Desensitization of α-Adrenergic Receptor-Mediated Smooth Muscle Contraction

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Abstract
Desensitization of α-adrenergic receptor-mediated smooth muscle contraction occur in aortas from New England Deaconess Hospital (NEDH) rats harboring pheochromocytoma (PHEO) and following chronic exposure to the α-adrenergic agonist phenylephrine in vitro. Endothelium is known to release an endothelial cell-derived relaxing factor that promotes smooth muscle relaxation. We wondered if the endothelium might contribute to the desensitization of contraction. The role of the endothelium in desensitization was studied using aortic rings with endothelium [E(+)] and with endothelium removed [E(-)]. Maximal phenylephrine (PE)-induced contraction (Emax) for E(+) was 1.7 ± 0.3 g in controls and 0.4 ± 0.1 g in PHEO (p < 0.001), demonstrating desensitization; however, for E(-), Emax was 2.4 ± 0.2 g in PHEO vs. 2.5 ± 0.2 g in controls, demonstrating restoration of maximal contraction when the endothelium was removed. However, sensitivity [-log EC50(M)] to PE in E(-) remained significantly lower in PHEO compared to controls (6.94 ± 0.12 vs. 7.51 ± 0.14, respectively, p < 0.001). Similarly, in aortic ring segments desensitized in vitro with phenylephrine, the maximal contraction in phenylephrine-exposed aortas was 60% of that seen in controls. Removal of the endothelium from the vessels pretreated with phenylephrine fully restored the maximal response and sensitivity of these vessels. Treatment of desensitized vessels with hemoglobin (5 ± 10−5M) restored the maximal contraction and sensitivity to phenylephrine. When the endothelium was removed prior to chronic exposure to phenylephrine, the sensitivity to phenylephrine decreased while the Emax remained similar to controls. Indomethacin and 8-(sulfophenyl)theophylline had no effect on contraction of the desensitized aortic ring segments. Our results demonstrate that the endothelium plays a major role in α-adrenergic receptor desensitization of blood vessels; this effect of the endothelium is likely mediated by endothelium-derived relaxing factor.

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