We tested the hypothesis that there is an enhanced susceptibility in hypertrophied cardiac muscle to develop decreased diastolic distensibility of the left ventricle in response to hypoxia. The effects of brief hypoxia (3 minutes) were studied in rats with and without chronic left ventricular pressure overload hypertrophy using an isolated buffer-perfused and isovolumic (balloon-in-left ventricle) heart preparation with excised pericardium and vented right ventricle. We compared hypertrophied hearts from hearts from hypertensive uninephrectomized Wistar-Kyoto rats (n = 12) with normotensive uninephrectomized age-matched controls (n = 13). Coronary flow was held constant and adjusted so that an identical flow per gram left ventricular weight was achieved in both groups. The left ventricular balloon volume was adjusted to produce an initial left ventricular end-diastolic pressure of 10 mm Hg in both groups and was held constant thereafter so that changes in left ventricular end-diastolic pressure during hypoxia represented changes in diastolic chamber distensibility. Under aerobic conditions, left ventricular systolic pressure was 66% higher in the hypertrophied hearts than in the controls, but there was no difference in the rate or extent of left ventricular relaxation as estimated by the exponential time constant of pressure decay and the asymptote to which pressure decayed. In response to hypoxia, left ventricular end-diastolic pressure was significantly higher in the hypertrophied hearts than in the controls (37 +/- 5 vs. 22 +/- 5 mm Hg, P less than 0.001). In response to hypoxia, the rate of left ventricular relaxation was depressed to a comparable degree in both groups, but there was a greater upward shift in the asymptote to which pressure decayed in the hypertrophied hearts. Hypoxia-induced coronary vasodilation as assessed by the change in coronary vascular resistance was similar in the hypertrophied and control hearts (2.9 +/- 0.5 vs. 2.3 +/- 0.9 mm Hg/[(ml/min)/g], NS). The degree of hypoxia-induced anaerobic metabolism as estimated by the coronary arterial-venous lactate concentration difference was also similar in both groups (-0.72 +/- 0.23 vs. -0.73 +/- 0.16 mM/liter, NS). It is concluded that brief hypoxia results in a greater decrease in diastolic distensibility of the left ventricle in the presence of chronic pressure overload hypertrophy than in its absence.