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

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.

N-terminal parathyroid hormone-related peptide hyperpolarizes endothelial cells and causes a reduction of the coronary resistance of the rat heart via endothelial hyperpolarization.

Parathyroid hormone-related peptide (PTHrP) is known to be a strong vasorelaxant peptide. The mechanisms by which PTHrP reduces the coronary resistance of the rat heart have not been worked out but seem to be independent of the classical PTH/PTHrP receptor-mediated, cAMP-dependent effect. In this study we hypothesized that PTHrP reduces the coronary resistance of the rat heart via endothelial cell hyperpolarization. Isolated microvascular endothelial cells from rat heart were incubated with PTHrP(1-36), and changes in the membrane potential were recorded via DiBAC fluorescence. Cells exposed to PTHrP showed a hyperpolarization of approximately 7mV. In the isolated Langendorff preparation, PTHrP-dependent vasodilatation of l-nitro-arginine-exposed hearts was abolished under depolarizing conditions (high potassium). Denudation of the endothelial cell layer significantly impaired the vasodilatory effect of PTHrP. In the presence of H89 (a cAMP/protein kinase A pathway antagonist) and indomethacin (a cyclooxygenase inhibitor), PTHrP dilated the vessels. In conclusion, PTHrP exerted a nitric oxide-independent vasodilatory effect that depends on endothelial cell hyperpolarization.

Sex-specific differences in ventricular expression and function of parathyroid hormone-related peptide.

OBJECTIVE: Parathyroid hormone-related peptide (PTHrP) expression is modulated by estrogen. It is expressed in coronary endothelial cells and involved in the endothelium-dependent regulation of coronary resistance and cardiac function. In the present study, we hypothesized that endogenously synthesized and released PTHrP contributes to sex-specific differences in the regulation of cardiac function. METHODS: The influence of sex on ventricular PTHrP expression in normotensive rats was determined via real-time PCR and immunoblot analysis. Sex-specific effects of exogenous PTHrP or endogenous released PTHrP were determined in vitro on isolated ventricular cardiomyocytes, Langendorff preparations on isolated hearts and in vivo using different agonistic or antagonistic PTHrP peptides. RESULTS: Ventricular expression of PTHrP was elevated in hearts from female rats compared to male counterparts. Addition of PTHrP(1-36) did not increase left ventricular function in hearts from either sex, but increased coronary flow in hearts from female rats significantly greater than in those from males. 5Ile-PTHrP(1-36), which was used to antagonize endogenously released PTHrP, reduced left ventricular function in females but not males in vitro and in vivo. Under conditions of increased endogenous PTHrP release, i.e. ischemia-reperfusion, antagonization of PTHrP significantly reduced post-ischemic recovery in hearts from females but not in those from males. CONCLUSIONS: Sex determines the ventricular expression of PTHrP mRNA and protein. The results indicate that PTHrP may improve cardiac function to a greater extent in women than in men following a brief period of ischemia.