ORIGINAL ARTICLE Roles of nitric oxide and prostaglandins in the hyperemic response to a maximal metabolic stimulus: redundancy prevails Marcos G. Lopez • Bruno M. Silva • Michael J. Joyner • Darren P. Casey Received: 26 August 2012 / Accepted: 30 November 2012 / Published online: 19 December 2012 Ó Springer-Verlag Berlin Heidelberg 2012 Abstract Vasodilatory mechanisms controlling post- exercise or post-ischemic hyperemia are thought to be under redundant control and remain incompletely under- stood. A maximal metabolic stimulus evoked by ischemic exercise (IE) might limit redundancy by full activation of multiple pathways. We tested whether nitric oxide (NO) and/or prostaglandins contribute to the hyperemic response to IE. 17 subjects were randomized into two groups and performed three trials of IE during control (saline), N G -monomethyl-L-arginine (L-NMMA; NOS inhibition) (protocol 1) or ketorolac (cyclooxygenase inhibition) infusion (protocol 2), and combined L-NMMA/ketorolac infusion via a brachial arterial catheter. Forearm blood flow (FBF) was measured with venous occlusion plethysmog- raphy following IE trials consisting of 5 min of ischemia and simultaneous rhythmic handgrip exercise (final 2 min). Peak and total (area under the curve) FBF and blood pressure (MAP) were measured for 3 min after each trial. Forearm vascular conductance (FVC) was calculated as FBF/MAP. Change (D) in peak FBF and FVC from baseline differed only between peak FBF for the saline and L-NMMA ? ketorolac trials in protocol 1. Peak DFBF was 26.8 ± 2.5, 30.0 ± 2.8, and 33.9 ± 3.6 ml 100 ml -1 min -1 for saline, L-NMMA, and L-NMMA ? ketorolac trials (P = 0.04). For protocol 1 (n = 8), total DFVC was 59.6 ± 4.3, 57.8 ± 6.0, and 59.9 ± 5.6 ml 100 ml -1 100 mmHg -1 for saline, L-NMMA, and L-NMMA ? ketorolac trials, (P = 0.82). For protocol 2 (n = 9), total DFVC was 54.2 ± 5.0, 56.9 ± 4.5, and 56.5 ± 5.3 ml 100 ml -1 100 mmHg -1 for saline, ketorolac, and ketorolac ? L-NMMA trials, (P = 0.69). These results suggest that NO and PGs are not obligatory for the hyperemic response to IE, and other vasodilator mechanisms predominate. Keywords Hyperemia Á Prostaglandins Á Nitric oxide Á Vasodilation Á Ischemia Introduction Exercise hyperemia is the increase in blood flow to skeletal muscle in response to increased metabolic demand. Hyperemia in excess of metabolic demand can also be elicited by periods of ischemia and is termed reactive hyperemia (Patterson and Whelan 1955). The vasodilator mechanisms and their interactions controlling these hyperemic responses remain incompletely understood. Redundant control mechanisms likely play a role in both responses such that if the contribution of one putative dilator mechanism is reduced, contributions from others increase and result in an overall response in the normal range (Joyner et al. 2001). Compared to ischemia alone, ischemic exercise (IE) elicits an overall larger hyperemic response (Sinoway et al. 1986; Wendelhag et al. 1999; Lopez et al. 2012). Communicated by Keith Phillip George. M. G. Lopez (&) Department of Anesthesiology, Vanderbilt University School of Medicine, 1161 21st Avenue, Nashville, TN 37232, USA e-mail: mglopez3@gmail.com B. M. Silva Laboratory of Exercise Sciences, Fluminense Federal University, Nitero ´i, Rio de Janeiro, Brazil M. J. Joyner Á D. P. Casey Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA 123 Eur J Appl Physiol (2013) 113:1449–1456 DOI 10.1007/s00421-012-2570-y