The extent to which total chronic cardiac denervation protects the ischemic myocardium was investigated in conscious dogs. The major hemodynamic difference after coronary artery occlusion was that left ventricular end-diastolic pressure rose significantly more, P less than 0.01, in the denervated group (12 +/- 1.5 mm Hg) than in the normal group (4.4 +/- 1.4 mm Hg). Blood flow (radioactive microspheres) in the ischemic endo- and epicardium fell to similar levels at 3-5 minutes after coronary occlusion, but was significantly less (P less than 0.01) in denervated dogs at 3 hours after occlusion in the endo- (0.05 +/- 0.01) and epicardium (0.30 +/- 0.02 ml/min per g), than in the endo- (0.13 +/- 0.03) and epicardium (0.42 +/- 0.05 ml/min per g) in the normal group. A subgroup of normal dogs was also studied, with left ventricular end-diastolic pressure increased by volume loading to levels similar to those observed in the denervated group after coronary occlusion; in these dogs, blood flow was similar to that in the other two groups 3-5 minutes after coronary artery occlusion, but, at 3 hours, was significantly more depressed (P less than 0.01) than that observed in normal dogs without volume loading in both endo- (0.03 +/- 0.01) and epicardial (0.25 +/- 0.03 ml/min per g) layers. Infarct size, as a fraction of the area at risk, was significantly greater (P less than 0.05) in the denervated group (60 +/- 4.3%) and in the subgroup of normal dogs with elevated left ventricular end-diastolic pressure (73 +/- 5.8%), compared with the normal group without volume loading (37 +/- 8.1%). Thus, in conscious dogs, total chronic cardiac denervation exerts an adverse effect on infarct size which may be related to the sustained elevation in left ventricular end-diastolic pressure and consequent impairment of collateral perfusion.