This study was designed to determine the effects of ketamine on contractions induced by norepinephrine (NE), K⁺ or histamine (Hist) and on agonist-induced calcium mobilization, in rabbit thoracic aorta with or without endothelium. Contractile responses to NE, K⁺ or Hist were markedly attenuated by prior exposure to ketamine. Subsequent addition of ketamine to the rabbit aorta undergoing an isometric contraction induced by NE, K⁺ or Hist also decreased the contractile responses in a calcium ion concentration-dependent manner. Preincubation with ketamine produced a concentration-dependent inhibition of contractile responses elicited by the addition of calcium ion (1.6 mM) to a Ca(++)-free depolarizing solution. However, the phasic contraction produced by NE with 2mM lanthanum pretreatment, which is release of intracellular calcium, was also inhibited by ketamine. Moreover, the tonic contraction produced by NE after depletion of the agonist-releasable pool of intracellular calcium, which is thought to be due to calcium influx, was depressed by ketamine. These data suggest that ketamine relaxes NE-contracted rings of rabbit thoracic aorta by decreasing calcium entry and by producing an extracellular calcium-independent relaxant effect.