Evaluation of Endothelial-Mediated Mechanisms of Passive Leg Movement Hyperemia: Impact of Age and Exercise Training

The hyperemic response to passive leg movement (PLM) is largely (~80%) nitric oxide (NO) mediated in young adults, whereas both the overall response and NO contribution (~20%) are diminished in older adults. A transient hyperemic response remains in both groups after NO blockade, however, the mechanisms contributing to this remaining response are unknown. Vasodilatory substances including prostaglandins (PG) and endothelial derived hyperpolarizing factors (EDHF) are primary candidates contributing to PLM response. Moreover, these underlying mechanisms of the PLM response are likely influenced by exercise training in both young and older adults but this remains to be determined. Thus, we sought to determine if 1) PG and EDHF contribute to the hyperemic response in older adults, and 2) exercise training alters the mechanisms contributing to changes in PLM (i.e., NO, PG, or EDHF). The leg blood flow (LBF) response to PLM was measured by Doppler ultrasound in 9 young (25±4 yr) and 9 older (69±5 yr) adult males. PLM was performed with intra-arterial infusions of saline (control), N G -monomethyl-L-arginine (L-NMMA) to inhibit NOS and NO production, and a combination of L-NMMA, ketorolac tromethamine (KET) to inhibit cyclooxygenase and PG production, and fluconazole (FLUC) to inhibit cytochrome P-450 and EDHF (L-NMMA+KET+FLUC). This PLM and drug infusion protocol were repeated following 8 weeks of single leg knee-extension (KE) exercise training to determine if the vasodilatory mechanisms regulating PLM-induced hyperemia are altered by exercise training. The hyperemic response to PLM (total LBF area under the curve) was significantly attenuated from control with infusion of L-NMMA in young adults (-287±280 mL, p<0.05) but remained unchanged in the older (-55±86 mL, P=0.70). Combined infusion of L-NMMA+KET+FLUC yielded similar results such that PLM decreased to the same degree as L-NMMA in young (-276±108 mL, p<0.05) with no significant change in older adults (-116±81 mL, P=0.36). Following 8 weeks of single leg KE training, maximal power (KE max ) improved in both young (+33±13 W, p<0.05) and older adults (+16±8 W, p<0.05). Despite improvements in KE max , the hyperemic response to PLM only increased in young adults by ~30% (454±194 v. 604±351 mL, p<0.05), while no improvement was observed in older adults (225±142 v. 236±89 mL, P=0.86). The contribution of NO to PLM did not change following exercise training in either young (-238±217 mL, P=0.14) or older (-62±82 mL, P=0.72) adults. Likewise, the contribution of PG and EDHF also did not change in both young (-306±222 mL, P=0.68) and older (-108±116 mL, P=0.77) adults. These findings indicate that PG and EDHF do not have an additive effect to NO on the hyperemic response to PLM in both young and older adults. Therefore, the remaining hyperemic response following combined NO, PG, and EDHF inhibition is likely driven by non-endothelial dependent mechanisms. Moreover, these data indicate that 8 weeks of KE specific exercise training significantly improves the hyperemic response to PLM in young but not older adults. Interestingly, the observed improvements to PLM were not directly mediated through the NO, PG, or EDHF pathways but by some other, currently unidentified, mechanism. National Institutes of Health R01HL142603 (to J.D. Trinity) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.