Structural prerequisites for the hypotensive action of parathyroid hormone

We assessed the vascular, phosphaturic, and calcemic responses to several synthetic parathyroid hormone (PTH) analogues. Bovine (b) PTH (1-34), human (h) PTH (1-34), hPTH (53-84), [Nle⁸,Nle¹⁸,Tyr³⁴]bPTH (1-34), and [Nle⁸,Nle¹⁸,Tyr³⁴]bPTH (3-34) were administered in doses between 1 and 500 μg/kg as bolus intravenous injections to male Wistar-Kyoto rats aged 18-26 wk. Antagonism of the action of PTH was assessed in rats pretreated with 10 or 100 μg/kg [Nle⁸,Nle¹⁸,Tyr³⁴]bPTH (3-34) followed by 10 μg/kg of bPTH (1-34), or with 10 μg/kg hPTH (53-84) followed by 10 μg/kg hPTH (1-34). Bovine PTH (1-34), hPTH (1-34), and [Nle⁸,Nle¹⁸,Tyr³⁴]bPTH (1-34) produced virtually identical log dose-dependent hypotension, with 100 μg/kg of each analogue producing a 56% reduction in mean arterial pressure. Neither hPTH (53-84) nor [Nle⁸,Nle¹⁸,Tyr³⁴]bPTH (3-34) demonstrated any effect on mean arterial pressure at doses up to 500 μg/kg. Pretreatment with the inactive analogues failed to antagonize the vasodilating response to either bPTH (1-34) or hPTH (1-34). The vasoactive analogues significantly increased urinary phosphorus excretion while the inactive analogues did not modify it. hPTH (1-34) produced a modest decrease in serum Ca²⁺ at 1 min after injection. The results document that the vasodilating effect of PTH is a specific action of the peptide. Deletion of the first two amino acid residues abolishes both the phosphaturic and hypotensive effects of the peptide. Acute changes in serum Ca²⁺ do not appear to be a prerequisite for the vasodilatory response. Inactive analogues of PTH do not antagonize the vascular actions of the peptide.