The aim of this study was to investigate the potential cardioprotective properties of chronic treatments with two drugs: the GABA B agonist, baclofen, and the NMDA polyamine site antagonist, ifenprodil. These substances modulate the central glutamatergic relays, particularly those located on the sympathetic drive to heart and vessels. Moreover, they have little toxic effects and are able to cross the blood brain barrier when systemically administered. The effects were investigated, at rest and during a progressive exercise test on a treadmill, in normotensive WKY rats. 24 animals were divided in 4 experimental groups: 2 control groups (2 intraperitoneal injections (i.p.) of 300 ml of saline per day), 1 group treated with ifenprodil (2 x 2.5 mg/kg/day, i.p.) and 1 group treated with baclofen (2 x 5 mg/kg/day, i.p.). The animals were treated during 14 days. After 13 days of treatment, a catheter was inserted in the left common carotid artery under pentobarbital anaesthesia. The next day, the animals were submitted to the exercise test. This test had 4 steps (speed of the treadmill: 5, 15, 25 and 35 cm/min), each 3 minutes long; blood pressure and heart rate were recorded at the second minute of each step. We calculated at each level an index of myocardial oxygen demand: the rate x pressure x product (RPP = systolic arterial pressure multiplied by the heart rate; in mmHg x beats/min, here divided by 1000). Chronic treatments with baclofen and ifenprodil modified neither the resting blood pressure nor the heart rate; however both drugs reduced the exercise induced increase of the RPP as compared to placebo treated animals. This reduction reached statistical significance at the third and the fourth steps of the test. At the last step, the RPP of rats treated with ifenprodil was 79+/-4 as compared to placebo treated rats: 96+/-3 (respectively n=5 and n=7; p<0.05). Similarly, baclofen reduced the increase of the RPP at this last step: 74+/-5 v.s. 98+/-2 in control animals (n=5 v.s. n=7, p<0.05). In a study conducted in parallel, we demonstrated that a chronic treatment with these two drugs did not alter the baroreflex function. In Conclusion, baclofen and ifenprodil reduced the exercise induced increase in myocardial oxygen demand but did not depress neither the resting cardiac function nor the baroreflex reactivity. This suggests that these two compounds could constitute prototypes of non depressive centrally acting cardioprotective drugs.