Blood supply can be increased in rabbit skin by a stable prostacyclin derivative without potentiation of plasma extravasation

Abstract

Prostacyclin (PGI2) and prostaglandin E2 were reported to enhance oedema formation in skin, when studied in experimental models of inflammation (Williams, 1979). This phenomenon was attributed to their vasodilating activities, and it was concluded that prostaglandins are endowed with a proinflammatory activity.As PGI2 is only of limited stability in aqueous solution, difficulties in the interpretation of dose-related responses were overcome by the availability of a stable prostacyclin analogue ZK 36 374(Skuba]Ia& Vorbriiggen, i98i)Cfor structure see Fig. i). ZK 36 374 is characterized by a profile of pharmacological and biochemical effects known for the parent compound (Schror er aL, 1981).The aim of this study was to establish the influence of topically applied ZK 36 374 on cutaneous blood flow and oedema formation and to evaluate its possible proinflammatory potential. RESULTSThe vasodilator activity of ZK 36 374 resulting in hyperaemia was assessed in the shaved dorsal skin of conscious rabbits. A non-invasive technique, measuring the Doppler signal of a laser beam was applied to evaluate blood flow. As shown in Figure t, blood flow increases in a dose-related manner when ZK 36 374 is administered topically. The lowest effective dose for vasodilation was 600 ng. Hyperaemia was measured after 3 h, a period after which all doses produced maximal effects. Blood flow returned to normal after approximately 5-6 h (600 ng) or 24 h (60 fig) (not shown).Although the rate of penetration for skin is unknown for ZK 36 374, the long-lasting and dose-dependent hyperaemia suggest a slow release from a reservoir-most likely the stratum corneum, since the half life in plasma was found to be approximately 15 min.The influence of vasodilation produced by ZK 36 374 on oedema formation was assessed by measuring Evans' blue leakage induced by either histamine or croton oil. ZK 36 374 was applied 3 h before intradermal injection of histamine and the plasma leakage was determined 30 min thereafter. Croton oil was applied together with ZK 36 374 topically and the oedema volume was measured after 5 h. Oedema volume was determined photometrically as cxtravasatcd dye and related to the blood concentration of Evans' blue.144

Iloprost

“…After low doses, which already stimulated cutaneous blood flow for up to 4 hr, the proinflammatory effects of croton oil or histamine were not altered by iloprost. Only when higher doses of iloprost were applied, plasma extravasation induced by both irritants was enhanced (17). A synergistic interaction was also seen between iloprost and the platelet-activating factor on guinea pig and human skin (5).…”