assay (ELISA). The plasma concentration of IL‐6 was found to increase throughout the exercise, reaching peak values immediately after completion of the run (50‐fold increase). Using the microdialysis technique, the interstitial concentration of IL‐6 was found to increase dramatically from 0 ± 0 pg ml−1 to 3618 ± 1239 pg ml−1 in the peritendinous tissue in the hours following the exercise. The pattern of changes was similar in plasma and peritendinous tissue, although approximately 100‐fold higher in the latter. For comparison the interstitial muscle concentration was found to be 465 ± 176 pg ml−1 when measured 2 h post‐exercise and 223 ± 113 pg ml−1 and 198 ± 96 pg ml−1 48 h and 96 h post‐exercise, respectively. The present study demonstrates that the connective tissue around the human Achilles tendon produces significant amounts of IL‐6 in response to prolonged physical activity, which might contribute to the exercise‐induced increase in IL‐6 found in plasma.

Microdialysis studies indicate that mechanical loading of human tendon during exercise elevates type I collagen production in tendon. However, the possibility that the insertion of microdialysis fibers per se may increase the local collagen production due to trauma has not been explored. Insulin-like growth factor I (IGF-I) and its binding proteins (IGFBPs), which are known to stimulate collagen production in animal tendons, may regulate the translation of mechanical loading to collagen synthesis. Systemic and tissue levels of IGF-I, IGFBP, and type I collagen metabolism markers [procollagen I COOH-terminal propeptide (PICP) and COOH-terminal telopeptide of type I collagen] were measured by microdialysis in peritendinous tissue of the human Achilles tendon in an exercise group (performing a 36-km run, n = 6) and a control group (no intervention, n = 6). An increase in local PICP concentration was seen in both groups after 72 h and stayed elevated in the exercise group at 96 h (P < 0.05). IGFBP-1 in both serum and dialysate increased in the exercise group immediately after exercise (P < 0.05), whereas IGFBP-3 decreased systemically (P < 0.05). Elevation of local IGFBP-4 was observed in both the control and exercise groups after 48 h (P < 0.05). Total IGF-I did not change in locally or systemically in either group. Our results indicate an increased local production of PICP in human peritendinous tissue in response to prolonged mechanical loading with part of the increase due to trauma from the sampling technique. Care must therefore be emphasized to minimize the numbers of insertions with microdialysis. We demonstrated an elevation of IGFBP-1 both systemically and peritendinously in response to prolonged acute exercise. The local increased collagen synthesis was preceded by an elevation of local concentration of IGFBP-4, suggesting that IGFBP-4 may have a key role in the IGF-axis effect on the human collagen synthesis in vivo.