PHARMACOLOGICAL MODULATION OF THE CUTANEOUS VASCULATURE IN THE ISOLATED-PERFUSED PORCINE SKIN FLAP

The isolated perfused porcine skin flap (IPPSF), an ex vivo model syst em used in cutaneous toxicology and pharmacology, is capable of assess ing 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, tol azoline, and norepinephrine to affect Vasculature resistance and gluco se utilization was investigated in the IPPSF. Norepinephrine infusions between 10(-7) and 10(-5) M increased Vascular resistance in a dose-d ependent manner; half-maximal (EC(50)) and maximal responses occurred at 3.18 x 10(-6) and 10(-5) M, respectively. In non-preconstricted fla ps, neither acetylcholine, nitroglycerin, nor tolazoline vasodilated t he IPPSF; however, acetylcholine, nitroglycerin, and tolazoline each l owered Vascular resistance in a dose-dependent manner in norepinephrin e-preconstricted flaps. Maximal relaxation was induced at 10(-4), 10(- 6), and 5 x 10(-5) M, by tolazoline, acetylcholine, and nitroglycerin, respectively, whereas the EG(50) values were 2.88 x 10(-7), 1.35 x 10 (-8), and 1.72 x 10(-7) M, respectively. In flaps pretreated with nore pinephrine and methylene blue (a potential blocker of edothelium-deriv ed relaxing factor), no concentration of acetylcholine, and only the h ighest concentration of nitroglycerin, lowered Vascular resistance. in non-preconstricted flaps, glucose utilization decreased in norepineph rine-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 classic in vitro and in vivo models. Thus, the IPPSF would be a relevant model for investigating the delivery and/or toxicity of pharmacologically active compounds.