Parathyroid hormone-related protein-(1-34) inhibits intrinsic pump activity of isolated murine lymph vessels

Parathyroid hormone-related protein (PTHrP) was originally found as a tumor-derived vasoactive factor and has also been known to produce significant relaxation of vascular smooth muscles. Thus effects of PTHrP-(1-34), a PTH receptor-binding domain, on spontaneous lymphatic pump activity was investigated in isolated pressurized lymph vessels of mice. Low concentrations (1 × 10−10 and 3 × 10−10 M) of PTHrP-(1-34) dilated lymph vessels and reduced the frequency of pump activity, whereas high concentrations (1 × 10−9 to 1 × 10−8 M) of PTHrP-(1-34) caused dilation with cessation of the lymphatic pump activity. N ω-nitro-l-arginine methyl ester (l-NAME; 3 × 10−5 M) but not indomethacin (1 × 10−5 M) significantly reduced the PTHrP-(1-34)-induced inhibitory responses of the lymphatic pump activity. In the presence of l-NAME (3 × 10−5 M) and l-arginine (1 × 10−3 M), the l-NAME-induced inhibition in the PTHrP-(1-34)-mediated responses was significantly reduced. Glibenclamide (1 × 10−6 M) significantly suppressed the inhibitory responses of the lymphatic pump activity induced by PTHrP-(1-34) and S-nitroso- N-acetyl-penicillamine. The PTHrP-(1-34)-mediated inhibitory responses were significantly reduced by treatment with PTHrP-(7-34) (1 × 10−7 M). These results suggest that PTHrP-(1-34) inhibits spontaneous pump activity of the isolated lymph vessels via PTH receptors and that production and release of endogenous nitric oxide and activation of ATP-sensitive K+ channels in the lymph vessels contribute to the PTHrP-(1-34)-mediated inhibitory responses of the lymphatic pump activity.