Renal vasodilation and microvessel adenylate cyclase stimulation by synthetic parathyroid hormone-like protein fragments

Abstract

The hypercalcemia caused by malignancy factor, also called parathyroid hormone-related protein (PTHrP), exhibits most of the biological activities of parathyroid hormone (PTH) in kidney and bone. On the basis of the well-documented vascular action of PTH, we characterized the vasodilator action of human (h) PTHrP-(1–34) on a preparation of the isolated rat kidney, and its activity to stimulate adenylate cyclase in microvessels isolated from rabbit kidney cortex. Injection of sequential cumulative doses of hPTHrP-(1–34) into the isolated kidney preparation produced increasing vasodilation up to 10 −18 M (EC 50 of 3 × 10 −9 M) and decreasing responses thereafter. The maximal effect represented 26% of the reference relaxation induced by papaverine. Single injections of hPTHrP-(1–34) resulted in a greater (over 60%) vasodilatation. These results were reminiscent of the tachyphylaxis that occurs after repeated exposure to the peptide. The (3–34) PTH antagonist inhibited the hPTHrP-induced vasodilatation. Human PTHrP-(1– 34) was equipotent with hPTH-(1–34) (EC 50 values of 3 × 10 −9 M) but 5-fold less potent than rat (r) PTH-(1–34) in stimulating microvessel adenylate cyclase. GTP enhanced the enzyme responses to the peptides but reduced their potency. Both (3–34) and (7–34) PTH antagonists were inhibitors of hPTHrP- or PTH-stimulated microvascular adenylate cyclase. Synthetic hPTHrP-(1–16) had neither vasodilator nor adenylate cyclase-stimulating activity. This hPTHrP fragment exhibited some inhibitory effect on the hPTHrP-(1–34)-induced stimulation of microvessel adenylate cyclase. These results indicate that hPTHrP possesses PTH-like activity to cause vasorelaxation and to stimulate microvascular adenylate cyclase in the kidney.