Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress

Abstract

Abstract-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 83Ϯ5 mm Hg at baseline to 97Ϯ6 mm Hg (PϽ0.05) because of a 57Ϯ20% 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 24Ϯ1 mm Hg under baseline conditions, whereas it increased MABP even further after sunitinib administration (32Ϯ3 mm Hg; PϽ0.05). Reactive oxygen species scavenging with a mixture of antioxidants lowered MABP by 13Ϯ2 mm Hg before but only by 5Ϯ2 mm Hg (PϽ0.05) 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. (Hypertension. 2012;59:151-157.) Key Words: endothelin 1 Ⅲ hypertension Ⅲ oxidative stress Ⅲ pulmonary hypertension Ⅲ vascular endothelial growth factor A ngiogenesis inhibition, by targeting the tyrosine kinases of the vascular endothelial growth factor (VEGF) receptors (VEGFRs), has become an established treatment of several tumor types. This therapy is associated with adverse effects, including the development of hypertension and cardiac and renal toxicity. 1 Hypertension has been reported in Յ60% of patients treated with sunitinib, an orally active multitarget receptor tyrosine kinase inhibitor (RTKI), targeting, among others, the VEGFR-1 and -2, which is used as first-line treatment of metastatic renal cell carcinoma or imatinib-resistant gastrointestinal stromal tumors. 1 In addition, impaired cardiac function, as reflected by a decrease in left ventricular ejection fraction of 10% to 15%, has been observed in Յ28% of patients treated with sunitinib. 2 Angina pectoris and increased levels of biomarkers reflecting ischemic myocardial damage may als...

Mechanisms of Hypertension and Renal Injury During Vascular Endothelial Growth Factor Signaling Inhibition

“…12 In a study performed in awake swine, the rise in BP induced by the NOS inhibitor N-nitro-l-arginine was increased after 1 week administration of sunitinib, causing a 12 mm Hg rise in mean arterial pressure, implying an increase rather than a decrease in NO availability. 38 Collectively, although not uniformly positive, the studies reviewed here support the view that VSP inhibition associates with a decrease in NO availability, contributing to the rise in BP.…”

“…35 Likewise, in swine, the rise in BP induced by sunitinib could not be lowered by a cocktail of antioxidants, whereas the same cocktail lowered BP in sunitinib-naive animals. 38 Collectively, these observations do not support the idea that increased oxidative stress contributes to the development of hypertension induced by VSP inhibitors.…”

“…Finally, in swine, we observed that the decrease in systemic and coronary vascular resistance in response to treadmill exercise was identical before and after sunitinib administration. 38 Enhanced oxidative stress may be another mechanism contributing to the development of hypertension in response to VSP inhibition. 51 Activation of the endothelin system during VSP inhibition may also result in oxidative stress through activation of the ET A receptor/NADPH oxidase pathway.…”

Role of Endogenous Vascular Endothelial Growth Factor in Endothelium-Dependent Vasodilation in Humans

“…A recent study in swine showed an increase in blood pressure within a few hours after administration of sunitinib, a tyrosine kinase inhibitor targeting the VEGF pathway. 16 The fast onset of changes in blood pressure makes rarefaction a less likely cause of VEGF targeting tyrosine kinase inhibitor-induced hypertension and suggests that rarefaction is a consequence rather than a cause of hypertension in this group of patients.…”

Endothelin Receptor Antagonists (ERA) in Hypertension and Chronic Kidney Disease: a Rose with Many Thorns

“…A reduction in NO bioavailability has been proposed as the mediating mechanism, however recent data in animals [74] and humans [75] suggests that angiogenesis inhibition results in substantial increases of ET-1 levels. Even more, a recent study reveals that hypertension is mediated by endothelin and not oxidative stress or NO [76]. Furthermore, ERAs prevented the development of hypertension during angiogenesis inhibition in rats [74,77].…”