It has been suggested that the midbrain periaqueductal gray (PAG) is a neural integrating site for the interaction between the muscle pressor reflex and the arterial baroreceptor reflex. The underlying mechanisms are poorly understood. The purpose of this study was to examine the roles -aminobutyric acid (GABA) and nitric oxide (NO) play in modulating the PAG integration of both reflexes. In order to activate muscle afferents, static contraction of the triceps surae muscle was evoked by electrical stimulation of the L7 and S1 ventral roots of 18 anesthetized cats. In the first group of experiments (n=6), the pressor response to muscle contraction was attenuated by bilateral microinjection of muscimol (GABA receptors agonist) into the lateral PAG (MAP: 24±5 mmHg) as compared to control (MAP: 46±8 mmHg). Conversely, the pressor response was significantly augmented by 0.1 mM of bicuculline (GABA A receptor antagonist, MAP: 65±10 mmHg). In addition, the effect of GABA A receptor blockade on the reflex response was significantly blunted after sinoaortic denervation and vagotomy (n=4). In the second group of experiments (n=8), the pressor response to contraction was significantly attenuated by microinjection of L-arginine into the lateral PAG (MAP: 26±4 mmHg after Larginine injection and 45±7 mmHg in control). Of note, the effect of NO attenuation was antagonized by bicuculline and was reduced following the denervation. These data demonstrate that GABA and NO within the PAG modulate the pressor response to muscle contraction, and that NO attenuation of the muscle pressor reflex is mediated via arterial baroreflex engaged- GABA increase. The results suggest that the PAG plays an important role in modulating the cardiovascular responses when muscle afferents are activated.