Our objective was to test the hypothesis that acute exposure of human skin vasculature to nicotine may have deleterious effects on endothelial function. Vasoconstriction and vasorelaxation in isolated perfused human skin flaps (approximately 8 x 18 cm) derived from dermolipectomy specimens were assessed by studying changes in skin perfusion pressure measured by a pressure transducer, and skin perfusion was assessed by a dermofluorometry technique (n = 4 or 5). It was observed that nicotine (10(-7) M) amplified (P < 0.05) the norepinephrine (NE)-induced concentration-dependent (10(-7)-10(-5) M) increase in skin vasoconstriction compared with the control. This amplification effect of nicotine in NE-induced skin vasoconstriction was not blocked by the nicotine-receptor antagonist hexamethonium (10(-6) M) or the cyclooxygenase inhibitor indomethacin (10(-5) M). It was also observed that ACh and nitroglycerin (NTG) elicited a concentration-dependent (10(-8)-10(-5) M) vasorelaxation in skin flaps preconstricted with 8 x 10(-7) M of NE. The vasorelaxation induced by ACh was attenuated (P < 0.05) in the presence of nicotine (10(-7) M) compared with the control. However, skin vasorelaxation induced by NTG was not affected by nicotine (10(-7) M). ACh and NTG are known to induce endothelium-dependent and -independent vasorelaxation, respectively. The present findings were interpreted to indicate that acute exposure of human skin vasculature to nicotine was associated with 1) amplification of NE-induced skin vasoconstriction and 2) impairment of endothelium-dependent skin vasorelaxation. Cyclooxygenase products and nicotine receptors blocked by hexamethonium were not involved in the amplification of NE-induced skin vasoconstriction by nicotine. These findings may provide further insight into the pathogenesis of skin vasospasm in skin flap surgery and skin ischemic disease associated with cigarette smoking or use of smokeless tobacco.
The aim of this project was to investigate the role of ETA and ETB receptors in the mediation of endothelin (ET)-1-induced vasoconstriction in human skin. This information should provide important insights into the design of pharmacological intervention against skin vasospasm induced by ET-1 in peripheral vascular disease or surgical trauma. Vasoconstriction in response to intra-arterial drug infusion in isolated perfused human skin flaps (8 × 18 cm) derived from dermolipectomy specimens was assessed by studying changes in skin perfusion and perfusion pressure under constant flow rate in each drug treatment ( n = 4). It was observed that ET-1 (10−10 to 10−8 M) and norepinephrine (NE, 10−8 to 10−5 M) caused skin vasoconstriction in a concentration-dependent manner, with the vasoconstrictor potency of ET-1 ∼200-fold higher than NE. The ETA-receptor antagonist BQ-123 but not the ETB-receptor antagonist BQ-788 blocked the vasoconstrictor effect of ET-1. This observation was confirmed by studying skin perfusion using the dermofluorometry technique. In addition, ETB-receptor agonists BQ-3020 and sarafotoxin S6c (10−9 to 10−6 M) did not evoke skin vasoconstriction. BQ-3020 also did not elicit skin vasoconstriction even in the presence of 10−5M of N ω-nitro-l-arginine methyl ester and indomethacin. Furthermore, results from saturable and competitive ET-1 radioligand membrane receptor binding assays revealed that high-affinity and capacity binding sites are predominantly the ETA receptor subtype in endothelium-denuded skin arteries and veins of 0.5–1.5 mm diameter, with an ETA-to-ETBreceptor ratio of 83:17 in arteries ( n= 5) and 78:22 in veins ( n = 7). Results from the present functional and radioligand receptor binding studies clearly indicate that ET-1 is a very potent vasoconstrictor in human skin and its vasoconstrictor effect is primarily mediated by ETAreceptors, with no significant participation from ETB receptors.
