Boulet LM, Stembridge M, Tymko MM, Tremblay JC, Foster GE. The effects of graded changes in oxygen and carbon dioxide tension on coronary blood velocity independent of myocardial energy demand. Am J Physiol Heart Circ Physiol 311: H326 -H336, 2016. First published May 23, 2016 doi:10.1152/ajpheart.00107.2016.-In humans, coronary blood flow is tightly regulated by microvessels within the myocardium to match myocardial energy demand. However, evidence regarding inherent sensitivity of the microvessels to changes in arterial partial pressure of carbon dioxide and oxygen is conflicting because of the accompanied changes in myocardial energy requirements. This study aimed to investigate the changes in coronary blood velocity while manipulating partial pressures of end-tidal CO 2 (PETCO2) and O2 (PETO2). It was hypothesized that an increase in PETCO 2 (hypercapnia) or decrease in PETO2 (hypoxia) would result in a significant increase in mean blood velocity in the left anterior descending artery (LAD Vmean) due to an increase in both blood gases and energy demand associated with the concomitant cardiovascular response. Cardiac energy demand was assessed through noninvasive measurement of the total left ventricular mechanical energy. Healthy subjects (n ϭ 13) underwent a euoxic CO 2 test (PETCO2 ϭ Ϫ8, Ϫ4, 0, ϩ4, and ϩ8 mmHg from baseline) and an isocapnic hypoxia test (PETO 2 ϭ 64, 52, and 45 mmHg). LADVmean was assessed using transthoracic Doppler echocardiography. Hypercapnia evoked a 34.6 Ϯ 8.5% (mean Ϯ SE; P Ͻ 0.01) increase in mean LAD Vmean, whereas hypoxia increased LAD Vmean by 51.4 Ϯ 8.8% (P Ͻ 0.05). Multiple stepwise regressions revealed that both mechanical energy and changes in arterial blood gases are important contributors to the observed changes in LAD Vmean (P Ͻ 0.01). In summary, regulation of the coronary vasculature in humans is mediated by metabolic changes within the heart and an inherent sensitivity to arterial blood gases. coronary vessels; hypoxia; carbon dioxide; echocardiography; dynamic end-tidal forcing THE CORONARY VASCULATURE IS capable of regulating myocardial perfusion to maintain oxygen delivery in the face of changing oxygen demands. The coronary resistance vessels can rapidly dilate in response to local tissue hypoxia, thereby increasing coronary blood velocity in the major vessel branches (30, 56). Similarly, in response to increased cardiac energy demand, dilatation of coronary vessels will result in an increase in coronary blood flow to maintain oxygen delivery (59). When the effect of specific stimuli on changes in coronary blood flow is investigated, it is vital to consider the effect of stimuli on cardiac energy demand. Increases in cardiac effort manifest as an increase in the rate of muscle contraction and the prevailing afterload, both increasing the overall energy expenditure and, therefore, coronary blood flow (2,20,56). The capacity of the coronary vessels to increase blood flow is often referred to as the coronary flow reserve (CFR) and can be assessed using a number of k...