Identification of novel candidate metabolic dilators through direct myocardial interstitial sampling with increased sympathetic drive

When the heart works harder, it consumes more oxygen (M[Formula: see text]O 2 ), and coronary blood flow must rise in parallel. A long-hypothesized “metabolic dilator” is thought to couple these processes, but its identity remains unknown. In fully anesthetized, open-chest swine, we infused dobutamine at 0, 1, and 10 μg/kg/min to raise heart rate and contractility. During each stage we measured coronary flow, left-ventricular pressure–volume loops, ECG, and aortic pressure. Arterial and coronary venous blood were collected to calculate M[Formula: see text]O 2 , and a catheter in the left-ventricular free wall allowed for sampling of extracellular fluid. Mass spectrometry was utilized to identify untargeted metabolomics profiled to dose-dependent interstitial changes. Dobutamine produced a graded rise in M[Formula: see text]O 2 and coronary flow. The metabolomic response included canonical adrenergic pathways, activation of the TCA cycle, thiamine-dependent pyruvate entry, catecholamine turnover, and arginine/nitric oxide metabolism, consistent with expected increases in oxidative metabolism and sheer-associated signaling. In addition, novel metabolites most strongly associated with M[Formula: see text]O 2 converged on olfactory receptor signaling, including propionate, lipid aldehydes such as octanal, and trace amines such as 3-methoxytyramine with potential chemosensory receptor activity. Additional associations included thiamine pyrophosphate, glucosamine-6-phosphate, and quinolinic acid. No blood contamination markers were detected, validating true interstitial sampling. Alongside expected adrenergic metabolic shifts, novel candidate signals (short-chain fatty acids, lipid-derived aldehydes, and trace amines) emerged as potential links between myocardial work and coronary dilation. These metabolites may serve as biomarkers of early ischemia and therapeutic targets to restore coronary reserve in microvascular angina and heart failure, where current therapies remain limited. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.