Various laboratories have reported that local subcutaneous or subdermal injection of VEGF(165) at the time of surgery effectively attenuated ischemic necrosis in rat skin flaps, but the mechanism was not studied and enhanced angiogenesis was implicated. In the present study, we used the clinically relevant isolated perfused 6 x 16-cm pig buttock skin flap model to 1) test our hypothesis that VEGF(165) is a potent vasodilator and acute VEGF(165) treatment increases skin perfusion; and 2) investigate the mechanism of VEGF(165)-induced skin vasorelaxation. We observed that VEGF(165) (5 x 10(-16)-5 x 10(-11) M) elicited a concentration-dependent decrease in perfusion pressure (i.e., vasorelaxation) in skin flaps preconstricted with a submaximal concentration of norepinephrine (NE), endothelin-1, or U-46619. The VEGF(165)-induced skin vasorelaxation was confirmed using a dermofluorometry technique for assessment of skin perfusion. The vasorelaxation potency of VEGF(165) in NE-preconstricted skin flaps (pD(2) = 13.57 +/- 0.31) was higher (P < 0.05) than that of acetylcholine (pD(2) = 7.08 +/- 0.24). Human placental factor, a specific VEGF receptor-1 agonist, did not elicit any vasorelaxation effect. However, a specific antibody to VEGF receptor-2 (1 microg/ml) or a specific VEGF receptor-2 inhibitor (5 x 10(-6) M SU-1498) blocked the vasorelaxation effect of VEGF(165) in NE-preconstricted skin flaps. These observations indicate that the potent vasorelaxation effect of VEGF(165) in the skin vasculature is initiated by the activation of VEGF receptor-2. Furthermore, using pharmacological probes, we observed that the postreceptor signaling pathways of VEGF(165)-induced skin vasorelaxation involved activation of phospholipase C and protein kinase C, an increase in inositol 1,4,5-trisphosphate activity, release of the intra-cellular Ca(2+) store, and synthesis/release of endothelial nitric oxide, which predominantly triggered the effector mechanism of VEGF(165)-induced vasorelaxation. This information provides, for the first time, an important insight into the mechanism of VEGF(165) protein or gene therapy in the prevention/treatment of ischemia in skin flap surgery and skin ischemic diseases.
Pang. Pharmacological characterization of vasomotor activity of human musculocutaneous perforator artery and vein. J Appl Physiol 89: 2268-2275, 2000.-Vasospasm is one of the main causes of skin ischemic necrosis in cutaneous and musculocutaneous flap surgery, but the pathogenic mechanism is unclear. We planned to test the hypothesis derived from clinical impression that veins are more susceptible to vasospasm than arteries in flap surgery and, once established, that venous vasospasm is difficult to resolve and more detrimental than arterial vasospasm. To this end, we investigated the differences in sensitivity to vasoconstrictors and vasodilators between the human musculocutaneous perforator (MCP) artery and vein by measuring the isometric tension of arterial and venous rings suspended in organ chambers. Vascular contraction was expressed as a percentage of the tension induced by 50 mM KCl. Relaxation was expressed as a percentage of contraction induced by a submaximal concentration (3 ϫ 10 Ϫ9 M) of endothelin-1 (ET-1). We observed that the vasoconstrictor potency of norepinephrine was significantly higher in the MCP vein than in the MCP artery. The vasoconstrictor potency of ET-1 and the thromboxane A 2 mimetic U-46619 were similar in the MCP vein and artery, but the maximal contraction induced by ET-1 and U-46619 was significantly higher in the MCP vein than in the MCP artery. On the other hand, the MCP vein was less sensitive than the MCP artery to the relaxation effect of nitroglycerin, nifedipine, and lidocaine. These differences between the human MCP artery and vein in response to vasoactive agents lend support to the clinical impression in flap surgery that veins appear to be more susceptible to vasospasm than arteries and venous vasospasm seems to be more difficult to resolve than arterial vasospasm in cutaneous and musculocutaneous flap surgery.
While visiting Jamaica, a 50-year-old woman stumbled on an outdoor wooden staircase and sustained an injury to the right leg. The wound was cleaned topically and the patient was given antibacterial therapy. Five weeks later, in Canada, she presented with an ulcer at the injury site. An excisional biopsy showed copious broad, septate, melanized fungal filaments penetrating into tissue. Culture yielded a nonsporulating melanized mycelium. The isolate was strongly inhibited by cycloheximide and benomyl but grew at 37 degrees C. After 16 weeks cultivation on modified Leonian's agar at 25 degrees C, it developed pycnidia characteristic of Lasiodiplodia theobromae, a common tropical phytopathogen mainly known previously as a rare agent of keratitis and onychomycosis in humans. The patient was not given antifungal chemotherapy, and the ulcer, which had been broadly excised in the biopsy procedure, ultimately resolved after treatment with saline compresses. The six-month follow-up showed no sign of infection. This case, interpreted in light of previously reported cases, shows that on rare occasions L. theobromae is able to act as an agent of subcutaneous phaeohyphomycosis and that, when this occurs, debridement alone may be sufficient to eradicate it.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.