Michael J R, Yang J, Farrukh I S, Gurtner G H
Medical Service, Veterans Affairs Medical Center, Salt Lake City, Utah.
J Appl Physiol (1985). 1993 Mar;74(3):1310-9. doi: 10.1152/jappl.1993.74.3.1310.
We studied the effects of three chemically distinct protein kinase C activators on pulmonary vascular tone in the buffer-perfused isolated rabbit lung. The three activators, 12-deoxyphorbol 13-isobutyrate (12,13-phorbol), mezerein, and 1-oleoyl-2-acetyl-sn-glycerol, produce concentration-dependent increases in pulmonary arterial pressure, whereas the inactive compound 4 alpha-phorbol 12,13-dibutyrate does not affect pulmonary arterial pressure. Reducing calcium availability with verapamil, a calcium-free buffer, or a chelator of intracellular calcium significantly decreases the response to 12,13-phorbol or mezerein. Pretreatment with phloretin, an inhibitor of protein kinase C, has no affect on the vasoconstriction caused by infusion of a KCl bolus, but it does inhibit in a dose-dependent manner the response to 12,13-phorbol and mezerein. 12,13-Phorbol at a concentration of 2.5 microM, but not of 1 microM, stimulates prostacyclin and thromboxane synthesis by the isolated lung. Because inhibitors of thromboxane synthesis significantly decrease the response, thromboxane likely contributes to the vasoconstriction produced by higher concentrations of 12,13-phorbol and mezerein. Pretreatment with isoproterenol or nitroprusside reduces the increase in pulmonary arterial pressure caused by the protein kinase C activators but does not reverse vasoconstriction, even though subsequent treatment with verapamil does. In summary, activating protein kinase C in the isolated rabbit lung causes long-lasting pulmonary vasoconstriction, reducing calcium availability decreases the response, part of the increase in pulmonary arterial pressure appears secondary to thromboxane generation, and pretreatment with isoproterenol or nitroprusside prevents the vasoconstriction, but posttreatment with these vasodilators is ineffective.
我们研究了三种化学性质不同的蛋白激酶C激活剂对缓冲液灌注的离体兔肺肺血管张力的影响。这三种激活剂，即12 - 脱氧佛波醇13 - 异丁酸酯（12,13 - 佛波醇）、大戟二萜醇和1 - 油酰基 - 2 - 乙酰 - sn - 甘油，可使肺动脉压呈浓度依赖性升高，而无活性的化合物4α - 佛波醇12,13 - 二丁酸酯则不影响肺动脉压。用维拉帕米、无钙缓冲液或细胞内钙螯合剂降低钙的可用性，可显著降低对12,13 - 佛波醇或大戟二萜醇的反应。用蛋白激酶C抑制剂根皮素预处理，对氯化钾推注引起的血管收缩没有影响，但它确实以剂量依赖性方式抑制对12,13 - 佛波醇和大戟二萜醇的反应。浓度为2.5微摩尔而非1微摩尔的12,13 - 佛波醇可刺激离体肺合成前列环素和血栓素。由于血栓素合成抑制剂可显著降低反应，血栓素可能参与了较高浓度的12,13 - 佛波醇和大戟二萜醇引起的血管收缩。用异丙肾上腺素或硝普钠预处理可降低蛋白激酶C激活剂引起的肺动脉压升高，但即使随后用维拉帕米治疗也不能逆转血管收缩。总之，在离体兔肺中激活蛋白激酶C会导致持久的肺血管收缩，降低钙的可用性会降低反应，肺动脉压升高的部分原因似乎是血栓素生成，用异丙肾上腺素或硝普钠预处理可防止血管收缩，但用这些血管扩张剂进行后期治疗无效。
