Fragment-specific actions of parathyroid hormone in isolated perfused rat hearts

Different regions within the parathyroid hormone (PTH) molecule are known t o have different biological activities. In the heart. the physiological act ions of the intact PTH molecule are known as positive chronotropy and coron ary vasodilatation. However, it is unclear which region of the PTH exerts w hich physiological action in the heart. Therefore, to clarify this point, w e examined the hemodynamic effect of intact PTH(1-84) and selected PTH anal ogs, namely, PTH(1-34), PTH(2-34), [Nle8, 18Tyr34]PTH(3-34), PTH(4-34), [Ty r34]PTH(7-34), and PTH(13-34) in isolated perfused rat hearts. Both PTH(1-8 4) and PTH(1-34) significantly increased heart rate and decreased coronary perfusion pressure. In contrast, neither PTH(2-34) nor [Nle8,18Tyr34]PTH(3- 34) increased heart rate, but they did decrease coronary perfusion pressure . Peptides further truncated at the amino terminus, PTH(4-34), [Tyr34]PTH(7 -34), and PTH(13-34), had no effect on hemodynamics. Furthermore, the prote in kinase A inhibitor H89, but not the protein kinase C inhibitor H7. atten uated the hemodynamic effects of PTH(1-34) or PTH(2-34), while it prevented those of [Nle8,18Tyr34]PTH(3-34). These results clearly demonstrate that t he first amino acid of PTH is essential for its chronotropic property where as the first 3 amino acids of PTH are involved in its coronary vasodilatory action. Furthermore, protein kinase A. but not protein kinase C. appears t o be involved in the chronotropic and coronary vasodilatory actions of PTH.