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Transcript Expression of the Tuberoinfundibular Peptide (TIP)39/PTH2 Receptor System and Non-PTH1 Receptor-Mediated Tonic Effects of TIP39 and Other PTH2 Receptor Ligands in Renal Vessels

Renovascular Pharmacology and Physiology, Institut National de la Santé et de la Recherche Médicale and University Louis Pasteur Medical School, Strasbourg F67085, France

Address all correspondence and requests for reprints to: Jean-Jacques Helwig, Ph.D., Pharmacologie and Physiologie Rénovasculaires, Equipe Mixte Institut National de la Santé et de la Recherche Médicale- University Louis Pasteur 0015, 11 rue Humann, Bâtiment 4, 1er étage, F67085 Strasbourg Cedex, France. E-mail: . jean-jacques.helwig{at}pharmaco-ulp.u-strasbg.fr

Although lower than in brain, the type 2 PTH receptor (PTH2-R) has been shown to be expressed throughout the cardiovascular system. Tuberoinfundibular peptide (TIP) purified from brain is thought to be the endogenous selective ligand of the PTH2-R. In the present studies, TIP and PTH2-R mRNA expressions were evidenced by RT-PCR in rat intrarenal arteries as well as in renovascular smooth muscle cells cultured from these arteries. In the isolated perfused rat kidney (IPK), peptides known to bind to both PTH1- and PTH2-Rs, such as rat PTH (1–34) and the hybrid PTH/PTHrP peptide, [Ile⁵, Trp²³]PTHrP (1–36), failed to exhibit improved vasodilatory effect, compared with human PTHrP (1–36), which binds only to the PTH1-R. Thus, a non-PTH1-R seemed not to be involved in the vasodilatory effects of these peptides. On the other hand, TIP exhibited complex vasoactivity, constricting the IPK at 10 nM and dilating the IPK at 1, 100, and 1000 nM. Moreover, [p-benzoyl-L-Phe⁴,Ile⁵,Trp²³]PTHrP (1–36), initially described as a selective PTH2-R antagonist, also displayed a strong vasodilatory effect and therefore could not be used to check that TIP-induced vasoactivity was mediated by the PTH2-R. However, both [p-benzoyl-L-Phe⁴,Ile⁵,Trp²³]PTHrP (1–36) and TIP displayed similar or even enhanced vasodilation in IPK in which PTH1-R-induced vasodilation was fully desensitized by sustained exposure to human PTHrP (1–36). Importantly, in IPK desensitized to the vasodilatory action of PTHrP (1–36), the hybrid PTH/PTHrP peptide and rat PTH (1–34), whose vasodilatory responses appeared exclusively PTH1-R dependent in naive IPK, produced a new and strong vasodilation. In conclusion, TIP and PTH2-R mRNAs are expressed in renal vessels and TIP appears as a new vasoactive peptide. Whether TIP interacts with PTH2-R could not be shown. However, these studies reveal the ability of TIP, as well as of other peptides known to bind to the PTH2-R, to dilate renal vessels in a PTH1-R-independent manner. Moreover, results obtained in IPK desensitized to the vasodilatory action of PTHrP (1–36) strongly suggest that TIP, along with PTHrP, might be coordinately involved in the regulation of renal hemodynamics.

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