In dogs anaesthetised with chloralose, infusion of synthetic substance P into the femoral artery caused marked elevation of femoral arterial blood flow which was well sustained during the infusion period. Doses less than 59 fmol/kg/min increased femoral arterial flow only, but larger doses caused transient hypotension accompanied by tachycardia. The administration of substance P by i.v. and intravertebral (i.vert.) arterial routes caused hypotension and tachycardia of similar pattern and magnitude to those produced by intrafemoral (i.f.) arterial infusion of equivalent doses. I.v. injection of substance P into rats and rabbits caused qualitatively similar cardiovascular effects to those in dogs, but higher doses were required for threshold responses. Substance P had little effect on the spontaneously beating isolated guinea-pig heart. Like many other vasodilator substances in vivo, substance P caused constriction of the isolated perfused ear vein from the rabbit. The results suggest that the major cardiovascular effect of synthetic substance P is vasodilatation and that a direct action on vascular smooth muscle is involved.