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Background: It is not clear what the optimal timing of diazoxide administration for cardioprotection in human myocardium is. We aimed to establish it. We next checked whether protection depended on adenosine triphosphate (ATP)-inhibited potassium (KATP) channels., Methods: Isolated human right atrial trabeculae were subjected to 90-minute hypoxia and 120-minute reoxygenation in vitro, followed by adding 10(-4) M norepinephrine. Diazoxide (100 microM) was added (1) as a 10-minute preconditioning signal with 10-minute washout before hypoxia or (2) 10-minute pretreatment without washout before hypoxia or (3) throughout hypoxia or (4) 10 minutes before and throughout hypoxia or (5) during the first 20 minutes of reoxygenation only. In the control, no diazoxide was added. In another set of experiments, diazoxide (100 microM) was present throughout hypoxia in control, while we tried to inhibit its protective effect with glibenclamide (1, 10, 100 microM) or 5-hydroxydecanoate (100 microM)., Results: The presence of diazoxide throughout hypoxia improved recovery of contractility during reoxygenation, allowed for significant response to norepinephrine at the end of reoxygenation, prevented "ischemic contracture" development, and reduced release of troponin I to tissue bath during hypoxia. Adding diazoxide 10 minutes before hypoxia conferred significantly weaker protective effects in all the above respects. We failed to show a protective effect of diazoxide used as a preconditioning signal or during reoxygenation. Neither 5-hydroxydecanoate nor glibenclamide significantly influenced protective effects of diazoxide added during hypoxia., Conclusions: Administration of diazoxide throughout hypoxia provided maximal protective effect, suggesting that diazoxide may be an important adjunct to cardioplegic solution. The protection offered by diazoxide used during hypoxia appears independent of its influence on KATP channels.