Desensitization of alpha-adrenergic receptor-mediated smooth muscle contraction: role of the endothelium.
Desensitization of alpha-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 alpha-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 less than 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 less than 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 x 10(-5) M) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Hiremath
A N
AN
Department of Medicine, Stanford University School of Medicine, California.
Hu
Z W
ZW
Hoffman
B B
BB
D000310:Adrenal Gland Neoplasms / Q000503:physiopathology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009368:Neoplasm Transplantation; D010656:Phenylephrine / Q000494:pharmacology; D010673:Pheochromocytoma / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D014184:Transplantation, Homologous
D006454:Hemoglobins; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D007213:Indomethacin