The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. This study interrogated the local metabolic hypothesis, which proposes that myocardial oxygen tension, indexed by coronary venous PO₂ (CvPO₂), determines the degree of coronary pressure-flow autoregulation by increasing the production of vasodilator metabolites as coronary perfusion pressure (CPP) is reduced. We tested this hypothesis by examining the extent to which dobutamine-induced increases in myocardial oxygen consumption (MVO₂) under both normoxic and hypoxemic conditions, influences coronary autoregulatory capability. Experiments were performed on open-chest anesthetized swine during 20 mmHg stepwise changes in coronary perfusion pressure (CPP) from 140 to 40 mmHg, via servo-controlled roller pump. Measurements were made in 3 conditions: a) normoxia (n = 7); b) normoxia with dobutamine (10 μg/kg/min, iv; n = 7); and c) hypoxemia (PaO₂ 36-38 mmHg) plus dobutamine (n = 5). Under control-normoxic conditions, CvPO₂ decreased from 38 ± 2 to 22 ± 1 mmHg and coronary blood flow fell from 0.93 ± 0.15 to 0.32 ± 0.03 ml/min/g as CPP was reduced from 140 to 40 mmHg. Administration of dobutamine significantly increased heart rate (~60%; P < 0.001), but the combination of hypoxemia plus dobutamine did not further influence heart rate. Further, dobutamine with and without hypoxemia significantly increased MVO₂ (P < 0.001); however, CvPO₂ was reduced (P < 0.001) only in the presence of hypoxemia. Calculation of closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (value of 1 represents perfect autoregulation) was unaffected by dobutamine alone but tended to increase when dobutamine infusion was combined with reductions in PaO₂ ≤ 40 mmHg (P = 0.069). Additional analysis of the autoregulatory slope within this same CPP range revealed no differences between groups. However, there was a significant inverse association between Gc and CvPO₂, measured at CPP of 100 mmHg, in the absence and presence of dobutamine-induced increases in MVO₂ ± hypoxemic conditions (P < 0.001, r = -0.722). The relationship of coronary resistance (CPP range of 120 to 60 mmHg) relative to respective CvPO₂ revealed that decreases in CvPO₂ were not associated with changes in coronary resistance until CvPO₂ fell below a relative threshold of ~ 25 mmHg (r = 0.88). These findings support the interpretation that the sensitivity of coronary autoregulatory behavior is directly coupled with the activation of local metabolic vasodilator pathways below a critical level of myocardial oxygenation. This work was supported by National Institutes of Health grant R01 HL158723. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.