Hino T, Nyby M D, Fittingoff M, Tuck M L, Brickman A S
Department of Endocrinology, Veterans Affairs Medical Center, Sepulveda, CA 91343.
Hypertension. 1994 Mar;23(3):402-8. doi: 10.1161/01.hyp.23.3.402.
Parathyroid hormone and parathyroid hormone-related protein lower blood pressure and relax contracted arteries. Parathyroid hormone also attenuates angiotensin II-induced vasoconstriction. To determine the cellular mechanism or mechanisms by which parathyroid hormone analogues antagonize pressor effects, we examined the effect of these peptides on angiotensin II-induced calcium mobilization in fura 2-AM-loaded cultured rat vascular smooth muscle cells. Either 100 nmol/L parathyroid hormone or parathyroid hormone-related protein significantly reduced the amount of calcium mobilized by 100 nmol/L angiotensin II. The attenuating effect of these peptides was mimicked by 10 mmol/L forskolin and 10 mmol/L isobutylmethylxanthine and was not dependent on the presence of extracellular calcium. This effect of the parathyroid hormone analogues was reduced when cells were pretreated with 100 mmol/L 2',5'-dideoxyadenosine, an adenylate cyclase inhibitor. Combined inhibition of cyclic nucleotide-dependent protein kinases eliminated the inhibitory effect of parathyroid hormone, whereas protein kinase C inhibition had no effect. Parathyroid hormone analogues decreased the amount of calcium released by inositol 1,4,5-trisphosphate in digitonin-permeabilized vascular smooth muscle cells. This effect was inhibited by treatment with 2',5'-dideoxyadenosine. These results suggest that these peptides attenuate inositol 1,4,5-trisphosphate-sensitive calcium mobilized by angiotensin II via an adenylate cyclase-dependent mechanism. This may be a mechanism by which acute administration of parathyroid hormone or parathyroid hormone-related peptide antagonizes vasoconstriction.
甲状旁腺激素和甲状旁腺激素相关蛋白可降低血压并舒张收缩的动脉。甲状旁腺激素还可减弱血管紧张素II诱导的血管收缩。为了确定甲状旁腺激素类似物拮抗升压作用的细胞机制，我们研究了这些肽对用fura 2-AM负载的培养大鼠血管平滑肌细胞中血管紧张素II诱导的钙动员的影响。100 nmol/L的甲状旁腺激素或甲状旁腺激素相关蛋白均可显著减少100 nmol/L血管紧张素II所动员的钙量。10 mmol/L的福斯可林和10 mmol/L的异丁基甲基黄嘌呤可模拟这些肽的减弱作用，且该作用不依赖于细胞外钙的存在。当细胞用100 mmol/L的2',5'-二脱氧腺苷（一种腺苷酸环化酶抑制剂）预处理时，甲状旁腺激素类似物的这种作用会减弱。联合抑制环核苷酸依赖性蛋白激酶可消除甲状旁腺激素的抑制作用，而抑制蛋白激酶C则没有效果。甲状旁腺激素类似物可减少洋地黄皂苷通透的血管平滑肌细胞中由肌醇1,4,5-三磷酸释放的钙量。用2',5'-二脱氧腺苷处理可抑制该作用。这些结果表明，这些肽通过一种腺苷酸环化酶依赖性机制减弱血管紧张素II所动员的对肌醇1,4,5-三磷酸敏感的钙。这可能是急性给予甲状旁腺激素或甲状旁腺激素相关肽拮抗血管收缩的一种机制。
