Epinephrine is widely used as a vasoconstrictor or inotrope in shock, albeit it may typically induce or augment lactic acidosis. Ongoing debate addresses the question of whether hyperlactatemia per se is a sign of tissue perfusion deficit or aerobic glycolysis. We wanted to test the hypothesis that epinephrine has selective detrimental effects on visceral perfusion and metabolism. We performed rigorous regional venous blood gas analyses as well as intraperitoneal microdialysis. We used a mathematical model to calculate regional arterio-venous CO₂ content gradients and estimated the magnitude of the Haldane effect in a porcine model of prolonged hypotensive shock induced by endotoxin infusion (mean arterial blood pressure <60 mmHg). Subsequently, vasopressors (epinephrine or norepinephrine) were administered and adjusted to maintain systemic mean arterial pressure > 70mmHg for four hours. Epinephrine caused systemic hyperlactatemia and acidosis. Importantly, both systemic and regional venous lactate to pyruvate ratios increased. Epinephrine was associated with decreasing portal blood flow despite apparently maintained total splanchnic blood flow. Epinephrine increased gastric venous to arterial pCO₂ gradients and CO₂ content gradients with decreasing magnitude of the Haldane effect, and the regional gastric respiratory quotient remained higher after epinephrine as opposed to norepinephrine infusion. In addition, epinephrine induced intraperitoneal lactate and glycerol release. We did not observe these adverse hemodynamic or metabolic changes related to norepinephrine with the same arterial pressure goal. We conclude that high CO₂ content gradients with decreasing magnitude of the Haldane effect pinpoint the most pronounced perfusion deficiency to the gastric wall when epinephrine, as opposed to norepinephrine, is used in experimental endotoxin shock.