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 r elaxation of vascular smooth muscles. Thus effects of PTHrP-(1-34), a PTH r eceptor-binding domain, on spontaneous lymphatic pump activity was investig ated in isolated pressurized lymph vessels of mice. Low concentrations (1 x 10(-10) and 3 x 10(-10) M) of PTHrP-( 1-34) dilated lymph vessels and redu ced the frequency of pump activity, whereas high concentrations (1 3 10(-9) to 1 x 10(-8) M) of PTHrP-(1-34) caused dilation with cessation of the lym phatic pump activity. N-omega-nitro-L-arginine methyl ester (L-NAME; 3 x 10 (-5) M) but not indomethacin (1 x 10(-5) M) significantly reduced the PTHrP -(1-34)-induced inhibitory responses of the lymphatic pump activity. In the presence of L-NAME (3 x 10(-5) M) and L-arginine (1 x 10(-3) M), the L-NAM E-induced inhibition in the PTHrP-(1-34) mediated responses was significant ly reduced. Glibenclamide (1 x 10(-6) M) significantly suppressed the inhib itory responses of the lymphatic pump activity induced by PTHrP( 1-34) and S-nitroso-N-acetyl-penicillamine. The PTHrP-(1-34)- mediated inhibitory res ponses were significantly reduced by treatment with PTHrP-(7-34) (1 x 10(-7 ) M). These results suggest that PTHrP-(1-34) inhibits spontaneous pump act ivity of the isolated lymph vessels via PTH receptors and that production a nd release of endogenous nitric oxide and activation of ATP-sensitive K+ ch annels in the lymph vessels contribute to the PTHrP-(1-34)- mediated inhibi tory responses of the lymphatic pump activity.