The phenomenon of local hyperemia in response to muscle contraction is a product of various factors including, but not limited to, metabolic signals (e.g., pCO2/pO2, lactate, K+, adenosine), endothelium-derived factors (e.g., nitric oxide [NO], prostacyclin, and endothelium derived hyperpolarizing factor [EDHF]), and erythrocyte ATP release . With respect to metabolic signals, increased metabolic flux/demand associated with a given exercise is associated with elevations in local pCO2, lactate, and adenosine levels which, collectively, potentiate vasodilation through arteriole smooth muscle cell relaxation . Moreover, K+-efflux from working skeletal muscle under conditions of high action potential frequency can hyperpolarize smooth muscle cells and promote vasodilation [1, 3]. Endothelium-derived factors that interact with vascular smooth muscle cells and likely mediate hyperemia are released in response to blood flow shear stress as well as mechanical deformation/compression of the arterioles [4, 5]. Finally, mechanical deformation and/or decreased oxygen saturation levels during exercise may elicit erythrocyte ATP release promoting vasodilation [6, 7]. The relative contribution of these vasodilatory mediators, in sum and over the time course of the response, has been difficult to quantify due to heterogeneity in metabolic perturbations throughout the skeletal muscle as well as heterogeneity in the vascular phenotype throughout the skeletal muscle arterioles [8, 9]. Regardless, it is likely that at the local tissue level, exercise-induced hyperemia involves a complex interaction of many or all of these factors.
While the formulation of ‘pre-workout’ supplements (PWS) varies markedly from product to product, many of these formulas contain a variety of ingredients, blended together, which may act to enhance blood flow in response to resistance training stimuli (i.e., exercise induced hyperemia). PWS “blends”, particularly those marketed for increased blood flow (e.g., N.O.-Xplode®, Nitraflex®, etc.), often include, but are not limited to, creatine, L-arginine, and L-citrulline. Creatine supplementation with resistance training has been shown to significantly increase peripheral blood flow with resistance training, but it is unclear if the mechanism is due to changes in NO synthesis or total body water . L-arginine, which can be used to form NO in a NO synthase (NOS) catalyzed reaction , supplementation has been shown to increase muscle blood volume following resistance training stimuli . Moreover, supplementation with L-citrulline, a precursor to L-arginine, has been shown to dose-dependently increase plasma arginine levels and NO-dependent signaling in healthy men and women . Collectively, many of the blood flow potentiating ingredients including in a PWS are included in an effort to increase NO synthesis via provision of additional substrate for NOS catalyzed NO formation (i.e., feed forward).
Recently, the PWS Reckless™ (Maxium Human Performance [MHP] LLC, West Caldwell, NJ USA) was designed and includes not only the aforementioned ingredients, but also additional ingredients which may potentiate blood flow via alternative mechanisms. Indeed, the Reckless™ formula also includes the less common PWS ingredients L-norvaline, ancient peat and apple fruit extract (elevATP®), and Spectra™. L-norvaline acts as an arginase inhibitor and has been shown to augment NO production in animal models [14, 15]. Thus, L-norvaline may act synergistically with L-argininie and L-citruline by increasing bioavailability of L-arginine for NO formation. Spectra™, a “full-spectrum” antioxidant product comprised of fruit, vegetable and herb extracts, may also act in a synergistic fashion with other ingredients by reducing NO scavenging by reactive oxygen species and improving NO bioavailability . Finally, ancient peat and apple fruit extract has been shown to enhance circulating ATP levels [17, 18] which may augment blood flow in a NOS independent manner [19, 20]. Indeed, although many PWS marketed to increase the blood flow response to resistance training focus on NO modulation, the contribution of NO to resistance exercise induced hyperemia is not absolute and likely partially includes ATP-sensitive potassium channels  which may interact with ingredient(s) found in a PWS (e.g., elevATP®).
While many studies have demonstrated the effects of individual ingredients, investigations of formulations with many potentially synergistic ingredients are sparse. Notably, many PWS formulations, including Reckless™, also include additional ingredients targeting such things as increases in perceived energy (e.g., caffeine), strength/performance (e.g., caffeine, β-alanine), and focus (e.g., whole coffee fruit extract). Considerable attention has been given to the NO potentiating effects of PWS, but, other ingredients, in theory, may accentuate factors mediating hyperemia from the exercise stimulus as a result of greater effort, training loads, etc.
To our knowledge, little is known regarding the effectiveness of PWS in different training conditions (varying time under tension, load, etc.). With varying training conditions there are likely differences in local perturbations of the factors contributing to exercise-induced hyperemia (e.g., metabolic signals, redox status, endothelium-derived factors, ATP concentration, etc.). Moreover, relative muscle activation varies markedly with high (80% of 1-repetition maximum [1-RM]) vs. low (30% of 1RM) training loads . Thus, variations in training factors such as time-under-tension/training load may also interact differentially with PWS ingredients secondary to resultant differences in local perturbations and relative muscle fiber recruitment.
While the ergogenic value of improved local blood flow in response to resistance training is controversial, it may help to facilitate muscle repair [23–27]. Moreover, the post-exercise blood flow response which contributes to tissue volumizing (i.e., the “muscle pump”), is often sought by recreational and competitive resistance trainees alike. Herein, we sought to determine the effect of a multi-ingredient PWS on leg extensor resistance training-mediated hyperemia with different relative training loads. Training loads were pre-determined as low (30% of 1-RM) and high (80% of 1-RM) loads. Resistance exercise bouts included four sets to repetition failure under both conditions. Four sets to failure were selected to 1) ensure marked differences in time-under-tension between the load conditions and 2) to improve generalizability to practical settings as larger training adaptations occur with a greater number of sets . We hypothesized that 1) greater time under tension would be associated with a greater exercise-induced hyperemia (femoral artery blood flow) and 2) PWS would be associated with increased circulating concentrations of NO metabolites and an accentuated exercise-induced hyperemic response. In addition, we sought to explore a potential interaction between PWS and exercise load.