The role of the pertussis toxin-sensitive guanine nucleotide binding regulatory protein in pre- and postjunctional alpha 2-adrenoceptor-mediated responses has been investigated in the pithed rat. Pertussis toxin (50 micrograms/kg i.v., administered 3 days prior to experimentation) markedly inhibited the alpha 2-adrenoceptor-mediated vasopressor response to B-HT 933, but had no effect on the alpha 2-adrenoceptor-mediated cardiac neuroinhibitory effect of B-HT 933. Thus, postjunctional alpha 2-adrenoceptor activation in vascular smooth muscle, but not prejunctional alpha 2-adrenoceptor activation on sympathetic neurons, utilizes a pertussis toxin-sensitive guanine nucleotide binding regulatory protein.