Pharmacologic Modulation of the Cutaneous Vasculature in the Isolated Perfused Porcine Skin Flap

Abstract

The isolated perfused porcine skin flap (IPPSF), anex vivomodel system used in cutaneous toxicology and pharmacology, is capable of assessing the percutaneous absorption of vasoactive compounds. However, the vascular responses of the IPPSF to classical pharmacologic agents have not been calibrated. The ability of acetylcholine, nitroglycerin, tolazoline, and norepinephrine to affect vasculature resistance and glucose utilization was investigated in the IPPSF. Norepinephrine infusions between 10−7and 10−5M increased vascular resistance in a dose‐dependent manner; half‐maximal (EC50) and maximal responses occurred at 3.18 × 10−6and 10−5M, respectively. In non‐preconstricted flaps, neither acetylcholine, nitroglycerin, nor tolazoline vasodilated the IPPSF; however, acetylcholine, nitroglycerin, and tolazoline each lowered vascular resistance in a dose‐dependent manner in norepinephrine‐preconstricted flaps. Maximal relaxation was induced at 10−4, 10−6, and 5 × 10−5M, by tolazoline, acetylcholine, and nitroglycerin, respectively, whereas the EC50values were 2.88 × 10−7, 1.35 × 10−8, and 1.72 × 10−7M, respectively. In flaps pretreated with norepinephrine and methylene blue (a potential blocker of edothelium‐derived relaxing factor), no concentration of acetylcholine, and only the highest concentration of nitroglycerin, lowered vascular resistance. In non‐preconstricted flaps, glucose utilization decreased in norepinephrine‐infused flaps, increased in nitroglycerin‐ and tolazoline‐infused flaps, and was biphasic in acetylcholine‐infused flaps. These results indicate that the IPPSF responds to pharmacologic agents in a manner similar to classicin vitroandin vivomodels. Thus, the IPPSF would be a relevant model for investigating the delivery and/or toxicity of pharmacologically active compounds.