The sulfur containing non-essential amino acid L-cysteine known as neurotoxin is suggested to play a physiological role (ref. 1). When injected into the cisterna magna of conscious rats, L-cysteine produces an increase in blood pressure, equivalent to a neurotransmitter of L-glutamate (ref. 2). The present study examined if the rostral ventrolateral medulla (RVLM), which has cardiovascular sympathetic premotor neurons, responds to microinjected L-cysteine in anesthetized rats. The RVLM was directly accessed by the ventral surface of the medulla under urethane anesthesia (1.3 g/kg, i.p.) and catheters were inserted into the terminal aorta for arterial blood pressure measurement and the femoral vein for drug injections (refs. 3-5). The rat was immobilized by i.v. injection of pancuronium bromide (1 mg/kg, additional 0.5 mg/kg) and ventilated by a respirator. An adequacy of anesthesia was assessed by arterial blood pressure stability and/or the absence of a withdrawal response to a firm tow pinch. In the RVLM identified with pressor response to L-glutamate (0.01 M, 46 nl), seven times repeated injections of L-cysteine (0.1 M, 46 nl) produced stable pressor responses without fading (21.4 ± 1.5 mmHg, mean ± SD, for 62.7 ± 3.9 mmHg), suggesting no neurotoxic action for acute repetitive stimulation with L-cysteine less than this dose in the RVLM. Microinjections of L-cysteine increased blood pressure in a dose-dependent manner (0.003 M to 0.1 M), while L-glutamate did from 0.001 M. An equivalent increase of 15 mmHg was obtained with 0.03 M of L-cysteine and 0.01 M of L-glutamate. Preliminary examinations showed that there were no detectable changes in blood pressure for microinjection of each structurally related amino acid: D-cysteine, N-acetyl-L-cysteine, DL-homocysteine with ranging from 0.003 M to 0.03 M, except a pressor response to L-homocysteine at 0.03 M. The pressor response to L-cysteine (0.03 M, 21.3 ± 6.2 mmHg, n=8) was significantly blocked (2.4 ± 3.4 mmHg, p<0.01 by t-test) after prior injections of both types of ionotropic excitatory amino acid receptor antagonists MK801 (20 mM, 68 nl) and 6-cyano-7-nitroquinoxaline- 2,3-dione (CNQX, 2 mM, 68 nl), suggesting involvement of NMDA receptors and non-NMDA receptors in the pressor action of L-cysteine in the RVLM of the rat. The findings indicate that 1) neurons in the RVLM of anesthetized rats produce dose-dependently the pressor response to L-cysteine possibly in a molecular structural specific manner, and 2) the pressor response is mediated by ionotropic excitatory amino acids NMDA and non-NMDA receptors.