The broad list of commercial applications for multi-walled carbon nanotubes (MWCNT) can be further expanded with the addition of various surface chemistry modifications. For example, standard commercial grade MWCNT (C-grade) can be carboxylated (COOH) or nitrogen-doped (N-doped) to suite specific utilities. We previously reported dose-dependent expansions of cardiac ischemia/reperfusion (I/R) injury, 24 hours after intratracheal instillation of C-grade, COOH, or Ndoped MWCNT in mice. Here we have tested the hypothesis that airway exposure to MWCNT perturbs cardiovascular adenosinergic signaling, which could contribute to exacerbation of cardiac I/R injury. One hundred microliters of Vehicle or identical suspension volumes containing 100 μg of C-grade, COOH, or N-doped MWCNT were instilled into the trachea of CD-1 ICR mice. One day later we measured cyclic adenosine monophosphate (cAMP) concentrations in cardiac tissue and evaluated arterial adenosinergic smooth muscle signaling mechanisms related to nitric oxide synthase (NOS) and cyclooxygenase (COX) in isolated aortic tissue. We also verified cardiac I/R injury expansion and examined both lung histology and bronchoalveolar lavage fluid cellularity in MWCNT exposed mice. Myocardial cAMP concentrations were reduced (p < 0.05) in the C-grade group by 17.4% and N-doped group by 13.7% compared to the Vehicle group. Curve fits to aortic ring 2-Cl-Adenosine concentration responses were significantly greater in the MWCNT groups vs. the Vehicle group. Aortic constrictor responses were more pronounced with NOS inhibition and were abolished with COX inhibition. These findings indicate that addition of functional chemical