Cardiopulmonary bypass (CPB) is associated with significant postoperative morbidity, but its effects on the neuromuscular system are unclear. Recent studies indicate that even relatively short periods of mechanical ventilation result in significant neuromuscular effects. Carbon monoxide (CO) has gained recent attention as therapy to reduce the deleterious effects of CPB. We hypothesized that 1) CPB results in impaired neuromuscular transmission and reduced diaphragm force generation; and 2) CO treatment during CPB will mitigate these effects. In adult male Sprague-Dawley rats, diaphragm muscle-specific force and neuromuscular transmission properties were measured 90 min after weaning from normothermic CPB (1 h). During CPB, either low-dose inhaled CO (250 ppm) or air was administered. The short period of mechanical ventilation used in the present study ( approximately 3 h) did not adversely affect diaphragm muscle contractile properties or neuromuscular transmission. CPB elicited a significant decrease in isometric diaphragm muscle-specific force compared with time-matched, mechanically ventilated rats ( approximately 25% decline in both twitch and tetanic force). Diaphragm muscle fatigability to 40-Hz repetitive stimulation did not change significantly. Neuromuscular transmission failure during repetitive activation was 60 +/- 2% in CPB animals compared with 76 +/- 4% in mechanically ventilated rats (P < 0.05). CO treatment during CPB abrogated the neuromuscular effects of CPB, such that diaphragm isometric twitch force and neuromuscular transmission were no longer significantly different from mechanically ventilated rats. Thus, CPB has important detrimental effects on diaphragm muscle contractility and neuromuscular transmission that are largely mitigated by CO treatment. Further studies are needed to ascertain the underlying mechanisms of CPB-induced neuromuscular dysfunction and to establish the potential role of CO therapy.