Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Hypertension. 2012 Jan;59(1):151-7. doi: 10.1161/HYPERTENSIONAHA.111.182220. Epub 2011 Nov 28.
Angiogenesis inhibition with agents targeting tyrosine kinases of vascular endothelial growth factor receptors is an established anticancer treatment, but is, unfortunately, frequently accompanied by systemic hypertension and cardiac toxicity. Whether vascular endothelial growth factor receptor antagonism also has adverse effects on the pulmonary and coronary circulations is presently unknown. In chronically instrumented awake swine, the effects of the vascular endothelial growth factor receptor antagonist sunitinib on the systemic, pulmonary, and coronary circulation were studied. One week after sunitinib (50 mg PO daily), mean aortic blood pressure (MABP) had increased from 83±5 mm Hg at baseline to 97±6 mm Hg (P<0.05) because of a 57±20% increase in systemic vascular resistance as cardiac output decreased. In contrast, sunitinib had no discernible effects on pulmonary and coronary hemodynamics or cardiac function. We subsequently investigated the mechanisms underlying the sunitinib-induced systemic hypertension. Intravenous administration of NO synthase inhibitor N(G)-nitro-l-arginine increased MABP by 24±1 mm Hg under baseline conditions, whereas it increased MABP even further after sunitinib administration (32±3 mm Hg; P<0.05). Reactive oxygen species scavenging with a mixture of antioxidants lowered MABP by 13±2 mm Hg before but only by 5±2 mm Hg (P<0.05) after sunitinib administration. However, intravenous administration of the dual endothelin A/endothelin B receptor blocker tezosentan, which did not lower MABP at baseline, completely reversed MABP to presunitinib values. These findings indicate that sunitinib produces vasoconstriction selectively in the systemic vascular bed, without affecting pulmonary or coronary circulations. The sunitinib-mediated systemic hypertension is principally attributed to an increased vasoconstrictor influence of endothelin, with no apparent contributions of a loss of NO bioavailability or increased oxidative stress.
血管内皮生长因子受体酪氨酸激酶抑制剂的血管生成抑制作用是一种已确立的抗癌治疗方法，但不幸的是，它经常伴有全身高血压和心脏毒性。血管内皮生长因子受体拮抗作用是否也对肺循环和冠状动脉循环有不良影响目前尚不清楚。在慢性仪器化清醒猪中，研究了血管内皮生长因子受体拮抗剂舒尼替尼对全身、肺和冠状动脉循环的影响。在舒尼替尼（每天 50mg PO）治疗 1 周后，由于全身血管阻力增加 57%±20%，心输出量降低，平均主动脉血压（MABP）从基线时的 83±5mmHg 增加到 97±6mmHg（P<0.05）。相比之下，舒尼替尼对肺和冠状动脉血流动力学或心脏功能没有明显影响。我们随后研究了舒尼替尼引起的全身高血压的机制。在基线条件下，静脉给予一氧化氮合酶抑制剂 N(G)-硝基-L-精氨酸可使 MABP 增加 24±1mmHg，而在给予舒尼替尼后，MABP 进一步增加（32±3mmHg；P<0.05）。在给予舒尼替尼之前，用抗氧化剂混合物清除活性氧可使 MABP 降低 13±2mmHg，但仅降低 5±2mmHg（P<0.05）。然而，静脉给予双重内皮素 A/内皮素 B 受体阻滞剂特索恩坦，在基线时不会降低 MABP，可完全将 MABP 逆转至舒尼替尼给药前的值。这些发现表明，舒尼替尼选择性地引起全身血管床血管收缩，而不影响肺或冠状动脉循环。舒尼替尼介导的全身高血压主要归因于内皮素的血管收缩作用增加，而一氧化氮生物利用度丧失或氧化应激增加的作用不明显。
