The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System

Kappers, Mariëtte H.W.; Smedts, Frank; Horn, Thomas F.W.; Esch, Joep H.M. van; Sleijfer, Stefan; Leijten, Frank; Wesseling, Sebastiaan; Strevens, Helena; Danser, A.H. Jan; Meiracker, Anton H. van den

doi:10.1161/hypertensionaha.111.173559

Cited by 117 publications

(93 citation statements)

References 38 publications

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“…We and others have demonstrated in rats that coadministration of an ET-1 receptor antagonist with an RTKI can largely or completely prevent the rise in MABP, suggesting that activation of the ET pathway plays an important role in the sunitinib-induced MABP rise. 11,12 These observations in rats are fully supported by the present findings in swine, because the sunitinib-induced increase in SVRi and MABP completely reversed to presunitinib values in response to acute administration of the ET A /ET B receptor blocker tezosentan.…”

Section: Discussionsupporting

confidence: 82%

“…Indeed, sunitinib treatment for 8 days was accompanied by a decreased urinary nitrate excretion in adult rats and in patients receiving various inhibitors of the VEGF pathway, and the RTKI vandetanib decreases systemic plasma nitrate/nitrite levels in treated patients. 8,12,38 Results of clinical studies using FMD of the brachial artery as an index of NO bioavailability are conflicting. In one study, administration of the RTKI telatinib 9 was associated with a decrease in FMD from 6.0% to 3.9%, whereas in another study administration of the RTKI vandetanib had no effect on FMD (12.0% before and 13.8% after vandetanib).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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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...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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“…It has recently been shown that renal cGMP excretion is reduced in rats with sunitinib‐induced hypertension,25, 26 which may be a consequence of low renal NO bioavailability 11, 16, 24. In keeping with this finding, the phosphodiesterase inhibitor sildenafil failed to attenuate the arterial pressure rise in sunitinib‐treated rats 26.…”

Section: Introductionmentioning

confidence: 76%

“…Renal NO X excretion is less in sunitinib‐treated rats than in controls,11, 16 which is indicative of reduced NO formation and availability 29. Oral nitrate supplementation has been shown to lower arterial pressure in humans30 and in rats 21, 22.…”

Section: Discussionmentioning

confidence: 92%

“…Reduced renal NO availability may contribute to sunitinib‐induced hypertension by increasing RVR and renal sodium reabsorption. This notion is supported by reduced renal nitrite and nitrate (NO X ) excretion in rats with early sunitinib‐induced hypertension 11, 16. Furthermore, a recent study in patients showed reduced renal NOx excretion in response to the VEGF receptor antagonistic RTKI pazopanib 17.…”

Section: Introductionmentioning

confidence: 94%

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Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

Witte

Mühlbauer

Braun

et al. 2018

JAHA

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BackgroundThe tyrosine kinase inhibitor sunitinib causes hypertension associated with reduced nitric oxide (NO) availability, elevated renal vascular resistance, and decreased fractional sodium excretion. We tested whether (1) nitrate supplementation mitigates sunitinib‐induced hypertension and NO contributes less to renal vascular resistance as well as fractional sodium excretion regulation in sunitinib‐treated rats than in controls; and (2) renal soluble guanylate cyclase (sGC) is downregulated and sGC activation lowers arterial pressure in rats with sunitinib‐induced hypertension.Methods and ResultsArterial pressure responses to nitrate supplementation and the effects of systemic and intrarenal NO synthase (NOS) inhibition on renal hemodynamics and fractional sodium excretion were assessed in sunitinib‐treated rats and controls. Renal NOS and sGC mRNA as well as protein abundances were determined by quantitative polymerase chain reaction and Western blot. The effect of the sGC activator cinaciguat on arterial pressure was investigated in sunitinib‐treated rats. Nitrate supplementation did not mitigate sunitinib‐induced hypertension. Endothelium‐dependent reductions in renal vascular resistance were similar in control and sunitinib‐treated animals without and with systemic NOS inhibition. Selective intrarenal NOS inhibition lowered renal medullary blood flow in control but not in sunitinib‐treated rats without significant effects on fractional sodium excretion. Renal cortical sGC mRNA and sGC α1‐subunit protein abundance were less in sunitinib‐treated rats than in controls, and cinaciguat effectively lowered arterial pressure by 15‐20 mm Hg in sunitinib‐treated rats.ConclusionsRenal cortical sGC is downregulated in the presence of intact endothelium‐dependent renal vascular resistance regulation in developing sunitinib‐induced hypertension. This suggests that sGC downregulation occurs outside the renal vasculature, increases renal sodium retention, and contributes to nitrate resistance of sunitinib‐induced hypertension.

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SCAI expert consensus statement: Evaluation, management, and special considerations of cardio‐oncology patients in the cardiac catheterization laboratory (Endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologıa Intervencionista)

Iliescu

Grines

Herrmann

et al. 2015

Cathet Cardio Intervent

129

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In the United States alone, there are currently approximately 14.5 million cancer survivors, and this number is expected to increase to 20 million by 2020. Cancer therapies can cause significant injury to the vasculature, resulting in angina, acute coronary syndromes (ACS), stroke, critical limb ischemia, arrhythmias, and heart failure, independently from the direct myocardial or pericardial damage from the malignancy itself. Consequently, the need for invasive evaluation and management in the cardiac catheterization laboratory (CCL) for such patients has been increasing. In recognition of the need for a document on special considerations for cancer patients in the CCL, the Society for Cardiovascular Angiography and Interventions (SCAI) commissioned a consensus group to provide recommendations based on the published medical literature and on the expertise of operators with accumulated experience in the cardiac catheterization of cancer patients.

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The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System

Cited by 117 publications

References 38 publications

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

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

Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

SCAI expert consensus statement: Evaluation, management, and special considerations of cardio‐oncology patients in the cardiac catheterization laboratory (Endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologıa Intervencionista)

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