Parathyroid hormone-related protein relaxes rat gastric smooth muscle and shows cross-desensitization with parathyroid hormone

Previously, we reported that parathyroid hormone (PTH) is a potent and effective relaxant of rat gastrointestinal smooth muscle. Since the recently discovered PTH-related protein (PTHrP) has amino-terminal homology with PTH and acts like PTH on bone and kidney, we decided to study the effects of synthetic PTHrP analogs on the isometric tension of rat fundic strips. Rat (r) PTH-(1–34), human (h) PTHrP-(1–34), and [Tyr0]hPTHrP-(1–34) relaxed acetylcholine-stimulated fundic strips in a dose-dependent manner, with an IC50 of 6, 10, and 31 nM, respectively. However, maximal doses of [Tyr0]hPTHrP-(1–34) were considerably less effective than the other two peptides. Addition of rPTH-(1–34) or hPTHrP-(1–34) to a maximally effective dose of [Tyr0]hPTHrP-(1–34) produced no further relaxation, indicating that [Tyr0]hPTHrP-(1–34) also has antagonistic properties. Bovine PTH-(3–34), an established in vitro antagonist of PTH, partially inhibited the relaxant effect of PTHrP. Fundic strips that had been desensitized by preincubation for 30–45 minutes with either rPTH-(1–34) or hPTHrP-(1–34) (330–500 nM) were also insensitive to the relaxant action of either peptide, but in the same preparations, the relaxation produced by vasoactive intestinal peptide was unaffected. These studies indicate that PTHrP and PTH can interact with the same receptor. Whether PTHrP influences gastrointestinal motility in normal or tumor-bearing persons remains to be investigated.