In hypertensive subjects, a single bout of dynamic exercise results in an immediate lowering of blood pressure back toward normal. This postexercise hypotension (PEH) also occurs in the spontaneously hypertensive rat (SHR). In both humans and SHRs, PEH features a decrease in sympathetic nerve discharge, suggesting the involvement of central nervous system pathways. Given that substance P is released in the nucleus tractus solitarius (NTS) by activation of baroreceptor and skeletal muscle afferent fibers during muscle contraction, we hypothesized that substance P acting at neurokinin-1 (NK-1) receptors in the NTS might contribute to PEH. We tested the hypothesis by determining, in conscious SHRs, whether NTS microinjections of the NK-1 receptor antagonist SR-140333 before exercise attenuated PEH. The antagonist, in a dose (60 pmol) that blocked substance P- and spared D,L-homocysteic acid-induced depressor responses, significantly attenuated the PEH by 37%, whereas it had no effect on blood pressure during exercise. Vehicle microinjection had no effect. The antagonist also had no effect on heart rate responses during both exercise and the PEH period. The data suggest that a substance P (NK-1) receptor mechanism in the NTS contributes to PEH.