Involvement of protein kinase C in hypoxia-induced desensitization of the beta-adrenergic system in human endothelial cells.

In order to better understand the mechanisms whereby oxygen deficiency promotes blunting of the endothelial beta-adrenergic receptor (beta-AR) system we examined the effects of hypoxia on beta-AR, adenylate cyclase (AC) activity and phosphoinositide turnover in cultures of human pulmonary artery and umbilical vein endothelial cells. 1 hr of hypobaric hypoxia (290 mm Hg) increased basal levels of inositol mono-, bis-, and tris-phosphate to those following histamine stimulation under normoxia. Basal and isoproterenol-stimulated AC activities were lowered after 1 hr of hypoxia. beta-AR density was decreased after 2-3 hrs of hypoxia and after treatment of EC with histamine, platelet activating factor or phorbol myristate acetate (PMA). In protein-kinase C (PK-C)-downregulated EC, neither hypoxia nor PMA influenced beta-AR density or AC activity. Hypoxia-induced desensitization of beta-AR signal transduction in EC may involve hypoxia-stimulated phosphoinositide turnover and subsequent PK-C activation.