PARATHYROID HORMONE ADENYLATE CYCLASE COUPLING IN VASCULAR SMOOTH-MUSCLE CELLS/

Parathyroid hormone (PTH) has been implicated in hypertension, but PTH infusion results in vasodilation. PTH activates adenylate cyclase in vascular smooth muscle, but little is known about the factors that reg ulate PTH receptor/ adenylate cyclase coupling in vascular cells. To c haracterize hormone-receptor signaling, we measured cyclic AMP levels in rat arterial smooth muscle cells in culture exposed to PTH (bovine 1-34). PTH yielded time- and concentration-dependent increases in cycl ic AMP levels. Compared with isoproterenol, PTH was more potent, with a threshold at 2x10(-9) versus 5x10(-8) mol/L and half maximal respons es at 10(-8) versus 2.4x10(-7) mol/L. PTH-induced increases in cyclic AMP were independent of extracellular calcium, cyclooxygenase metaboli tes, phospholipase C, and protein kinase C because PTH-induced increas es in cyclic AMP were not prevented by variations in extracellular cal cium, indomethacin, angiotensin II, vasopressin, and protein kinase C activators or inhibitors. PTH/adenylate cyclase coupling was G protein -dependent because increases in cyclic AMP were prevented by preincuba tion with cholera toxin but not with pertussis toxin. Prolonged exposu re to PTH resulted in time- and concentration-dependent homologous des ensitization of cyclic AMP responses. Desensitization occurred proxima l to G protein/adenylate cyclase because after prolonged PTH, response s to forskolin and cholera toxin remained intact. Desensitization was independent of protein kinase A and receptor sequestration because cyc lic AMP responses remained after prolonged exposure to forskolin and p retreatment with phenylarsine oxide, colchicine, and cytochalasin D. W e conclude that in vascular smooth muscle cells, PTH is coupled to ade nylate cyclase through a cholera toxin-sensitive G protein. Prolonged exposure to PTH results in desensitization of PTH receptors. Because a denylate cyclase is a potent vasodilator signaling pathway, these cell ular effects could account for the in vivo observation that PTH infusi on results in vasodilation. In contrast, states of prolonged PTH exces s may not be associated with vasodilation because PTH-induced cyclic A MP increases are desensitized.