To study the mechanisms of myocardial ischemia during isometric exercise, handgrip was sustained, for 4.5 min at 25% of maximum by 11 patients with at least one significant coronary stenosis each, during cardiac catheterization. After recovery, the handgrip that was repeated with simultaneous infusion of nitroglycerin (50 micrograms over 4 min) directly into the diseased vessel. The cardiovascular response was assessed by hemodynamic and by computer-assisted measurements of stenosis. During the first handgrip test pulmonary capillary wedge pressure rose 56% (15 to 23 mm Hg; p less than .001), the heart rate-systolic pressure product rose 33% (p less than .01), and the diseased epicardial arteries constricted. Luminal area in the stenotic segment was reduced by 35% (p less than .01), resulting in a 243% increase in estimated stenotic flow resistance (30 to 103 mm Hg/ml/sec; p less than .001). During handgrip with intracoronary nitroglycerin, the pressure-rate product again increased 33%, but relative to resting control, capillary wedge pressure fell 4 mm Hg in association with a 32% increase in luminal area of the stenosis and a 28% reduction in flow resistance (all significantly different from the response to handgrip alone: p less than .001, .01, and .005, respectively). Thus, coronary vasoconstriction, not increased pressure-rate product, is the dominant mechanism for ischemic left ventricular dysfunction during isometric exercise in patients with significant coronary stenoses.