Badahman A H, Wilson T W
Cardiovascular Risk Factor Reduction Unit, University of Saskatchewan, Saskatoon, Canada.
Can J Physiol Pharmacol. 1994 Jun;72(6):632-6. doi: 10.1139/y94-089.
Angiotensin II (AII) stimulates arachidonate release from renal endothelial and other cells. Arachidonate is then metabolized by cyclooxygenase to prostaglandin (PG) H2, then PGI2 and thromboxane A2 (TXA2). PGH2 and TXA2 activate the same receptor and should augment AII-mediated vasoconstriction, whereas PGI2 is a vasodilator. We had previously shown that inhibiting TXA2 synthesis with furegrelate (FRG) redirects PGH2 metabolism toward PGI2, causing renal vasodilation. Because TXA2 synthesis inhibition may be incomplete and unmetabolized PGH2 may cause vasoconstriction, we reasoned that adding a PGH2/TXA2 receptor antagonist (BMS 180,290, formerly SQ 29548 (SQ)) to furegrelate should cause further renal vasodilation in the presence of AII. Eight groups of 10 Sprague-Dawley rats received 120-min intravenous infusions of vehicle, FRG (2 mg.kg-1 plus 2 mg.kg-1.h-1), SQ (2 mg.kg-1 plus 2 mg.kg-1.h-1), FRG plus SQ, AII (10 ng.kg-1.min-1), AII plus FRG, AII plus SQ, or AII plus FRG plus SQ. Mean arterial pressure (MAP), p-[14C]aminohippurate clearance (CPAH), and [3H]insulin clearance were averaged for each rat for the final 90 min in three clearance periods. MAP did not change with any treatment. Estimating renal vascular resistance as MAP/CPAH confirmed a renal vasoconstrictor effect of this dose of AII: 58.1 +/- 6.3 vs. 47.3 +/- 6.8 (arbitrary units) with the vehicle (p < 0.05). FRG, SQ, or their combination did not affect renal vascular resistance, but adding FRG or SQ to AII prevented AII-mediated renal vasoconstriction. Adding both to AII caused net renal vasodilation to 24.8 +/- 2.6 (p < 0.05 vs. vehicle). Inulin clearance changed in the same direction in all groups, but the changes were less marked. We conclude that stimulation of renal arachidonate release by AII combined with TXA2 synthesis inhibition and receptor antagonism results in vasodilation. This renal effect could be due to increased and unopposed renal vasodilator PG (principally PGI2) action.
血管紧张素II（AII）刺激肾内皮细胞和其他细胞释放花生四烯酸。花生四烯酸随后被环氧合酶代谢为前列腺素（PG）H2，然后是前列环素I2（PGI2）和血栓素A2（TXA2）。PGH2和TXA2激活相同的受体，应该会增强AII介导的血管收缩，而PGI2是一种血管扩张剂。我们之前已经表明，用呋咱甲氢龙（FRG）抑制TXA2合成会使PGH2代谢转向PGI2，从而引起肾血管舒张。由于TXA2合成抑制可能不完全，未代谢的PGH2可能会导致血管收缩，我们推断在存在AII的情况下，向呋咱甲氢龙中添加PGH2/TXA2受体拮抗剂（BMS 180,290，原SQ 29548（SQ））应该会导致进一步的肾血管舒张。八组，每组10只Sprague-Dawley大鼠接受120分钟的静脉输注，输注的药物分别为溶媒、FRG（2mg·kg-1加2mg·kg-1·h-1）、SQ（2mg·kg-1加2mg·kg-1·h-1）、FRG加SQ、AII（10ng·kg-1·min-1）、AII加FRG、AII加SQ或AII加FRG加SQ。在三个清除期的最后90分钟内，对每只大鼠的平均动脉压（MAP）、对-[14C]氨基马尿酸清除率（CPAH）和[3H]胰岛素清除率进行平均。任何治疗均未使MAP发生变化。将肾血管阻力估计为MAP/CPAH，证实了该剂量的AII具有肾血管收缩作用：溶媒组为58.1±6.3，而用药后为47.3±6.8（任意单位）（p<0.05）。FRG、SQ或它们的组合均未影响肾血管阻力，但在AII中添加FRG或SQ可防止AII介导的肾血管收缩。在AII中同时添加两者会导致肾净血管舒张至24.8±2.6（与溶媒组相比，p<0.05）。所有组的菊粉清除率变化方向相同，但变化不太明显。我们得出结论，AII刺激肾花生四烯酸释放，再加上TXA2合成抑制和受体拮抗作用，会导致血管舒张。这种肾脏效应可能是由于肾血管舒张性PG（主要是PGI2）作用增强且未受到拮抗。
