ly-53857 and Ischemia

Ischemic necrosis resulting from vasospasm is a common complication in skin flap surgery, and serotonin released by traumatized platelets is likely to play an important role in the pathogenesis of skin vasospasm in flap surgery. We studied the pathogenic role of serotonin and its pharmacologic intervention thereof in skin flap ischemic necrosis in pigs. We observed that serotonin caused a concentration-dependent (10(-8)-10(-5) M) increase in perfusion pressure in isolated perfused pig skin flaps. This vasoconstrictive effect of serotonin was blocked by S1C/2-serotonergic receptor antagonists LY53857 (10(-5) M) and ketanserin (10(-5) M), but not by an alpha 1-adrenoceptor antagonist (prazosin 10(-5) M), or a thromboxane A2 (TxA2)/endoperoxide receptor antagonist (SQ30741 10(-5) M). The vasoconstrictive effect of serotonin was more pronounced (p < 0.05) in the presence of an endothelium-derived nitric oxide (NO) synthesis inhibitor [N omega-monomethyl-L-arginine (L-NA) or NG-nitro-L-arginine (L-NMMA) 10(-5) M] but not a cyclooxygenase inhibitor (indomethacin 10(-5) M). In in vivo studies, serotonin infusion (5 micrograms/kg/min intravenously, i.v.) significantly (p < 0.05) decreased pig random pattern skin flap capillary blood flow. This in vivo vascular effect was also completely blocked in pigs pretreated with LY53857 (0.4 mg/kg i.v.). In a separate experiment without serotonin infusion, i.v. prazosin (2-8 micrograms/kg), dazmegrel (2-6 mg/kg), or SQ30741 (2-4 mg/kg) had no significant effect on skin flap capillary blood flow as compared with control. On the other hand, i.v. sergolexole or LY53857 significantly (p < 0.05) increased skin flap capillary blood flow in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic alpha-Antagonists; Animals; Arginine; Dose-Response Relationship, Drug; Ergolines; In Vitro Techniques; Ischemia; Ketanserin; Necrosis; omega-N-Methylarginine; Prostaglandin H2; Prostaglandins H; Regional Blood Flow; Serotonin; Serotonin Antagonists; Skin; Surgical Flaps; Swine; Thromboxane A2; Vasoconstriction

Three experiments were conducted to study the effect of ketanserin and LY53857, S2-serotonergic receptor antagonists, on skin blood flow and viability in acute random pattern skin flaps (4 x 10 cm) in the pig. In experiment 1, the dose-response effect of intravenous ketanserin (0, 0.15, 0.25, 0.35, and 0.50 mg/kg) on skin flap capillary blood flow was studied 6 hr after skin flap surgery, using the radioactive microsphere (15 microns) technique and under pentobarbital anesthesia. Significant (P less than 0.05) increase in skin flap blood flow was seen at the dosages of 0.25 and 0.35 mg/kg compared with the saline-treated control. In experiment 2, the effect of five-day intramuscular ketanserin and LY53857 treatment (0.30 mg/kg/day; in divided doses) on skin flap viability was studied. The drug treatments were started two days preoperatively. It was observed that the length of skin flap viability in ketanserin (6.6 +/- 0.2 cm; n = 40 flaps) and LY53857 (6.8 +/- 0.3 cm; n = 40 flaps) treated flaps were significantly (P less than 0.05) higher than the saline-treated control (5.5 +/- 0.1 cm; n = 48 flaps). Ketanserin treatment started 30 min after flap surgery also significantly (P less than 0.05) increased the length of skin flap viability (6.1 +/- 0.1 cm) compared with the control. There was no significant difference in skin viability between ketanserin and LY53857 treated skin flaps. The preceding study on the effect of ketanserin treatment on random pattern skin flap viability was repeated in experiment 3. Again, it was observed that intramuscular ketanserin treatment significantly (P less than 0.05) increased the skin flap viability. It was concluded that ketanserin and LY53857 treatment resulted in significant augmentation of porcine acute random pattern skin flap viability. This is the first experimental evidence to indicate that S2-serotonergic receptors participate in the pathogenesis of skin flap ischemia.

Topics: Animals; Dose-Response Relationship, Drug; Ergolines; Graft Survival; Ischemia; Ketanserin; Regional Blood Flow; Serotonin Antagonists; Skin; Surgical Flaps; Swine