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 x 10(-10) and 3 x 10(-10) M) of PTHrP-(1-34) dilated lymph vessels and reduced the frequency of pump activity, whereas high concentrations (1 x 10(-9) to 1 x 10(-8) M) of PTHrP-(1-34) caused dilation with cessation of the lymphatic 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-NAME-induced inhibition in the PTHrP-(1-34)-mediated responses was significantly reduced. Glibenclamide (1 x 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 x 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.
Mizuno
R
R
First Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.
Ono
N
N
Ohhashi
T
T
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008208:Lymphatic System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D026423:S-Nitroso-N-Acetylpenicillamine
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; C431128:parathyroid hormone-related protein (7-34); C054296:parathyroid hormone-related protein (1-34); D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D010396:Penicillamine; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin