Pizurki L, Rizzoli R, Bonjour J P
Department of Medicine, University Hospital of Geneva, Switzerland.
Am J Physiol. 1990 Aug;259(2 Pt 2):F389-92. doi: 10.1152/ajprenal.1990.259.2.F389.
We studied the effect of (D-Trp12,Tyr34)bovine parathyroid hormone-(7-34)amide [(D-Trp12,Tyr34)bPTH(7-34)NH2], a recently described highly potent antagonist of parathyroid hormone (PTH), on the adenosine 3',5'-cyclic monophosphate (cAMP) and the sodium-dependent phosphate transport (NaPiT) responses to bPTH-(1-34) or PTH-related protein [PTHrP(1-34)] in renal epithelial cells. In this system, bPTH and PTHrP increased cAMP production and inhibited NaPiT in a similar manner. (D-Trp12,Tyr34)bPTH(7-34)NH2 did not influence either cAMP or NaPiT, but markedly attenuated the responses to PTH or PTHrP. The effect was concentration dependent, and a maximal inhibition of PTH or PTHrP effects was obtained with a 10(3)- to 10(4)-fold greater concentration of the antagonist. In contrast, the same concentration of the unsubstituted counterpart, (Tyr34)bPTH(7-34)NH2, which abolished the PTH- or PTHrP-induced stimulation of cAMP production, did not affect the inhibition of NaPiT caused by either peptide. Thus (D-Trp12,Tyr34)bPTH(7-34)NH2 inhibited the effects of PTH and PTHrP on both cAMP synthesis and Pi transport in renal cells. Because of the effects of this analogue on a transport function affected by these two peptides under physiological and pathophysiological conditions, it appears to be a promising antagonist.
我们研究了（D-色氨酸12，酪氨酸34）牛甲状旁腺激素-（7-34）酰胺[（D-色氨酸12，酪氨酸34）bPTH（7-34）NH2]，一种最近描述的甲状旁腺激素（PTH）的高效拮抗剂，对肾上皮细胞中腺苷3'，5'-环磷酸（cAMP）以及对bPTH-（1-34）或甲状旁腺激素相关蛋白[PTHrP（1-34）]的钠依赖性磷酸盐转运（NaPiT）反应的影响。在该系统中，bPTH和PTHrP以相似的方式增加cAMP生成并抑制NaPiT。（D-色氨酸12，酪氨酸34）bPTH（7-34）NH2既不影响cAMP也不影响NaPiT，但显著减弱对PTH或PTHrP的反应。该作用呈浓度依赖性，使用比拮抗剂浓度高10³至10⁴倍时可最大程度抑制PTH或PTHrP的作用。相比之下，相同浓度的未取代类似物（酪氨酸34）bPTH（7-34）NH2可消除PTH或PTHrP诱导的cAMP生成刺激，但不影响这两种肽引起的NaPiT抑制。因此，（D-色氨酸12，酪氨酸34）bPTH（7-34）NH2抑制了PTH和PTHrP对肾细胞中cAMP合成和磷酸盐转运的作用。由于该类似物对这两种肽在生理和病理生理条件下所影响的转运功能有作用，它似乎是一种有前景的拮抗剂。
