The influence of diabetes on the response of isolated rabbit renal arteries to 5-hydroxytryptamine (5-HT) was examined. 5-HT induced a concentration-related contraction that was higher in arteries from diabetic rabbits than in arteries from control rabbits. Endothelium removal did not significantly modify 5-HT contractions in arteries from control rabbits but enhanced the response to 5-HT in arteries from diabetic rabbits. Incubation with NG-nitro-L-arginine (L-NA) enhanced contractions to 5-HT in arteries from control and diabetic rabbits. In arteries with endothelium, this L-NA enhancement was lower in diabetic rabbits than in control rabbits. In arteries without endothelium, incubation with L-NA enhanced the maximal contractions to 5-HT in control rabbits but did not in diabetic rabbits. Indomethacin inhibited 5-HT-induced contraction of arteries from control rabbits and enhanced the maximal contraction to 5-HT of arteries from diabetic rabbits. In summary, diabetes enhances contractile response of rabbit renal artery to 5-HT. In control animals, this response is regulated by both endothelial and non-endothelial (neuronal) nitric oxide (NO) and by a vasoconstrictor prostanoid. Diabetes impairs the release of non-endothelial NO and the vasoconstrictor prostanoid