Beta-adrenergic regulation of secretion from Clara cell adenomas of the mouse lung

Abstract

Ethylnitrosourea-induced pulmonary adenomas of the mouse have been reported as being predominantly Clara cell in origin. The response of these tumor cells in vivo to the secretory agonist, isoproterenol (10 mg/kg) and the antagonist, propranolol (2.0 mg/kg) 1 hour after intraperitoneal injection into 120-day-old tumor-bearing mice was examined. Ultrastructural morphometry was used to quantitate the secretory response of tumor cells by measuring the volume density of the secretory granules. In the intact animal, isoproterenol stimulated secretion in the Clara cell adenomas (40% decrease in volume density with no change in surface to volume ratio of granules), while propranolol prevented this effect. In addition, beta-adrenergic receptors on isolated tumor cells were demonstrated by radioligand-binding assay by using [125I]iodocyanopindolol (ICYP). Scatchard analysis of data derived from whole cells indicates a maximum receptor-binding capacity of 27 fmoles/mg of protein and a KD of 0.029 nM. Isoproterenol displacement of ICYP binding yields an IC50 of 8 X 10(-7) M and a calculated KD of 3.36 X 10(-7) M. The beta 2 identity of these receptors was determined by utilizing the relatively specific beta 1 and beta 2 antagonists practolol and ICI-118,551, respectively. Practolol failed to displace more than 30% of ICYP binding even at 100 microM, while ICI-118,551 displacement of ICYP yielded a linear Hofstee plot (r = 0.93) and a KD of 5.04 X 10(-9) M. These findings suggest that the secretory activity of Clara cell-like pulmonary adenomas is under beta-adrenergic control similar to that of normal bronchiolar Clara cells.