The hypotensive actions of osteogenic and nonosteogenic parathyroid hormone fragments.
Parathyroid hormone (PTH), hPTH-(1-84), and its hPTH-(1-34), hPTH-(1-31)NH2, and hPTH-(1-30)NH2 fragments reduced the tail artery pressure in anesthetized female Sprague-Dawley rats by 42.4-67.1% within about 1 minute after injection into a femoral vein, but reduced the pressure by only 8.5-36.2% 2-19 minutes after subcutaneous injection. hPTH-(1-84) and hPTH-(1-34) stimulate both adenylyl cyclase and phospholipase-C in their target cells, but the hypotensive action must have been stimulated specifically by adenylyl cyclase activation, because hPTH-(1-30)NH2 and hPTH-(1-31)NH2, which can only stimulate adenylyl cyclase, were potently hypotensive when injected intravenously whereas hPTH-(7-84), which can only stimulate phospholipase-C, was not significantly hypotensive when injected intravenously. Since PTH's osteogenic action is also mediated by adenylyl cyclase stimulation, it was expected that the hypotensive response might be used to screen new PTH constructs for possible osteogenicity. Indeed, the osteogenic activities of subcutaneously injected hPTH-(1-31)NH2, hPTH-(1-34), and hPTH-(1-84) correlated closely to their hypotensive activities, with hPTH-(1-34) being much more hypotensive and significantly more osteogenic than the other two molecules. hPTH-(1-31)NH2 and hPTH-(1-84) were equally osteogenic and hypotensive. However, this correlation broke down with hPTH-(1-30)NH2 which does not stimulate bone formation, but in the present study it stimulated adenylyl cyclase and reduced tail artery pressure almost as much as hPTH-(1-31)NH2 and hPTH-(1-34). Nevertheless, the ability to significantly reduce arterial pressure is a common property of osteogenic PTH and PTH fragments and is thus a rapidly determinable preliminary indicator of in vivo bioactivity of PTH fragments.
Whitfield
J F
JF
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada.
Morley
P
P
Ross
V
V
Preston
E
E
Soska
M
M
Barbier
J R
JR
Isaacs
R J
RJ
Maclean
S
S
Ohannessian-Barry
L
L
Willick
G E
GE
D000262:Adenylyl Cyclases / Q000096:biosynthesis / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001846:Bone Development / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D006973:Hypertension / Q000188:drug therapy*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D010281:Parathyroid Hormone; D010446:Peptide Fragments; D000262:Adenylyl Cyclases