Vasodilatory effect of tuberoinfundibular peptide (TIP39): requirement of receptor desensitization and its beneficial effect in the post-ischemic heart.

Abstract Tuberoinfundibular peptide of 39 residues (TIP39) is a member of the parathyroid hormone (PTH) family and a highly specific ligand of the PTH-receptor type 2 (PTH-2r). Recent studies have shown vasoactive properties of TIP39 in the kidney. This effect was stronger after desensitization of the parathyroid hormone-receptor type 1 (PTH-1r). The aims of our study were three-fold: (1) to investigate the influence of TIP39 on coronary resistance (CR), (2) to investigate a possible cross-talk between vascular PTH-receptors in the cardiovascular system, and (3) to investigate whether the endogenously released PTHrP during ischemia induces such a desensitizing effect. Experiments were performed on isolated rat hearts that were perfused with a constant pressure (Langendorff mode) and the coronary flow was determined. Under basal conditions, TIP39 showed no influences on CR. However, TIP39 reduced the CR by approximately 22% after pre-treatment of the hearts with a PTH-1r agonist. This TIP39 effect was abolished either by co-administration of a PTH-2r antagonist or by inhibition of nitric oxide (NO) formation. In an ischemia-reperfusion model endogenously released PTHrP desensitized the PTH-1r and pre-ischemic addition of TIP39 reduced post-ischemic CR by about 28%. Again, this effect was completely abolished in the presence of the PTH-2r antagonist or the PTH-1r-antagonist or by inhibition of NO formation. However, no effect was observed when TIP39 was washed-out prior to ischemia or if the treatment with TIP39 was restricted to the reperfusion. Furthermore, a pre-ischemic application of the NO-dependent vasorelaxant bradykinin provoked a similar effect on the post-ischemic CR than TIP39. In conclusion, a NO-dependent vasodilatory effect of TIP39 was demonstrated if the PTH-1r is desensitized by either exogenously applicated PTHrP peptides or endogenously released PTHrP.