The Arterio-Venous Difference for Immunoreactive Parathyroid Hormone and the Production of Adenosine 3′,5′-Monophosphate by Isolated Perfused Bone: Studies with Analogs of Parathyroid Hormone*

Abstract

Recent studies suggest that the uptake of immunoreactive parathyroid hormone (iPTH) displays different characteristics in liver, kidney, and bone. Using the isolated perfused canine bone, we have characterized the uptake of two synthetic analogs of PTH, bovine PTH-(3–34) [bPTH-(3–34)] and [Nle⁸,Nle¹⁸,Tyr³⁴]bPTH-(3–34) amide, which had previously been shown to inhibit PTH-stimulated adenylate cyclase activity in renal membranes. During the infusion of synthetic bPTH-(1–34) (3 ng/ml), extraction of iPTH by isolated perfused bone averaged 37 ± 1%, and _cAMP production rose from 6.2 ± 2.0 to 21 ± 3 pmol/min. Extraction of bPTH-(3–34) was similar (35 ± 2%), but _cAMP levels did not increase over baseline with PTH concentrations as high as 100 ng/ml. Simultaneous infusion of bPTH-(1–34) and bPTH-(3–34) at molar ratios of 1:2 led to a 50% inhibition of PTH-stimulated cAMP increases. The extraction by bone of the more potent in vitro inhibitor of renal cortical adenylate cyclase [Nle⁸,Nle¹⁸,Tyr³⁴34]bPTH-(3–34) NH₂2 (3 ng/ml) averaged 39 ± 2%. In contrast, cAMP production rose from a baseline of 5.6 ± 0.5 to 12.5 ± 2.0 pmol/min, demonstrating agonist activity for the analog. These studies show that [Nle³, Nle¹⁸,Tyr³⁴]bPTH-(3–34) NH₂2 has agonist properties in isolated perfused bone, and unsubstituted bPTH-(3–34) inhibits PTHstimulated cAMP release by perfused bone.