Mexiletine and quinidine are often administered to patients with severe congestive heart failure, but their hemodynamic effects have not been adequately studied in these individuals. In a randomized, crossover study, the hemodynamic responses to single oral doses of quinidine (600 mg) and mexiletine (400 mg) were compared in 20 patients with marked left ventricular dysfunction. Quinidine predominantly caused vasodilation, with mean arterial, left ventricular filling, and right atrial pressures all decreasing (-7 +/- 2, -2.3 +/- 1.0, and -1.1 +/- 0.5 mm Hg, respectively) and the systemic vascular resistance also declining (-308 +/- 84 dynes.sec.cm5). In contrast, the systemic vascular resistance increased (314 +/- 84 dynes.sec.cm-5) and the mean arterial, left ventricular filling, and right atrial pressures also increased (+2 +/- 2, +6.1 +/- 1.8, and +1.8 +/- 0.6 mm Hg, respectively) after mexiletine. Cardiac performance declined with mexiletine (cardiac and stroke work indexes decreasing -0.3 +/- 0.1 L/min/m2 and -5 +/- 1 gm.m/m2, respectively), but there was no significant change in cardiac or stroke work indexes with quinidine (+0.1 L/min/m2 and -0.3 +/- 0.9 gm.m/m2, respectively). The response to the two agents significantly differed for all parameters measured (p less than 0.005). These hemodynamic changes were accompanied by clinical effects. Mexiletine induced increased dyspnea in five patients and quinidine led to symptomatic hypotension in two patients. Plasma concentrations of mexiletine and serum concentrations of quinidine were within or below the therapeutic range in all patients. In conclusion, mexiletine and quinidine exert different hemodynamic effects when given to patients with severe congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)