Nitroglycerin (NTG) traditionally has bben avoided in the treatment of pain caused by acute myocardial infarction because of the belief that NTG-induced decrease in arterial pressure and concomitant reflex increase in heart rate might extend the ischemic process. However, recent experimental and clinical investigations cast doubt on this concept. For example, when the left anterior descending coronary artery is acutely occluded in normal dogs or in dogs when chronic coronary occlusions and extensive collaterals, NTG reduces ST-segment evevation (and presumably myocardial ischemia). This salutary effect occurs despite lowering of systemic arterial pressure, as long as excessive reflex tachycardia does not result; the magnitude of ischemia reduction is potentiated when methoxamine or phenylephrine are administered simultaneously to abolish the NTG -induced hypotension and reflex tachycardia. NTG and methoxamine treatment also results in 1) reduction of infarct size as (as assessed by gross morphologic examinations and myocardial CPK levels) in dogs subjected to 5 hours of coronary occlusion, and 2) increase in ventricular fibrillation (VF) threshold and reduction of the incidence of spontaneously occurring VF in dogs with acute coronary occlusion. Finally, the effectiveness of NTG during acute myocardial iinfarction (AMI) in man has been studied. Multiple precordial electrodes were used to measure changes in the degree of ST-segment elevation; these changes were used as an index of alterations in myocardial ischemic injury. Patients with normal pulmonary capillary wedge pressures ( less than 15 mm Hg) did not benefit consistently from NTG alone; however, when phenylephrine was administered with NTG (to abolish NTG-induced arterial pressure reduction and reflex increase in heart rate), ST-segment elevation diminished consistently. In patients with elevated wedge pressures ( greater than 15 mm Hg), NTG alone consistently reduced ischemia; addition of phenylephrine often partially reversed this benefit. Thus, administration of NTG, alone or with phenylephrine, appears to reduce myocardial ischemic injury during AMI in man; however, the response to phenylephrine depends upon the presence or absence of LV failure prior to treatment. These experimental and clinical results suggest this form of therapy may be use in reducing infarct size in man, although additional studies are necessary to determine the functional significance of these acute electrophysiologic alterations.