Conger J D, Kim G E, Robinette J B
Department of Medicine, University of Colorado Health Sciences Center, Denver.
Am J Physiol. 1994 Sep;267(3 Pt 2):F443-9. doi: 10.1152/ajprenal.1994.267.3.F443.
The renin-angiotensin system, endothelin (ET), and vasoconstrictor prostaglandins have been reported in separate studies to mediate the renal vasoconstrictor effect of cyclosporin A (CsA). However, direct comparison of the relative importance of these potential mediators has not been performed. In this study, the attenuating effects of comparable agonist-inhibiting doses of receptor antagonists for angiotensin II (ANG II), DuP-753 at 2.5 mg/kg, for ETA, BQ-123 at 0.5 mg/kg, and for thromboxane A2 (TxA2), SQ-29,548 at 1.6 mg.kg-1.h-1, or saline vehicle on acute CsA (20 mg/kg) renal vasoconstriction were compared in anesthetized Sprague-Dawley rats. All three receptor antagonists significantly limited the CsA-induced increase in renal vascular resistance; however, BQ-123 and SQ-29,548 were more effective than DuP-753. Because all three receptor antagonists demonstrated at least some attenuation of CsA-induced renal vasoconstriction, the potential role of acute CsA-related nitric oxide synthase (NOS) inhibition and nonspecific heterologous effects of specific receptor antagonists on other agonists were determined to exclude the possibilities that there was a general increased agonist sensitivity and that detection of a single or primary constrictor mediator was obscured by "crossover" receptor antagonist effects. CsA significantly reduced renal blood flow (39%) in the presence of the NOS inhibitor, N omega-nitro-L-arginine methyl ester, and there was negligible indication that receptor antagonists had nonspecific effects. It is concluded that CsA-induced renal vasoconstriction is complex and involves activation of multiple constrictor agonists independently or sequentially.
在多项独立研究中报告了肾素 - 血管紧张素系统、内皮素（ET）和血管收缩性前列腺素介导环孢素A（CsA）的肾血管收缩作用。然而，尚未对这些潜在介质的相对重要性进行直接比较。在本研究中，比较了血管紧张素II（ANG II）受体拮抗剂DuP - 753（2.5 mg/kg）、ETA受体拮抗剂BQ - 123（0.5 mg/kg）和血栓素A2（TxA2）受体拮抗剂SQ - 29,548（1.6 mg·kg⁻¹·h⁻¹）的等效激动剂抑制剂量或生理盐水载体对麻醉的Sprague - Dawley大鼠急性CsA（20 mg/kg）肾血管收缩的减弱作用。所有三种受体拮抗剂均显著限制了CsA诱导的肾血管阻力增加；然而，BQ - 123和SQ - 29,548比DuP - 753更有效。由于所有三种受体拮抗剂均显示出至少对CsA诱导的肾血管收缩有一定程度的减弱作用，因此确定了急性CsA相关一氧化氮合酶（NOS）抑制的潜在作用以及特定受体拮抗剂对其他激动剂的非特异性异源效应，以排除存在普遍增强的激动剂敏感性以及单一或主要收缩介质的检测被“交叉”受体拮抗剂效应掩盖的可能性。在NOS抑制剂Nω-硝基 - L - 精氨酸甲酯存在的情况下，CsA显著降低肾血流量（39%），并且几乎没有迹象表明受体拮抗剂有非特异性效应。得出的结论是，CsA诱导的肾血管收缩是复杂的，涉及多种收缩激动剂的独立或相继激活。
