THE HYPOTENSIVE ACTIONS OF OSTEOGENIC AND NONOSTEOGENIC PARATHYROID-HORMONE FRAGMENTS

Parathyroid hormone (PTH), hPTH-(1-84), and its hPTH-(1-34), hPTH-(1-3 1)NH2, and hPTH-(1-30)NH2 fragments reduced the tail artery pressure i n 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-(1-8 4) and hPTH-(1-34) stimulate both adenylyl cyclase and phospholipase-C in their target cells, but the hypotensive action must have been stim ulated specifically by adenylyl cyclase activation, because hPTH-(1-30 )NH2 and hPTH-(1-31)NH2, which can only stimulate adenylyl cyclase, we re potently hypotensive when injected intravenously whereas hPTH-(7-84 ), which can only stimulate phospholipase-C, was not significantly hyp otensive when injected intravenously. Since PTH's osteogenic action is also mediated by adenylyl cyclase stimulation, it was expected that t he hypotensive response might be used to screen new PTH constructs for possible osteogenicity. Indeed, deed, the osteogenic activities of su bcutaneously injected hPTH-(1-31)NH2, hPTH-(1-34), and hPTH-(1-84) cor related closely to their hypotensive activities, with hPTH-(1-34) bein g much more hypotensive and significantly more osteogenic than the oth er two molecules. hPTH-(1-31)NH2 and hPTH-(1-84) were equally osteogen ic and hypotensive. However, this correlation broke down with hPTH-(1- 30)NH2 which does not stimulate bone formation, but in the present stu dy it stimulated adenylyl cyclase and reduced tail artery pressure alm ost as much as hPTH-(1-31)NH2 and hPTH-(1-34). Nevertheless, the abili ty to significantly reduce arterial pressure is a common property of o steogenic PTH and PTH fragments and is thus a rapidly determinable pre liminary indicator of in vivo bioactivity of PTH fragments.