Vasodilatory and vascular mitochondrial respiratory function with advancing age: evidence of a free radically mediated link in the human vasculature

Recognizing the age-related decline in skeletal muscle feed artery (SMFA) vasodilatory function, this study examined the link between vasodilatory and mitochondrial respiratory function in the human vasculature. Twenty-four SMFAs were harvested from young (35 ± 6 yr, n = 9) and old (71 ± 9 yr, n = 15) subjects. Vasodilation in SMFAs was assessed, by pressure myography, in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP) while mitochondrial respiration was measured, by respirometry, in permeabilized SMFAs. Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (young: 92 ± 3, old: 45 ± 4%) and ACh (young: 92 ± 3, old: 54 ± 5%), with no significant difference in endothelium-independent vasodilation. Complex I and I + II state 3 respiration was significantly lower in the old (CI young: 10.1 ± 0.8, old: 7.0 ± 0.4 pmol·s−1·mg−1; CI + II young: 12.3 ± 0.6, old: 7.6 ± 0.4 pmol·s−1·mg−1). The respiratory control ratio (RCR) was also significantly attenuated in the old (young: 2.2 ± 0.1, old: 1.1 ± 0.1). Furthermore, state 3 (CI + II) and 4 respiration, as well as RCR, were significantly correlated (r = 0.49–0.86) with endothelium-dependent, but not endothelium-independent, function. Finally, the direct intervention with mitochondrial-targeted antioxidant (MitoQ) significantly improved endothelium-dependent vasodilation in the old but not in the young. Thus, the age-related decline in vasodilatory function is linked to attenuated vascular mitochondrial respiratory function, likely by augmented free radicals

Strong Relationship Between Vascular Function in the Coronary and Brachial Arteries: A Clinical Coming of Age for the Updated Flow-Mediated Dilation Test?

Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a noninvasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function (r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the noninvasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 μg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients were characterized as having dysfunctional coronary arteries (\u3e5% vasoconstriction) or relatively functional coronary arteries (\u3c5% vasoconstriction). Brachial artery function was determined by flow-mediated dilation, adhering to current guidelines. The acetylcholine-induced change in vessel diameter was smaller in patients with dysfunctional compared with relatively functional coronary arteries (−11.8±4.6% versus 5.8±9.8%, P\u3c0.001). Consistent with this, brachial artery flow-mediated dilation was attenuated in patients with dysfunctional compared with relatively functional coronaries (2.9±1.9% versus 6.2±4.2%, P=0.007). Brachial artery flow-mediated dilation was strongly correlated with the acetylcholine-induced change in coronary artery diameter (r=0.77, P\u3c0.0001) and was a strong indicator of coronary artery dysfunction (receiver operator characteristic=78%). The current data support that updates to the brachial artery flow-mediated dilation technique have strengthened the relationship with coronary artery function, which may now provide a clinically meaningful indication of coronary artery dysfunction

Stable isotope enrichments.

<p>Plasma ²H₅-phenylalanine (A), plasma ¹³KIC (B), muscle intracellular ²H₅-phenylalanine (C), and breath ¹³CO₂ (D) isotopic enrichments during recovery from a 90 min, metabolically matched load carriage (LC) or conventional endurance (CE) exercise bout, with and without (control, CON) essential amino acid (EAA) supplementation. Data are mean ± SD, n = 10 per group. Drink-by-time interactions were observed, EAA different than CON, <i>P</i> < 0.05.</p

Amino acids and insulin.

<p>Effects of load carriage, conventional endurance exercise, and essential amino acid supplementation on plasma essential amino acids (A), branched-chain amino acids (B), leucine (C), and insulin (D) during recovery. Data are mean ± SD, n = 10 per group. CE, conventional endurance exercise; LC, load carriage; CON, control; and EAA, essential amino acids. Drink x time (D x T) interaction for EAA, BCAA (branched-chain amino acids), leucine, and insulin. *Different from baseline for EAA groups, ^#from baseline for CON groups, and for EAA groups compared to ^†CON, D x T, <i>P</i> < 0.05.</p

Experimental design.

<p>Load carriage (LC) and conventional endurance (CE) exercise muscle protein synthesis and whole-body protein turnover protocols.</p

Baseline and 7 day lead-in dietary intake.

<p>Data are mean ± SD, n = 10 per group. Dietary intake was assessed using 24 h recalls (Food Processor SQL^® (version 10.0, ESHA Research, Salem, OR). CE, conventional endurance exercise; LC, load carriage; CON, control; and EAA, essential amino acids.</p><p>Baseline and 7 day lead-in dietary intake.</p

Whole-body protein turnover.

<p>Flux, synthesis, breakdown, oxidation, and net protein balance during recovery from a 90 min, metabolically matched load carriage (LC) or conventional endurance (CE) exercise bout, with and without (control, CON) essential amino acid (EAA) supplementation. Data are mean ± SD, n = 10 per group. *Drink main effect; EAA different than CON, <i>P</i> < 0.05.</p

Effects of load carriage, conventional endurance exercise, and essential amino acid supplementation on surrogate markers of muscle damage and muscle soreness during recovery.

<p>Data are mean ± SD, n = 10 per group. CE, conventional endurance exercise; LC, load carriage; CON, control; and EAA, essential amino acids; PE, post-exercise. Mode x time (M x T) interaction for deltoids, gluteus, and creatine kinase. Mode (M) and time (T) main effects for quadriceps, lactate dehydrogenase, and myoglobin. M and T effects indicate overall mean difference between modes and time, <i>P</i> < 0.05.</p><p>*Different from baseline (or 15-min PE) within mode and</p><p>^†corresponding time point for CE, M x T, <i>P</i> < 0.05.</p><p>Effects of load carriage, conventional endurance exercise, and essential amino acid supplementation on surrogate markers of muscle damage and muscle soreness during recovery.</p