The objective of the present investigation was to determine the influence of endogenously released vasoactive substances on the canine hind limb vasculature during graded arterial stenoses. The study was conducted on 28 mongrel dogs weighing between 22 to 36 Kg. Animals were divided into 6 groups which received either agonist (Serotonin or Acetylcholine) or antagonist (Methysergide, Parachlorophenylalanine (PCPA), Reserpine and PCPA, Indomethacin or Imidazole) or both;Resting, untreated animals did not show a significant variation in collateral and peripheral resistances following partial or complete occlusion of the femoral artery. Peripheral resistance dropped to less than 50 percent of resting level under elevated flow conditions. The collateral blood flow and resistance remained unchanged during this period. Methysergide and indomethacin treatments invoked a 2-3 fold increase in collateral and peripheral resistances, and collateral blood flow completely ceased during partial stenoses. During this period, nutritional blood was supplied to the collateral bed from the partially obstructed femoral vessel. This redistribution of flow caused a severe drop in flow supplied to the peripheral bed distal to stenosis. The methysergide induced reduction was presumably due to the localized vasoconstriction in a maximally dilated vascular bed, whereas indomethacin induced reduction in blood flow could be attributed to the treatment's inhibition of vasodilatory prostaglandins (principally PGI(,2)) that might have been released during graded stenoses. However, the nonspecific localized vasoconstrictor effects of indomethacin and its direct effect upon vascular tone in the region cannot be ruled out. The fact that there was no serotonin, PCPA, or reserpine + PCPA treatment effect on hind limb vasculature suggests that serotonin was not involved in producing the vascular responses observed in these preparations. Similarly imidazole did not produce significant effects on hind limb vasculature;It was concluded, therefore, that in these preparations, neither serotonin nor thromboxane A(,2) were involved in vascular changes during the process of occlusion. In contrast, vasoactive prostaglandins (principally PGI(,2)) were believed to be released and played the regulatory role in the maintenance of blood flow to the hind limb vasculature. Indomethacin abolished this regulatory response by inhibiting prostaglandin biosynthesis.