|Budget Amount *help
¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 2000 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1999 : ¥700,000 (Direct Cost : ¥700,000)
The purpose of this study is to elucidate the exact mechanism of the hemodynamic effects of parathyroid hormone (PTH) and to determine which region of PTH exerts positive chronotropy and coronary vasodilation using isolated perfused rat hearts.
1. Prazosin, propranolol, CVll974 (angiotensin II type 1 receptor blocker), TAK044 (endothelin-l receptor blocker) did not inhibit the chronotropic effect of PTH.
2. While verapamil or U73122 (phospholipase C inhibitor) did not inhibit the chronotropic effect of PTH, CsCl (If current inhibitor) or miconazole (adenylyl cyclase inhibitor) suppressed it significantly.
3. PTH increased cAMP level of the atrium but not the left ventricle.
4. PTH (1-84) and PTH (1-34) significantly increased heart rate, however, PTH (2-34), [Nle^<8,18>Tyr^<34>]PTH (3-34), PTH (4-34), [Tyr^<34>]PTH (7-34) and PTH (13-34) did not exert the positive chronotropic effect.
5. While PTH (l-84), PTH (l-34), PTH (2-34), [Nle^<8,18>Tyr^<34>]PTH (3-34) decreased coronary perfusion pressure, PTH (4-34), [Tyr^<34>]PTH (7-34) and PTH (13-34) did not have coronary perfuion pressure.
6. The protein kinase A inhibitor H89, but not the protein kinase C inhibitor H7, attenuated the hemodynamic effects of PTH (l-34) or PTH (2-34), while it prevented those of [Nle^<8,18>Tyr^<34>]PTH (3-34).
These results indicate that the chronotropic actions of PTH are mediated via selective activation of adenylyl cyclase to increase the I_f current and that the first amino acid of PTH is essential for its chronotropic property whereas the first 3 amino acids of PTH are involved in its coronary vasodilatory action. Furthermore, protein kinase A, but not protein kinase C, appears to be involved in the chronotropic and coronary vasodilatory actions of PTH.