Cullen J P, Bell D, Kelso E J, McDermott B J
Department of Therapeutics and Pharmacology, Centre for Cardiovascular and Genetics Research, School of Medicine, The Queen's University of Belfast, Whitla Medical Building, 97 Lisburn Road, Northern Ireland, Belfast BT9 7BL, UK.
Eur J Pharmacol. 2001 Apr 13;417(3):157-68. doi: 10.1016/s0014-2999(01)00905-0.
Increased plasma levels of endothelin-1 correlate with the severity of left ventricular hypertrophy in vivo. The aim of the study was to determine the relative contribution of stimulation of endothelin ET(A) and endothelin ET(B) receptors, and the associated activation of protein kinase C, to the hypertrophic response initiated by endothelin-1 in adult rat ventricular cardiomyocytes maintained in culture (24 h). Endothelin-1 (10(-7) M) increased the total mass of protein and the incorporation of [14C] phenylalanine into protein to 26% and 25% greater (P<0.05) than respective basal values. The total content of RNA and the incorporation of 2-[14C] uridine into RNA were increased by 23% and 21%, respectively, by endothelin-1 (10(-8) M). Actinomycin D (5x10(-6) M), an inhibitor of transcription, abolished the incorporation of [14C] phenylalanine and the increased protein mass elicited by endothelin-1 (10(-8) M). The selective agonists at the endothelin ET(B) receptor, sarafotoxin 6c (10(-7) M) and endothelin-3 (10(-7) M), increased the incorporation of [14C] phenylalanine to 13% and 13% greater than respective basal values. The incorporation of [14C]phenylalanine in response to endothelin-1 (10(-7) M) was reduced by 50% (P<0.05) by the selective antagonist at endothelin ET(A) receptors, ABT-627 (10(-9) M), while the response to sarafotoxin 6c was not attenuated. The selective antagonist at endothelin ET(B) receptors, A192621 (10(-10) M), abolished the response to sarafotoxin 6c (10(-7) M) and attenuated the response to endothelin-1 (10(-7) M) by 43% (P<0.05). The selective inhibitor of protein kinase C, bisindolylmaleimide (5x10(-6) M) attenuated the response to sarafotoxin 6c (10(-7) M) by 78% and that to endothelin-1 (10(-7) M), elicited in the presence of A192621 (10(-10) M), by 52%. In conclusion, these data implicate endothelin ET(B) receptors, in addition to endothelin ET(A) receptors, in endothelin-1-mediated cardiomyocyte hypertrophy and provide evidence for the involvement of protein kinase C, at least in part, in the hypertrophic signalling pathways associated with activation of each receptor subpopulation.
体内血浆内皮素 -1 水平升高与左心室肥厚的严重程度相关。本研究的目的是确定内皮素 ET(A) 和内皮素 ET(B) 受体的刺激以及相关的蛋白激酶 C 激活对培养（24 小时）的成年大鼠心室心肌细胞中内皮素 -1 引发的肥厚反应的相对贡献。内皮素 -1（10⁻⁷ M）使蛋白质总量以及 [¹⁴C] 苯丙氨酸掺入蛋白质的量分别比各自的基础值增加了 26% 和 25%（P<0.05）。内皮素 -1（10⁻⁸ M）使 RNA 的总含量以及 2-[¹⁴C] 尿苷掺入 RNA 的量分别增加了 23% 和 21%。转录抑制剂放线菌素 D（5×10⁻⁶ M）消除了 [¹⁴C] 苯丙氨酸的掺入以及内皮素 -1（10⁻⁸ M）引起的蛋白质质量增加。内皮素 ET(B) 受体的选择性激动剂，毒胡萝卜素 6c（10⁻⁷ M）和内皮素 -3（10⁻⁷ M），使 [¹⁴C] 苯丙氨酸的掺入量分别比各自的基础值增加了 13%。内皮素 ET(A) 受体的选择性拮抗剂 ABT -627（10⁻⁹ M）使内皮素 -1（10⁻⁷ M）引起的 [¹⁴C] 苯丙氨酸掺入量降低了 50%（P<0.05），而对毒胡萝卜素 6c 的反应未减弱。内皮素 ET(B) 受体的选择性拮抗剂 A1926₂₁（10⁻¹⁰ M）消除了对毒胡萝卜素 6c（10⁻⁷ M）的反应，并使对内皮素 -1（10⁻⁷ M）的反应减弱了 43%（P<0.05）。蛋白激酶 C 的选择性抑制剂双吲哚马来酰胺（5×10⁻⁶ M）使对毒胡萝卜素 6c（10⁻⁷ M）的反应减弱了 78%，并使在 A1926₂₁（10⁻¹⁰ M）存在下对内皮素 -1（10⁻⁷ M）的反应减弱了 52%。总之，这些数据表明除了内皮素 ET(A) 受体外，内皮素 ET(B) 受体也参与内皮素 -1 介导的心肌细胞肥大，并为蛋白激酶 C 至少部分参与与每个受体亚群激活相关的肥厚信号通路提供了证据。
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