We injected neuroexcitatory and neuroinhibitory agents into the depressor region of the caudal ventrolateral medulla of anesthetized rabbits and determined the effect on arterial pressure, myocardial contractility, cardiac output, and plasma catecholamines and neuropeptide Y. Brief excitation of the sympathoinhibitory neurons with medullary injection of L-glutamate reduced arterial pressure, peripheral vascular resistance, and myocardial contractility. Cardiac output was unaffected. Prolonged inhibition of the sympathoinhibitory neurons with medullary injection of muscimol increased arterial pressure, peripheral vascular resistance, and myocardial contractility. There was a progressive fall in cardiac output. These changes were accompanied by an increase in plasma neuropeptide Y and plasma norepinephrine, but no change in plasma epinephrine. Our findings indicate that the sympathoinhibitory vasomotor neurons in the caudal ventrolateral medulla tonically suppress the activity of sympathetic preganglionic neurons controlling myocardial contractility as well as peripheral vasomotor tone. Dysfunction of these medullary neurons could underly some forms of experimental hypertension.