There is clinical and experimental evidence to indicate that cigarette smoking may increase the risk of skin ischemic necrosis in flap surgery but the pathogenic mechanism remains unclear. The objectives of this project were to investigate the potential deleterious effects and mechanism of action of nicotine, a major by-product of cigarette smoking, in skin flap surgery in the pig. It was observed that 4-5 weeks of intramuscular nicotine injections (4 mg/kg; twice daily) significantly (p < 0.05) decreased the skin flap capillary blood flow and the length and area of skin flap viability in the pig. This nicotine treatment also induced a 1.6-fold increase in skin flap tissue content of norepinephrine compared with the saline-treated control. The estimated mean wet skin tissue content of norepinephrine (5 x 10(-7) M) was much higher than the circulating level of norepinephrine (1.8 x 10(-9) M) in nicotine-treated pigs. This level of norepinephrine (5 x 10(-7) M) was seen to induce a significant vasoconstrictor effect (75% increase over basal perfusion pressure) in isolated perfused pig skin flaps. It was also observed that the vasoconstrictor effect of norepinephrine was significantly (p < 0.05) enhanced in the presence of 10(-4) M N omega-monomethyl-L-arginine or NG-nitro-L-arginine, an endothelium-derived relaxing factor--nitric oxide (EDRF/NO) synthesis inhibitor. This vasoconstrictor effect was further enhanced in the presence of NG-nitro-L-arginine and 10(-5) M indomethacin, a cyclooxygenase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)