Mechanisms of Age‐related Compensatory Vasodilation: Insight from Passive Leg Movement

Abstract

Passive leg movement (PLM) provides a potentially clinically relevant assessment of nitric oxide (NO)‐mediated vascular function. In young individuals pharmacological inhibition of NO synthase (NOS) with L‐NG‐monomethyl arginine (L‐NMMA) decreases the hyperemic and vasodilatory response to PLM by ~ 80%. Aging is associated with a reduced PLM response that is not further attenuated by NOS inhibition, implying that the age‐related reduction is primarily NO‐mediated. Although the PLM response is reduced with age, older individuals exhibit a significant and transient increase in hyperemia during PLM. Currently, it is not clear what factors contribute to this remaining hyperemic response and if compensatory endothelial derived factors are responsible for the remaining, albeit, diminished response. Therefore, this study sought to determine the contribution of prostaglandins (PG) and epoxyeicosatrienoic acids (EETs) to the PLM‐induced hyperemic response. The hyperemic response to continuous PLM was determined under control (saline infusion), NOS inhibition by L‐NMMA, and combined inhibition of NOS by L‐NMMA, cyclooxygenase by Ketorolac (KET), and cytochrome p450 by Fluconazole (FLUC) (L‐NMMA+KET+FLUC) in 7 young (26±2 yrs.) and 7 old (69±2 yrs.) healthy men. Leg blood flow (LBF) was measured by Doppler ultrasound and changes in peak LBF and the overall LBF response, as measured by the area under the LBF response curve (i.e., AUC), were determined. Aging was associated with an attenuated LBF Peak (Young; 1490±184 ml/min, Old; 788±96 ml/min, p < 0.01) and LBF AUC (Young; 455±76 ml, Old; 217±44 ml, p < 0.02) response to PLM. In young men, LBF Peak (−431±147 ml/min, p = 0.03) and LBF AUC (−315±118 ml, p = 0.04) were significantly attenuated by L‐NMMA. The combination of LNMMA+KET+FLUC did not evoke a greater reduction beyond that induced by L‐NMMA for LBF Peak (−355±89 ml/min, p = 0.6) or LBF AUC (−302±40 ml, p = 0.9). In contrast, L‐NMMA failed to significantly alter the LBF Peak (−41±83 ml/min, p = 0.6) and LBF AUC (−56±38 ml, p = 0.2) response in the old, while the combined inhibition by LNMMA+KET+FLUC resulted in a significant, 50% reduction, in LBF AUC (−109±36 ml, p = 0.03) and tended to decrease LBF Peak (−92±44 ml/min, p = 0.08). Taken together, these findings indicate the vasodilatory response to PLM is predominantly NO‐mediated in the young, whereas with advancing age PGs and EETs appear to be the major dilating mechanisms. Importantly, the hyperemic and vasodilatory response to PLM is reduced with age indicating that these compensatory vasodilatory mechanisms are not able to fully correct for the age‐related reduction in endothelial function. Finally, despite pharmacological inhibition of three endothelial‐dependent vasodilatory pathways, a substantial hyperemic response remains in both the young and the old suggesting that a currently unidentified mechanism, likely acting directly on the smooth muscle, contributes to the remaining PLM‐induced response.Support or Funding InformationThis study was supported by Veteran Affairs Rehabilitation Research and Development Grant IK2RX001215 CDA2 (to J. D. Trinity) and Merit Grants E1697R and E6910R (to R. S. Richardson); American Heart Association Grant 14SDG1850039 (to J. D. Trinity); and National Heart, Lung, Blood Institute Grant PO1‐HL‐091830 (to R. S. Richardson)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.