Some of the presynaptic and postsynaptic excitatory and inhibitory actions of 5-hydroxytryptamine (5-HT) in the rat mesenteric arteries were reexamined with particular reference to the genetic hypertensive rat model. Mesenteric arteries were perfused and the perfusion pressure monitored in the presence or absence of 5-HT, norepinephrine or periarterial sympathetic nerve stimulation. The vasoconstrictor response to 5-HT was resistant to prazosin but effectively inhibited by cyproheptadine and ketanserin. The vasoconstrictor responses to norepinephrine and nerve stimulation were markedly potentiated by 5-HT, and this potentiation was blocked by ketanserin at concentrations which inhibited the 5-HT-induced vasoconstriction, while much higher concentrations were required for cyproheptadine. No significant difference was found in these regards between mesenteric arteries from the spontaneously hypertensive rats (SHR) and those from the normotensive Kyoto Wistar rats (WKY). 5-HT significantly increased the nerve stimulation-evoked 3H overflow in [3H]norepinephrine-treated mesenteric arteries of SHR, but reduced the 3H overflow in the WKY preparations. These results suggest that ketanserin-sensitive 5-HT2 receptors are involved in the potentiating effect of 5-HT in the rat mesenteric arteries, and that an increase in transmitter release by 5-HT may contribute to its potentiation of nerve stimulation-induced vasoconstriction in SHR.